| Onchocerciasis
and their treatments./ Oncocercosis y sus tratamientos. Data-Medicos
Dermagic/Express No. 74
21 Septiembre 1.999. 21 September 1.999.
~ Oncocercosis y sus Tratamientos ~
~ Onchocerciasis and their treatments~
EDITORIAL ESPANOL
=================
Hola amigos de la red que reciben DERMAGIC,,,, les envio una EXTRA edicion, con el tema ONCOCERCOSIS,,, La Dra Siviero de Argentina pide ayuda para un caso de ONCOCERCOSIS en cuero cabelludo y espalda,,, les envio estas 38 refrencias bibliograficas y la monografia de los productos SURAMIN y DIETHYLCARBAMAZINE,,,
y Maņana..... ZOSTER Y DOLOR
Saludos a todos !!!
Dr. Jose Lapenta R.,,,
EDITORIAL ENGLISH
=================
Hello friends of the net that DERMAGIC receives, I am sending a EXTRA edition, with the topic ONCOCERCOSIS, The Dra Siviero of Argentina requests help for a case of ONCOCERCOSIS in the scalp and back, I send these 38 bibliographical refrences and the monograph of the products SURAMIN and DIETHYLCARBAMAZINE.,,,
And Tomorrow..... ZOSTER AND PAIN
Greetings to ALL, !!
Dr. Jose Lapenta R.,,,
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REFERENCIAS BIBLIOGRAFICAS / BIBLIOGRAPHICAL REFERENCES
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1.) The entry of ivermectin and suramin into Onchocerca ochengi nodules.
2.) Acute renal failure in a patient receiving treatment with suramin.
3.) Human dirofilariasis.
4.) Activity of albendazole-ivermectin combination and other filaricidal drugs against
infective larvae, preadult, microfilariae and adult worms of Molinema dessetae in the
rodent Proechimys oris.
5.) Clinical pharmacokinetics of suramin in patients with onchocerciasis.
6.) Evaluation of suramin, ivermectin and CGP 20376 in a new macrofilaricidal drug screen, Onchocerca ochengi in African cattle.
7.) The chemotherapy of onchocerciasis XVIII. Aspects of treatment with suramin.
8.) Evaluation of ultrasonography for the detection of drug-induced changes in onchocercal nodules.
9.) Suramin and the time it takes to kill Onchocerca volvulus.
10.) The effects of ivermectin used in combination with other known antiparasitic drugs on adult Onchocerca gutturosa and O. volvulus in vitro.
11.) In vitro assessment of the activity of anthelmintic compounds on adults of Onchocerca volvulus.
12.) Chemotherapy of Onchocerca lienalis microfilariae in mice: a model for the evaluation of novel compounds for the treatment of onchocerciasis.
13.) Clinical pharmacokinetics of anthelmintic drugs.
14.) Dipetalonema viteae and Brugia pahangi transplant infections in gerbils for use in antifilarial screening.
15.) Drug activity against Onchocerca gutturosa males in vitro: a model for chemotherapeutic research on onchocerciasis.
16.) Suramin in the treatment of onchocerciasis: the efficacy of low doses on the parasite in an area with vector control.
17.) Study on the activity of antiparasitic agents against Onchocerca lienalis third stage larvae in vitro.
18.) Inhibition of NADP-linked malic enzyme from Onchocerca volvulus and Dirofilaria immitis by suramin.
19.) Suramin in the treatment of onchocerciasis: the efficacy of low doses on the parasite in an area with vector control.
20.) Analysis of enzymatically isolated adults of Onchocerca volvulus after treatment of patients with suramin or metrifonate.
21.) Onchocerca volvulus: effect of suramin on lactate dehydrogenase and malate dehydrogenase.
22.) An evaluation of the bovine -- Onchocerca gibsoni, Onchocerca gutturosa model as a tertiary screen for drugs against Onchocerca volvulus in man.
23.) Evaluation of microfilaricidal effects in the cornea from topically applied drugs in ocular onchocerciasis: Trials with levamisole and mebendazole.
24.) Effects of various concentrations of diethylcarbamazine citrate applied as eye drops in ocular onchocerciasis, and the possibilities of improved therapy from continuous non-pulsed delivery.
25.) The populatin dynamics of Onchocerca volvulus microfilariae during treatment with suramin and diethylcarbamazine.
26.) Microfilariae in the cerebrospinal fluid, and neurological complications, during treatment of onchocerciasis with diethylcarbamazine.
27.) Eotaxin Expression in Onchocerca volvulus-Induced Dermatitis after Topical Application of Diethylcarbamazine.
28.) [Apropos of 5 new cases of onchocerciasis edema].
29.) Suramin and the time it takes to kill Onchocerca volvulus.
30.) Migration and death of skin-dwelling Onchocerca volvulus microfilariae after treatment with ivermectin.
31.) Amocarzine investigated as oral onchocercacidal drug in 272 adult male patients from Guatemala. Results from three dose regimens spread over three days.
32.) The effect of antimalarial chloroquine therapy and prophylaxis on concurrent infection with Onchocerca volvulus in Ecuador.
33.) The reduction in microfilariae loads in the skin and eye after nodulectomy in Ecuadorian onchocerciasis.
34.) Onchocerciasis in southwestern Sudan: parasitological and clinical characteristics.
35.) Onchocerciasis in Ecuador. II. Epidemiology of the endemic foci in the province of Esmeraldas.
36.) [Studies on the Filariidae of Cervidae in southern Germany. 2. Filariidae of the red deer].
37.) Biopsy of Onchocerca nodules in the Igbos of Nigeria.
38.) SURAMINa, the product
39.) DIETHYLCARBAMAZINE The product
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1.) The entry of ivermectin and suramin into Onchocerca ochengi nodules.
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Cross HF; Bronsvoort BM; Wahl G; Renz A; Achu-Kwi D; Trees AJ
Liverpool School of Tropical Medicine, U.K. [email protected]
Ann Trop Med Parasitol (ENGLAND) Jun 1997 91 (4) p393-401 ISSN: 0003-4983
Language: ENGLISH
Document Type: JOURNAL ARTICLE
Journal Announcement: 9711
Subfile: INDEX MEDICUS
No currently available drug, which is safe for mass treatment, effectively kills
adults of Onchocerca volvulus, the causal agent of onchocerciasis in humans, or of O.
ochengi, a cattle parasite used as a model of O. volvulus. Since adults of both of
these filarial nematodes are found in well developed nodules, the lack of efficacy of
these drugs may be a result of their poor penetration into the nodules. To check if
this was the problem, the distributions of the microfilaricide, ivermectin, and the
partial macrofilaricide, suramin, in plasma, skin, nodule capsules and nodule
contents were determined in cattle naturally infected with O. ochengi in Cameroon.
The cattle were treated with either a single, subcutaneous injection of 500
micrograms ivermectin/kg, or with intravenous injections of [14C]-labelled suramin,
each of 10 mg/kg, given one a day for 6 days. Concentrations of ivermectin and
suramin in various tissues were then assayed by high-pressure liquid chromatography
and scintillation counting, respectively. On day 7 post-treatment (pt), suramin
concentrations were consistently highest in the nodule, contents and capsule wall
(11.0 and 8.9 nCi/g, respectively) and significantly less in skin and plasma (1.2 and
1.4 nCi/g, respectively; P < 0.05). The distribution of ivermectin on day 7 pt was
similar, with the highest concentrations in the capsule wall, nodule contents and
plasma (58.4 ng/g, 43 ng/g and 48.6 ng/ml, respectively; P > 0.05) and the
concentration in the skin (6.4 ng/g) significantly lower than those in the capsule or
plasma (P < 0.05). High intra-nodular concentrations of both drugs were maintained
for 5-7 days at least and those of ivermectin would be expected to kill nematodes
other than filariae. It is apparent that failure of ivermectin and suramin to kill
adult Onchocerca spp. is not because the drugs penetrate nodules inadequately.
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2.) Acute renal failure in a patient receiving treatment with suramin.
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Smith A; Harbour D; Liebmann J
University of New Mexico Cancer Research and Treatment Center, Albuquerque 87131,
USA.
Am J Clin Oncol (UNITED STATES) Aug 1997 20 (4) p433-4 ISSN: 0277-3732
Language: ENGLISH
Document Type: JOURNAL ARTICLE
Journal Announcement: 9711
Subfile: INDEX MEDICUS
Suramin has demonstrated modest activity against prostate cancer and is being
investigated in clinical trials. We describe a patient with metastatic prostate
cancer who developed nonoliguric renal failure during treatment with suramin. Other
potential causes of renal failure were not present in our patient and his renal
function gradually recovered with the cessation of suramin treatment. Acute renal
failure should be recognized as a potential complication of suramin treatment.
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3.) Human dirofilariasis.
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Jelinek T; Schulte-Hillen J; Loscher T
Department of Infectious Diseases and Tropical Medicine, University of Munich,
Germany.
Int J Dermatol (UNITED STATES) Dec 1996 35 (12) p872-5 ISSN: 0011-9059
Language: ENGLISH
Document Type: JOURNAL ARTICLE
Journal Announcement: 9706
Subfile: INDEX MEDICUS
BACKGROUND: Subcutaneous and pulmonary dirofilariasis in humans appears to be a
frequent disease in endemic areas, notably the Mediterranean region. Following
increased air travel in recent years, the incidence of human dirofilariasis has
increased in tourists as well. METHODS: The clinical and parasitologic aspects in a
series of six patients with cutaneous and pulmonary dirofilariasis, seen in a German
unit for infectious and tropical diseases, are reviewed. RESULTS: Four patients
presented with subcutaneous tumors due to infection with Dirofilaria repens, whereas
two patients had pulmonary infiltrates due to the canine heartworm, D, immitis. All
infections were acquired in the Mediterranean region. Symptoms were only slight and
nonspecific. Eosinophilia in the blood was absent in all patients. The serum IgE
levels were normal and signs of a specific humoral response to antigens of
Dirofilaria spp. were absent, although slightly elevated antibody levels to antigens
of Onchocerca volvulus could be demonstrated in all patients. The diagnosis was
established in all patients by the surgical removal of adult worms from the lesions.
Oral treatment with diethylcarbamazine (DEC) (2 mg per kg t.i.d.) over a period of 4
weeks was added to the surgical treatment in all patients. In one patient this
therapy was preceded by oral ivermectine (150 mg per kg). CONCLUSIONS:
Dirofilariasis has to be considered as a differential diagnosis in patients
presenting with subcutaneous or pulmonary tumors after travels to endemic areas
within the last few years. Effective therapy is possible by surgical removal of the
adult worms and oral ivermectine plus diethylcarbamazine.
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4.) Activity of albendazole-ivermectin combination and other filaricidal drugs against
infective larvae, preadult, microfilariae and adult worms of Molinema dessetae in the
rodent Proechimys oris.
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Duarte Z; Gantier JC; Gayral P
Faculte de Pharmacie, Universite de Paris Sud, Chatenay Malabry, France.
Parasite (FRANCE) Mar 1994 1 (1) p57-64 ISSN: 1252-607X
Language: ENGLISH
Document Type: JOURNAL ARTICLE
Journal Announcement: 9710
Subfile: INDEX MEDICUS
The efficacy of albendazole-ivermectin combination was tested an adult and
developing stages of Molinema dessetae in the rodent Proechimys oris. Albendazole
and ivermectin, both given alone, suramin and diethylcarbamazine were used as
reference compounds. The drug combination (albendazole at 10 mg/kg/ day x 5 days and
Ivermectin at 0.04 mg/kg/day x 5 days) was effective against infective larvae and
preadult worms, and substantially reduced the number of live adult worms. The known
filaricidal agents, diethylcarbamazine (400 mg/kg twice daily x 5 days), ivermectin
(0.2 mg/kg/day x 5 days), and suramin (40 mg/kg/day x 5 days), as well as albendazole
(50 mg/kg/day x 5 days) were active on infective larvae, preadult worms,
microfilariae and adult worms. All drugs had the same level of efficacity on
infective larvae. Albendazole had the highest efficacy against adult and preadult
worms and diethylcarbamazine was the most active on microfilariae. Although the drug
combination was not as effective against preadult and adult worms as albendazole
alone, the results indicate that albendazole-ivermectin combination at a low dose had
prophylactic effect and suggest a possible macrofilaricidal activity.
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5.) Clinical pharmacokinetics of suramin in patients with onchocerciasis.
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Eur J Clin Pharmacol 1998 May;54(3):249-51
Chijioke CP, Umeh RE, Mbah AU, Nwonu P, Fleckenstein LL, Okonkwo PO
Department of Pharmacology and Therapeutics, University of Nigeria Teaching Hospital, Enugu, Enugu State.
OBJECTIVE: Ten male patients with onchocerciasis received six weekly infusions of suramin according to the WHO-recommended regimen. RESULTS: In no case did the plasma concentration of suramin exceed 300 mg x l(-1), and serious toxicity was not observed. The apparent volume of distribution (median 20.6 l) was comparable to that reported for patients with prostatic carcinoma. Elimination from patients with onchocerciasis was relatively slow (median plasma clearance 6.2 ml x h(-1), median terminal elimination half-life 91.8 days). CONCLUSION: Microfilariae were eliminated in eight out of ten patients. Spontaneous nodule regression was noted in four patients.
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6.) Evaluation of suramin, ivermectin and CGP 20376 in a new macrofilaricidal drug screen,
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Onchocerca ochengi in African cattle.
Trop Med Parasitol 1995 Mar;46(1):31-7
Renz A, Trees AJ, Achu-Kwi D, Edwards G, Wahl G
Institut fur Tropenmedizin, Universitat Tubingen, FRG.
To aid the development of a macrofilaricidal agent for Onchocerca volvulus, the African bovine parasite, O. ochengi, was evaluated as a drug screen by testing three known filaricidal drugs. Groups of five Zebu cattle, naturally infected with more than 15 palpable O. ochengi nodules in the ventral skin, were treated with either suramin (10 mg/kg/day i.v. for 6 days), ivermectin (200 micrograms/kg, s.c.), CGP 20376 (20 mg/kg orally) or left untreated as controls and examined at intervals up to 137 days post-treatment (d.p.t.). After ivermectin treatment, microfilarial densities in the skin decreased within one week to virtually zero and remained at a very low level. A similar rapid and profound reduction was seen after CGP 20376 treatment, but by 137 d.p.t. microfilarial skin densities were approaching pre-treatment levels. With suramin, skin microfilarial densities fell to very low levels after 12 weeks but rose slightly by 137 d.p.t. Effects on the macrofilariae were assessed by sequential nodulectomies at -3 and 28, 84 and 137 d.p.t. By 137 d.p.t. embryogenesis was almost completely interrupted in the CGP 20376 and ivermectin treated animals, although not in the suramin treated group, but in all three groups the majority of remaining intrauterine microfilariae were pathologically altered. Degenerating intrauterine microfilariae accumulated in the ivermectin and in the CGP 20376, but not in the suramin treated worms. The motility of male and female worms was not reduced by any treatment except for female worms at 84 d.p.t. with CGP 20376. Viability of the worms as indicated by the MTT-formazan reduction assay was not reduced in any of the treatment groups.
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7.) The chemotherapy of onchocerciasis XVIII. Aspects of treatment with suramin.
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Trop Med Parasitol 1995 Mar;46(1):19-26
Awadzi K, Hero M, Opoku NO, Addy ET, Buttner DW, Ginger CD
Onchocerciasis Chemotherapy Research Centre (OCRC), Hohoe, Ghana.
We report the clinical and parasitological effects of a modified treatment regimen for suramin. Twenty adult males received up to 5 g (72.5 to 84.7 mg/kg) of suramin over 36 days. Detailed clinical and laboratory examinations were done before treatment and then at intervals over 2 years. Nodules were removed at 6, 13, 26 and 52 weeks for histology. Systemic tolerance was good. Anterior segment inflammation was however common and 2 patients required intervention to prevent posterior synechiae. No new posterior segment lesions developed; a rare improvement occurred in one patient with papillitis. Proteinuria, mostly mild, occurred in nearly all patients. Previously unreported renal glycosuria was documented in one patient. Microfilariae in the skin and anterior chamber did not change significantly for 5 or more weeks after which rapid reductions occurred. Ocular parasites were absent at 2 years and skin microfilariae were near zero. Peripheral blood eosinophil counts fell in parallel with those of microfilariae in the skin and anterior chamber and were normal at one and two years. These findings at 2 years may provide indirect evidence of a macrofilaricidal or a permanent chemosterilant effect on the adult worms. Nodule examination revealed an embryotoxic effect from week 6, a lethal effect on the male worms from month 3 and on the female worms from month 6 after treatment started. At one year 34% of the female worms examined were alive. Thus total doses of suramin in the range 72.5 to 84.7 mg/kg have only a modest lethal effect on the female worms. Suramin remains a restricted drug and a suitable replacement is urgently needed.
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8.) Evaluation of ultrasonography for the detection of drug-induced changes in onchocercal nodules.
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Am J Trop Med Hyg 1994 Dec;51(6):800-8
Darge K, Troeger J, Engelke C, Leichsenring M, Nelle M, Awadzi K, Buettner DW
Department of Paediatric Radiology, Children's Hospital, Heidelberg University, Germany.
Clinical trials of macrofilaricidal drugs against Onchocerca volvulus are impeded due to the lack of means for assessing in vivo drug-induced changes in the onchocercomas. The application of ultrasonography in the sequential monitoring of morphologic alterations of onchocercal nodules after six weeks of suramin therapy was evaluated in 20 male patients from Ghana with a total of 64 nodule sites. After each follow-up session, a number of onchocercal nodules were extirpated so that by the end of one year, all nodules had been removed for histologic examination. The sonomorphologic changes observed and their time of appearance correlated well with the histologic findings of the onchocercomas. Eighty-three percent of the onchocercal nodules became hyperechogenic and 22% developed echo-free areas at the end of the follow-up period. Absence of the lateral acoustic shadow increased by more than 30% and the lack of differentiation of the worm center from the capsule and the nodule from its surrounding tissue increased by the end of one-year posttreatment to 100% and 91%, respectively. A mean reduction of nodule size of 27% was also documented. The histologic studies revealed that the proportion of the dead female worms increased from 17% at the end of the suramin therapy to 48% six months later and reached 61% at one year. It is concluded that ultrasonographic monitoring of onchocercomas can provide essential information on drug effects and facilitate clinical trials of macrofilaricidal drugs, limiting histologic evaluation to a few objectively selected onchocercomas.
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9.) Suramin and the time it takes to kill Onchocerca volvulus.
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Trop Med Parasitol 1991 Dec;42(4):346-50
Duke BO
Department of Infectious and Parasitic Disease Pathology, Armed Forces Institute of Pathology, Washington.
The paper records the numbers of 1-2 mm shotty papules developing in the author's skin after 2-day courses of diethylcarbamazine (DEC) repeated every 16 days before, during and after a 7.1 G suramin course for cutaneous onchocerciasis. Assuming, from biopsy evidence, that each papule represented a dead Onchocerca volvulus microfilaria (mf), the number of mfs reaching the skin every 16 days did not begin to fall until 96 days after the first full dose of suramin; and only reached zero by day 224. The histopathology of nodules excised from Cameroonian patients before, and at intervals of 56-335 days after, the start of a 7.1 G suramin course, revealed changes in the worms that correlated over time with the disappearance of mfs from the skin. Suramin sterilized and killed the male worms between days 77 and 105 and, in the females, it adversely affected the staining and subsequent development of small morulae from about day 56. It was estimated that new embryogenesis ceased about 56-77 days after the first full dose; development of the last viable embryos to mfs was complete by about 136 days; and the last mfs, perhaps having reduced vitality, emerged from the females by 160 days and reached the skin within 16-32 days.
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10.) The effects of ivermectin used in combination with other known antiparasitic drugs on adult Onchocerca gutturosa and O. volvulus in vitro.
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Trans R Soc Trop Med Hyg 1990 May-Jun;84(3):411-6
Townson S, Dobinson AR, Townsend J, Siemienska J, Zea-Flores G
CAB International Institute of Parasitology, St Albans, Hertfordshire, UK.
The effects of ivermectin at a concentration of 3.13 x 10(-6) M used in combination with other antiparasitic drugs on the viability of adult Onchocerca in vitro were assessed using MTT colorimetry and worm motility levels. When ivermectin was used against male O. gutturosa over a 7 d period in combination with suramin (5 x 10(-5) M), CGP 6140 (3.13 x 10(-6) M), CGP 20376 (1.95 x 10(-7) M), mefloquine (3.13 x 10(-6) M), levamisole (3.13 x 10(-6) M), mebendazole (5 x 10(-5) M), flubendazole (5 x 10(-5) M) and albendazole (5 x 10(-5) M), there was either no increased effect or only a marginally increased effect on motility levels when compared with the use of ivermectin alone. MTT colorimetry revealed that in most cases there was a cumulative effect of the 2 drugs used in combination but not a synergistic effect. In a trial extended to 26 d it was demonstrated that the combination of ivermectin and suramin did not produce a greater inhibition of motility than ivermectin alone. Using female O. volvulus, the activity of ivermectin, CGP 6140 and the 2 drugs combined was examined. The motility of all 3 groups exposed to drug(s) was suppressed by 24 h compared with controls. MTT colorimetry performed on day 7, using the pre-weighed anterior end of each worm, illustrated that ivermectin alone produced a 43.4% inhibition of formazan formation compared with controls, CGP 6140 alone produced 50.6% inhibition, while the drug combination produced a 72% inhibition, equivalent to the heat-killed control.
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11.) In vitro assessment of the activity of anthelmintic compounds on adults of Onchocerca volvulus.
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Acta Leiden 1990;59(1-2):285-96
Strote G, Wieland S, Darge K, Comley JC
Department of Helminthology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, FRG.
The viability of adult Onchocerca volvulus and the effect of 12 known anthelmintic compounds on the parasites have been evaluated in an in vitro culture system. Three different parameters, a colorimetric assay, using NADH-dependent reduction of a tetrazolium salt to dark blue formazan by living adult worms, motility indices of male worms and lactate excretion of female worms were used to determine worm viability. The experiments showed that over a short term period of six days the viability of the worms did not decline significantly. The use of males isolated by dissection of whole nodules for the evaluation of drug effects in vitro is preferable to collagenase isolated worms. Mel W, milbemycin a and d, ivermectin, levamisole, CGP 6140 and, to a lesser extent, suramin immobilized male worms or significantly reduced the motility indices at a concentration of 10 microM. The tetrazolium reduction by male worms was not affected by levamisole, whereas the other active compounds demonstrated significant inhibitory effects. Diethylcarbamazine, mebendazole, flubendazole, metrifonate and CGP 20376 had no significant effect on male viability. Comparable activity was seen with the intact female worms isolated by collagenase digestion. Mel W, the milbemycins and ivermectin significantly inhibited tetrazolium reduction, whereas suramin and the other compounds had only slight or no inhibitory effects on female O. volvulus. Although one still has to aim at an improvement of the culture conditions, the in vitro test system using adult O. volvulus provides a basis for further research on potential antifilarial compounds.
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12.) Chemotherapy of Onchocerca lienalis microfilariae in mice: a model for the evaluation of novel compounds for the treatment of onchocerciasis.
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J Helminthol 1988 Sep;62(3):181-94
Townson S, Dobinson A, Connelly C, Muller R
CAB International Institute of Parasitology, St. Albans, Herts., UK.
The model of Onchocerca lienalis microfilariae (mf) injected into inbred CBA/Ca mice was studied for its usefulness as an additional primary/secondary drug screen for onchocerciasis. Invermectin, DEC, suramin, flubendazole, mebendazole, levamisole, Mel W, furapyrimidone, metrifonate, amoscanate and the new Ciba-Geigy compounds CGP 6140, CGP 20'376 and CGI 17658 all significantly reduced levels of mf at a dose of 5 X 100 mg/kg or less. An early dosing protocol, on days 3-7 after infection, was found to be generally more effective than dosing on days 11-15, followed by necropsy on day 18. In some cases there were important differences in levels of drug activity depending on whether the drug was administered by the subcutaneous or oral route, indicating that new compounds should be tested via both routes. Ivermectin was by far the most active compound examined, virtually clearing mf from the skin at a dose of 5 X 0.0063 mg/kg and producing a significant mf reduction (63.5%) at 5 X 0.0008 mg/kg following subcutaneous administration. In comparison, DEC was much less active, producing a 32.4% mf reduction at 5 X 25 mg/kg ranging up to a maximum of 72% reduction at 5 X 100 mg/kg. CGI 17658 was the most active compound examined next to ivermectin, almost 100% effective against skin mf at a dose of 5 X 6.25 mg/kg via the oral route while being less effective via subcutaneous administration (65% reduction). The lowest effective dose examined was 5 X 3.13 mg/kg (per os) which reduced mf levels by 64%. CGP 20'376 was also very active, resulting in a 46% (subcutaneous) and 62% (per os) reduction at a dose of 5 X 6.25 mg/kg. This mouse model has clearly identified all the known microfilaricides examined and also, to a lesser extent, those compounds considered to be principally macrofilaricides. We believe it has value as an additional drug screen for onchocerciasis, which will enable the evaluation of novel compounds against skin-dwelling Onchocerca mf at the primary/secondary level, providing complementary information to new in vitro screens using adult Onchocerca.
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13.) Clinical pharmacokinetics of anthelmintic drugs.
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Clin Pharmacokinet 1988 Aug;15(2):67-93
Edwards G, Breckenridge AM
Department of Pharmacology and Therapeutics, University of Liverpool, England.
A rational strategy for chemotherapy demands that dosage schedules be based on an adequate knowledge of clinical and biochemical pharmacology. Many anthelmintic drugs (e.g. suramin, diethylcarbamazine, hycanthone) were introduced before modern techniques for drug evaluation (controlled clinical trials) and before the development of specific and sensitive analytical methods for the assay of drugs and metabolites in biological fluids. Thus, many of the regimens used today for the treatment of parasitic diseases are largely empirically derived. By means of specific analytical methodology (high performance liquid chromatography, gas chromatography and mass-spectrometry) introduced in the 1960s, it is now possible to measure drugs and their metabolites with specificity and sensitivity. Much of this review deals with compounds which are active against the major systemic helminths, i.e., filariae (diethylcarbamazine, ivermectin and suramin) and schistosomes (niridazole, metrifonate, oxamniquine and praziquantel), but recent advances in the treatment of hydatid disease involving the benzimidazole carbamates albendazole and mebendazole are also discussed. Among the imidazole derivatives, mebendazole, a broad-spectrum anthelmintic, is poorly absorbed from the gastrointestinal tract after a therapeutic dose, but that fraction which is absorbed and escapes hepatic first-pass extraction is pharmacologically active against systemic helminths. Albendazole is more completely absorbed, but is almost undetectable in plasma due to its rapid conversion to an active sulphoxide metabolite. This compound may well become the drug of choice for the chemotherapy of echinococcosis. Levamisole, the 1-isomer of tetramisole, is rapidly and completely absorbed, but has not been widely used in systemic helminthiases because of severe side effects associated with prolonged dosage. Diethylcarbamazine is microfilaricidal against Onchocerca volvulus, but its use has been associated with major adverse effects resulting from its action on the microfilariae. These effects are related to the concentration of the drug in the plasma which, in turn, is influenced by urinary pH. The elimination half-life of diethylcarbamazine is prolonged and renal clearance reduced in alkaline urine. Under these conditions the microfilaricidal effect is enhanced, but the adverse reactions to treatment are more severe. Suramin is the only available antifilarial agent with macrofilaricidal activity. It has a long elimination half-life (36 to 54 days), and is highly (99.7%) bound to plasma protein which limits its removal from the blood.
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14.) Dipetalonema viteae and Brugia pahangi transplant infections in gerbils for use in antifilarial screening.
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J Helminthol 1988 Mar;62(1):1-9
Court JP, Stables JN, Lees GM, Martin-Short MR, Rankin R
Department of Biochemical Microbiology, Wellcome Reserach Laboratories, Beckenham, Kent, England.
Transplanted infections of Dipetalonema viteae and Brugia pahangi have been evaluated as tools for experimental chemotherapy. Attempts were made to establish these filariae in similar pharmacokinetic sites within the same host, so that direct comparisons of in vivo drug susceptibilities could be made. Unfortunately, it was not possible to establish B. pahangi in the subcutaneous tissues, the preferred site of D. viteae. Therefore, intraperitoneal B. pahangi and subcutaneously implanted D. viteae in gerbils were used for the study. D. viteae infections were significantly enhanced by concomitant infections with B. pahangi, while B. pahangi infection rates were unaffected by the presence of D. viteae. Experiments with amoscanate, CGP6140 and Mel W demonstrated the importance of employing both B. pahangi and D. viteae for antifilarial discovery work and the fundamental effect of parasite location on drug efficacy. D. viteae rapidly migrate from the peritoneal cavity of gerbils following implantation; twenty one hours after infection 73% of transplanted worms were found in the subcutaneous tissues. It was shown that the migration response could be used as a stringent parameter for demonstrating antifilarial activity. D. viteae were exposed to antifilarial drugs for 24 hours in vitro, washed and implanted into the peritoneal cavity of gerbils. At autopsy, 5 days later, 10(-8)M ivermectin and milbemycin D had prevented migration; CGP6140, amoscanate, suramin, flubendazole and furapyrimidone were also detected at less than 10(-6)M using this parameter. In all cases the migration response was more sensitive to drugs than parasite kill. Ivermectin's ability to inhibit worm migration through the tissues is discussed, with respect to the role of itinerant males in the reproductive cycle of Onchocerca volvulus.
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15.) Drug activity against Onchocerca gutturosa males in vitro: a model for chemotherapeutic research on onchocerciasis.
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J Helminthol 1987 Dec;61(4):271-81
Townson S, Connelly C, Dobinson A, Muller R
CAB International Institute of Parasitology, St Albans, Herts, UK.
An in vitro system for chemotherapeutic research using adult male Onchocerca gutturosa has been developed as a model for O. volvulus. Using a culture system consisting of medium MEM + 10% heat inactivated foetal calf serum (IFCS) + LLCMK2 (monkey kidney) feeder cells in an atmosphere of 5% CO2 in air, we examined the effects of a range of antiparasitic drugs on worm motility. Ivermectin, levamisole, furapyrimidone, Mel W, chloroquine, metrifonate, flubendazole, amoscanate and the Ciba-Geigy compounds CGP 6140, CGP 20'376 and CGI 17658 either immobilized or significantly reduced motility levels at a concentration of 5 X 10(-5) M or less within a 7-day period. Worms were affected at very low concentrations by ivermectin (effective conc. to reduce motility levels to 50% of controls, 3.14 X 10(-8) M), levamisole (7.95 X 10(-8) M), CGP 6140 (8.87 X 10(-9) M) and CGP 20'376 (2.78 X 10(-8) M). Difficulties were experienced in accurately repeating the immotile endpoint for levamisole due to an inconsistent partial recovery of motility. Over a 7-day period diethylcarbamazine had little effect on motility levels, while suramin caused a slight increase in activity compared to controls at some timepoints. Subsequent experiments demonstrated some differences in drug efficacy depending on the presence or absence of serum and feeder cells in the culture system probably because of drug avidly binding to serum proteins. However, serum and cells were found to be essential ingredients of the culture system to maintain worms in good condition, indicating that new drugs should be evaluated both in the presence and absence of serum and cells. Comparisons were made between the responses of O. gutturosa and Brugia pahangi to certain drugs and these species were found to significantly differ in their sensitivities to ivermectin and a novel compound (Wellcome), indicating that Onchocerca parasites should be used wherever possible for compound identification and development intended for the treatment of onchocerciasis. The in vitro system described here, using male O. gutturosa, provides a basis for further research and a practical alternative to O. volvulus.
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16.) Suramin in the treatment of onchocerciasis: the efficacy of low doses on the parasite in an area with vector control.
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Trop Med Parasitol 1985 Dec;36(4):244-8
Schulz-Key H, Karam M, Prost A
In a village hyperendemic for onchocerciasis in Burkina Faso, where the vector had been controlled by the Onchocerciasis Control Programme since 1976, 65 patients were treated with doses of 37 to 71 mg/kg suramin in 1979. The viability and fertility of the adult parasites were studied in 217 nodules excised from 42 patients one month to four years after treatment using the collagenase technique. Most of the worms had survived the treatment. Male worms were more susceptible to suramin than female worms. The development of intrauterine stages initially continued, but was completely suppressed after several months. The female worms remained sterile in those patients who had received more than 60 mg/kg suramin. In other ones 11 and 13% of the female worms showed new embryonic stages in the uteri during two follow-up examinations in the second year. In a final examination in 1983 the reproduction had declined again. However, the reproductivity of the superannuated worms had considerably decreased in the untreated patients as well. All patients had shown a very high microfilardermia in 1979. After treatment the microfilarial densities dropped to levels near zero depending on the dose of suramin administered, but in none of the patients was the reduction complete during the first year of the treatment. Microfilariae gradually reappeared in the second year in several patients who had received less than 60 mg/kg suramin. In the final follow-up in 1983 most of the treated patients had become negative in skin counts, although they still harboured viable worms.
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17.) Study on the activity of antiparasitic agents against Onchocerca lienalis third stage larvae in vitro.
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Trop Med Parasitol 1985 Jun;36(2):117-9
Court JP, Bianco AE, Townson S, Ham PJ, Friedheim E
The in vitro drug response of third stage larvae of the cattle filarial worm Onchocerca lienalis has been studied. Larvae were maintained in Minimum Essential Eagles medium supplemented with 10% inactivated foetal calf serum and exposed to the following drugs: Mel W, caparsolate sodium, suramin, ivermectin, flubendazole, levamisole and amoscanate plus 3 novel melaminylthioarsenites. Antiparasitic activity of these compounds has been assessed on their killing effects and their ability to totally inhibit the moult from the third to the fourth stage. Unfortunately, moulting occurred at a low rate in the culture system used and was not suitable as a quantitative parameter for describing drug activity. However, the results indicated that if the rate of ecdysis could be increased by improving the culture conditions, moulting could be used in this manner since exsheathment has inhibited by certain compounds at concentrations where killing effects were less than 50%. Of the compounds evaluated ivermectin demonstrated good activity, totally preventing ecdysis at 0.001 microgram/ml. The drug assay system used in this study may offer a starting point for the eventual development of a meaningful and specific in vitro screen for new anti-Onchocerca agents.
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18.) Inhibition of NADP-linked malic enzyme from Onchocerca volvulus and Dirofilaria immitis by suramin.
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Mol Biochem Parasitol 1981 Nov;4(1-2):53-60
Walter RD, Albiez EJ
NADP-linked malic enzyme (malate dehydrogenase (oxaloacetate-decarboxylating) NADP+, EC 1.1.1.40) has been partially purified from adult Onchocerca volvulus and Dirofilaria immitis. Suramin was found to inhibit the activity of malic enzyme from both filarial worms. The inhibition constants for suramin were calculated to be 0.011 microM and 0.015 microM for the enzymes from O. volvulus and D. immitis, respectively. In the case of NADP-linked malic enzyme from Trypanosoma brucei and chicken liver the inhibition by suramin was less pronounced. The inhibition constants were found to be 0.8 microM and 2.5 microM for the protozoan and vertebrate enzymes, respectively. The type of inhibition was competitive with respect to malate. The Michaelis constants for malate and pyruvate were determined to be 0.9 and 4.5 mM for O. volvulus and 0.85 and 5.0 mM for D. immitis, respectively. The low Km values for malate compared to those for pyruvate and the about 15-fold greater turnover in the direction of decarboxylation compared to carboxylation indicated that malic enzyme from both filarial sources might be involved in an alternative pathway leading from phosphoenolpyruvate via oxaleacetate, malate and pyruvate to lactate. It is suggested, that the inhibition of malic enzyme activity from O. volvulus by suramin might interfere with the generation of NADPH for biosynthetic reactions.
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19.) Suramin in the treatment of onchocerciasis: the efficacy of low doses on the parasite in an area with vector control.
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Trop Med Parasitol 1985 Dec;36(4):244-8
Schulz-Key H, Karam M, Prost A
In a village hyperendemic for onchocerciasis in Burkina Faso, where the vector had been controlled by the Onchocerciasis Control Programme since 1976, 65 patients were treated with doses of 37 to 71 mg/kg suramin in 1979. The viability and fertility of the adult parasites were studied in 217 nodules excised from 42 patients one month to four years after treatment using the collagenase technique. Most of the worms had survived the treatment. Male worms were more susceptible to suramin than female worms. The development of intrauterine stages initially continued, but was completely suppressed after several months. The female worms remained sterile in those patients who had received more than 60 mg/kg suramin. In other ones 11 and 13% of the female worms showed new embryonic stages in the uteri during two follow-up examinations in the second year. In a final examination in 1983 the reproduction had declined again. However, the reproductivity of the superannuated worms had considerably decreased in the untreated patients as well. All patients had shown a very high microfilardermia in 1979. After treatment the microfilarial densities dropped to levels near zero depending on the dose of suramin administered, but in none of the patients was the reduction complete during the first year of the treatment. Microfilariae gradually reappeared in the second year in several patients who had received less than 60 mg/kg suramin. In the final follow-up in 1983 most of the treated patients had become negative in skin counts, although they still harboured viable worms.
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20.) Analysis of enzymatically isolated adults of Onchocerca volvulus after treatment of patients with suramin or metrifonate.
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Tropenmed Parasitol 1980 Jun;31(2):143-8
Wolf H, Schulz-Key H, Albiez EJ, Geister R, Buttner DW
The application of a new technique is described permitting a better recognition of activities of drugs on macrofilariae of Onchocerca volvulus. In two villages of a hyperendemic focus in Liberia onchocercomata were excised from untreated persons and from patients treated with conventional doses of suramin or metrifonate. The adult worms were enzymatically isolated with collagenase and microscopically examined for degenerative alterations including calcifications and for the presence of eggs and embryos in the female parasites. Six weeks after the last dose of suramin the degenerative alterations could not be distinguished qualitatively from those in untreated worms, but a statistically significant macrofilaricidal efficacy could be shown by quantitative analyses, although more than half of the parasites were still alive at this early date. Metrifonate did not show any macrofilaricidal effect.
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21.) Onchocerca volvulus: effect of suramin on lactate dehydrogenase and malate dehydrogenase.
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Tropenmed Parasitol 1980 Mar;31(1):55-8
Walter RD, Schulz-Key H
Lactate dehydrogenase and malate dehydrogenases were partially purified and characterized from adult O. volvulus. The molecular weight of lactate dehydrogenase was determined to be 130 000, those of malate dehydrogenase I and II to be 120 000 and 65 000, respectively. The activities of both malate dehydrogenases and of the lactate dehydrogenase were strongly inhibited by suramin. The inhibition constants were determined to be in the range of 2 microM to 5 microM. The type of inhibition was found to be competitive with respect to the coenzyme NADH and to be non-competitive to the substrates. It is suggested that the mode of action of suramin in the therapy of Onchocerciasis might depend on the blokkade of reoxidation of NADH produced within the glycolytic pathway.
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22.) An evaluation of the bovine -- Onchocerca gibsoni, Onchocerca gutturosa model as a tertiary screen for drugs against Onchocerca volvulus in man.
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Tropenmed Parasitol 1979 Dec;30(4):469-74
Coperman DB
In this trial suramin, diethylcarbamazine, trichlorphon, levamisole, mebendazole, melarsonyl potassiu, Hoechst 33258 and tinidazole were administered to cattle infected with O. gibsoni and O. gutturosa to determine the usefulness of this screen in predicting the effect of drugs in man against. O. volvulus except for melarsonyl potassium which was macrofilarticidal against O. gutturosa but not O. gibsoni when cattle were slaughtered 6 weeks after treatment. It was concluded that cattle infected with O. gibsoni are a satisfactory substitute for chimpanzees infected with O. volvulus, as a tertiary screen for drugs against O. volvulus, but that their use would be restricted to centres in O. gibsoni endemic areas where the necessary facilities and specialised knowledge required to use cattle as experimental animals exist.
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23.) Evaluation of microfilaricidal effects in the cornea from topically applied drugs in ocular onchocerciasis: Trials with levamisole and mebendazole.
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Br J Ophthalmol 1978 Jul;62(7):440-4
Jones BR, Anderson J, Fuglsang H
Increasing concentrations of levamisole and of mebendazole were applied to 1 eye in groups of 4 patients with ocular onchocerciasis in northern Cameroon. No effect resulted from up to 3.0% mebendazole suspensions, but 3.0% levamisole solutions rapidly caused entry of microfilariae, straightening out and subsequent opacification of previously curled-up living microfilariae, the rapid formation of typical limbal globular infiltrates, and the subsequent formation of fluffy opacities around the microfilariae. These changes are typical of all other drugs so far studied that have a microfilaricidal action on O. volvulus--diethlycarbamizine citrate (DEC), suramin, and metrifonate. The efficacy of 3.0% levamisole approximated to that of 0.03% DEC. This is in keeping with published observations on the filaricidal activity of these 2 compounds. It is suggested that this system of drug testing should be considered for systematic use in the search for more effective and safer drugs for onchocerciasis.
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24.) Effects of various concentrations of diethylcarbamazine citrate applied as eye drops in ocular onchocerciasis, and the possibilities of improved therapy from continuous non-pulsed delivery.
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B, J Ophthalmol 1978 Jul;62(7):428-39
Jones BR, Anderson J, Fuglsang H
Diethylcarbamazine was given as eye drops in varying concentrations in a half-log dilution series from 1.0 to 0.0001% to patients with ocular onchocerciasis. Migration of microfilariae into the cornea, followed by their straightening and disintegration, was observed with delivery rates as low as 0.1 microgram/hour. Dose-related adverse inflammatory reactions, including the development of globular limbal infiltrates with itching and redness, were seen with delivery rates as low as 0.6 microgram/hour, but substantial inflammatory reactions, including severe vasculitis, were seen only with delivery rates of or above 1.0 microgram/hour. This suggests that it should be possible to achieve beneficial clearing of the microfilarial load, without adverse reactions, by continuous non-pulsed delivery of the drug. Technology exists for such delivery, either directly into the eye or systemically by a transdermal system that could give 3 to 7 days' treatment from each application. The observations reported suggest that after preliminary clearing of the microfilarial load by carefully controlled delivery of DEC it may be possible to maintain therapy by less strictly controlled delivery in DEC-medicated salt, or to use treatment with suramin, without incurring substantial adverse reactions, such as a deterioration in vision in cases in which the optic nerve is already compromised. Continuous non-pulsed DEC delivery systems could have a place in the management of onchocercal sclerosing keratitis. The unique opportunities for using the ocular model to define the requirements for beneficial non-damaging therapy with DEC should be explored in further field trials.
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25.) The populatin dynamics of Onchocerca volvulus microfilariae during treatment with suramin and diethylcarbamazine.
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Tropenmed Parasitol 1976 Jun;27(2):133-44
Duke BO, Vincelette J, Moore PJ
During treatment with suramin the numbers of O. volvulus microfilariae in the blood, urine, sputum, and anterior chambers of the eye fell before those in the skin. When diethylcarbamazine (DEC) was given after suramin, increased numbers of microfilariae appeared in the blood, urine, cerebrospinal fluid (CSF) and sputum, but the increase in the blood was less marked, and of shorter duration, than in similar patients receiving DEC without previous suramin. Microfilariae are thought to enter the urine, sputum and CSF directly from the blood by penetrating the capillary walls in the glomeruli, pulmonary alveoli, and choroid plexuses. Those in the aqueous humour do not appear to come directly from the bloodstream. The total numbers of microfilariae in the skin of some heavily infected onchocerciasis patients are estimated, as are the total numbers moving into the blood-stream under the influence of DEC and the proportion which escape into the urine, sputum and CSF. It is concluded that the majority of the microfilariae which appear in the blood during DEC therapy must be destroyed in the body, probably in the liver.
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26.) Microfilariae in the cerebrospinal fluid, and neurological complications, during treatment of onchocerciasis with diethylcarbamazine.
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Tropenmed Parasitol 1976 Jun;27(2):123-32
Duke BO, Vincelette J, Moore PJ
Microfilariae of Onchocerca volvulus were found in the cerebrospinal fluid (CSF) of 5/8 heavily infected onchocerciasis patients. During treatment with diethylcarbamazine citrate 10/11 patients showed increased numbers of 0. volvulus microfilariae in the CSF. Patients with concentrations of 8-31 mf/ml CSF developed severe vertigo, and some other neurological manifestations, during treatment. A hypothesis is put forward to account for this clinical piciture, and its importance in relation to the treatment of onchocerciasis is discussed.
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27.) Eotaxin Expression in Onchocerca volvulus-Induced Dermatitis after Topical Application of Diethylcarbamazine.
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J Infect Dis 1999 Oct;180(4):1394-1397
Pearlman E, Toe L, Boatin BA, Gilles AA, Higgins AW, Unnasch TR
Division of Geographic Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA. [email protected]
In persons with onchocerciasis, topical application of the anthelminthic diethylcarbamazine (DEC) induces clinical and histologic responses similar to acute papular onchodermatitis, including recruitment of eosinophils to the skin. To determine whether the eosinophil chemokine eotaxin is likely to be associated with eosinophil recruitment in onchodermatitis, DEC was applied to a 5-cm2 area on the skin of infected persons, and biopsies were taken from lesions 24 h later. Histologic analysis showed elevated dermal and epidermal eosinophils compared with tissue from an adjacent (untreated) site. Reverse transcription-polymerase chain reaction showed that eotaxin gene expression in DEC-treated skin was elevated 2- to 17-fold compared with control tissue. Eotaxin immunoreactivity was noted in mononuclear cells and eosinophils in the perivascular region of the dermis and in lymphatic and vascular endothelial cells. Together, these observations are consistent with a role for eotaxin in recruitment of eosinophils to the dermis in early stage onchocercal skin disease.
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28.) [Apropos of 5 new cases of onchocerciasis edema].
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Bull Soc Pathol Exot 1997;90(5):335-8
Nozais JP, Caumes E, Datry A, Bricaire F, Danis M, Gentilini M
Departement des maladies infectieuses, parasitaires et tropicales et de sante publique, CHU Pitie-Salpetriere, Paris, France.
We report 5 cases of onchocerciasis presenting as limb's swelling collected in the tropical disease unit of a parisian hospital between 1982 and 1993. They are 5 men which have lived between 3 weeks and 4 years in forested areas of Cameroon in four cases and Cote d'Ivoire in one case. The incubation period varied from 5 months to 2 years. The limb oedema was always located to one arm. It was associated with a blood eosinophilia above 2000/mm3 in 4 of 5 patients. The skin detection of microfilaria of Onchocerca volvulus was positive in every case. The serodiagnostic tests were negative for indirect immunoflurescent assay and immunoelectrophoresis with exception of one patient. These patients were cured with ivermectine and/or diethylcarbamazine. In addition, 26 other cases described in the literature are discussed.
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29.) Suramin and the time it takes to kill Onchocerca volvulus.
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Trop Med Parasitol 1991 Dec;42(4):346-50
Duke BO
Department of Infectious and Parasitic Disease Pathology, Armed Forces Institute of Pathology, Washington.
The paper records the numbers of 1-2 mm shotty papules developing in the author's skin after 2-day courses of diethylcarbamazine (DEC) repeated every 16 days before, during and after a 7.1 G suramin course for cutaneous onchocerciasis. Assuming, from biopsy evidence, that each papule represented a dead Onchocerca volvulus microfilaria (mf), the number of mfs reaching the skin every 16 days did not begin to fall until 96 days after the first full dose of suramin; and only reached zero by day 224. The histopathology of nodules excised from Cameroonian patients before, and at intervals of 56-335 days after, the start of a 7.1 G suramin course, revealed changes in the worms that correlated over time with the disappearance of mfs from the skin. Suramin sterilized and killed the male worms between days 77 and 105 and, in the females, it adversely affected the staining and subsequent development of small morulae from about day 56. It was estimated that new embryogenesis ceased about 56-77 days after the first full dose; development of the last viable embryos to mfs was complete by about 136 days; and the last mfs, perhaps having reduced vitality, emerged from the females by 160 days and reached the skin within 16-32 days.
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30.) Migration and death of skin-dwelling Onchocerca volvulus microfilariae after treatment with ivermectin.
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Trop Med Parasitol 1991 Mar;42(1):25-30
Duke BO, Soula G, Zea-Flores G, Bratthauer GL, Doumbo O
Department of Infectious and Parasitic Diseases Pathology, Armed Forces Institute of Pathology, Washington, D.C.
The effects of a single dose of ivermectin (122-200 micrograms/kg) on Onchocerca volvulus microfilariae (mf) in skin and lymph nodes were studied histologically in a qualitative and quantitative manner over seven days after treatment. Ivermectin caused mf to move from the subepidermal layer into the deeper layers of the dermis, subcutaneous fat and connective tissue, and the regional lymph nodes. No mf were seen migrating upwards through the epidermis. Dead mf were not seen before 24 hr and the numbers found dead in the dermis were far fewer than the total numbers in the skin before treatment. Inflammatory cellular reaction around dead mf in the tissues was usually minimal. The results suggest that most of the mf which disappear from the skin may be destroyed in the lymph nodes and that the histological reaction excited by mf dying under ivermectin is less violent than that after diethylcarbamazine.
A study of onchocerciasis with severe skin and eye lesions in a hyperendemic zone in the forest of southwestern Cameroon: clinical, parasitologic, and entomologic findings.
Am J Trop Med Hyg 1993 Jan;48(1):14-9
Somo RM, Enyong PA, Fobi G, Dinga JS, Lafleur C, Agnamey P, Ngosso A, Ngolle EM
Medical Research Station, Kumba, Cameroon.
Prior to the initiation of an onchocerciasis control program based on the mass administration of ivermectin in the rain forest of southwestern Cameroon, a preliminary baseline study of the area was conducted. The results of this study showed that onchocerciasis was hyperendemic in the area. Skin symptoms and signs were observed including pruritus (67.4% of the population examined), onchocerca nodules (51.6%), skin depigmentation (18.5%), and hanging groins (5.7%). Except for pruritus, the prevalence of these symptoms increased with age. Of the eyes examined, 44.9% had microfilariae in the anterior chamber, 33.5% had choroidoretinitis, 28.0% had punctate keratitis, 8.3% had papillary abnormalities, and 3.6% had sclerosing keratitis. Vision in 10.5% of the eyes examined was classified as blind or very poor (visual acuity = 0-0.10), in 15.7% as poor (visual acuity = 0.11-0.39), and in 73.8% as good (visual acuity = 0.4-1.00). Unlike previous reports that have linked serious ocular damage mainly to savanna onchocerciasis, the present study showed that forest onchocerciasis also caused significant ocular pathology, including blindness. Parasitologically, positive skin snips were recorded for 92.7% of the persons examined, with both sexes being equally infected. The parasite load, expressed as the geometric mean number of microfilariae per skin snip, was 53.6, and was much higher in males than in females. The flv vector, Simulium squamosum, had a high infection rate of 7.5% infective females in Bakumba and 6.8% infective females in Ngbandi, the two fly-catching points. The transmission potential was 266 infective larvae per person per month in Bakumba and 189 in Ngbandi.
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31.) Amocarzine investigated as oral onchocercacidal drug in 272 adult male patients from Guatemala. Results from three dose regimens spread over three days.
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Trop Med Parasitol 1991 Sep;42(3):240-62
Zea-Flores G, Beltranena F, Poltera AA, Lopez M, Moran M, Zea-Flores CE, de Ramirez I, Lecaillon JB, Zak F, Palomo M
Department of Onchocerciasis, Ministry of Health, Guatemala City.
The clinical investigations with three types of a three days regimen of amocarzine permitted to adjust the fixed dosing to the body weight related dosing and subsequently the administration of amocarzine from fasting state to drug intake after food. The main objective to reach a dose with predictable and sustained absorption was achieved, and this in turn proved to be onchocercacidal and safe. A combined clinicopharmacokinetic study showed enhancement and consistency of amocarzine absorption after food. Quantitative assessment of the urinary excretion confirmed the presence of the N-oxide metabolite, which qualitatively was visible by a urine colorimetry. This assay proved useful for drug monitoring. Ultrasonography of onchocercal skin nodules detected changes within the nodules following amocarzine therapy. Histology after nodul-ectomy at four months post-therapy showed that 57% of the female worms were dead, 24% necrobiotic, and 19% alive; male worms were more necrobiotic. Skin microfilariae were reduced within one week to about 10% of the initial level and after one year they remained at about 20%. Skin punch biopsies on day 5 showed that most microfilariae were dead or moribund. Ocular reduction of microfilariae was also observed, although it was slower than in the skin. The visual acuity improved within the one year's observation time. Ocular and clinical tolerability was good, with one exception of neurological disturbance, which was fully reversible. Sequential testing of the liver function showed average values within the normal range. In conclusion, a repeat low dose regimen of amocarzine (3 mg/kg twice daily post-prandially for three consecutive days) was well absorbed with predictable plasma levels, macro- and microfilaricidal with good local and systemic tolerability in patients with moderate to heavy onchocerciasis. Amorcarzine is recommended for further clinical investigations, particularly in females and juveniles. Urine colorimetry and nodular ultrasonography are recommended for optional monitoring of amocarzine.
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32.) The effect of antimalarial chloroquine therapy and prophylaxis on concurrent infection with Onchocerca volvulus in Ecuador.
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Trans R Soc Trop Med Hyg 1991 Sep-Oct;85(5):634-8
Guderian RH, Anselmi M, Beck BJ, Mackenzie CD, Williams JF, Proano JR, Cooper PJ
Onchocerciasis Project, Community Development Vozandes, Hospital Vozandes, Quito,
Ecuador.
The effect of chloroquine phosphate on Onchocerca volvulus in vivo was studied in Ecuadorians undergoing treatment for malaria. All persons with a diagnosis of acute malaria and treated with 2500 mg of chloroquine over 3 d showed a 100% reduction of dermal O. volvulus microfilariae 7 d after treatment. However, 28 d after treatment the microfilarial densities returned to their pre-treatment levels and at 35 d they had increased to 121.6% of their pre-treatment values. Treatment did not appear to have any effect on the adult O. volvulus examined histologically in extirpated nodules. Patients treated for acute malaria and subsequently kept on a prophylactic regimen of 500 mg chloroquine weekly showed a reduction of 56.7% from pre-treatment microfilarial density after 27 weeks. Patients who underwent nodulectomy as well as treatment for acute malaria and were given 500 mg of chloroquine prophylactically for 27 weeks showed a reduction in dermal microfilarial density of 93.6%. Symptoms of onchocerciasis were reduced in the latter group of patients, with the elimination of all acute dermatological changes within 6 weeks. Ocular examination of these surgically and chemotherapeutically treated individuals revealed reductions of 94.9% of microfilariae in the anterior chamber, 95.9% of live microfilariae in the cornea, and 95.1% of dead microfilariae in the cornea. There was a reduction of 69.8% in corneal fluffy opacities. No alteration in the visual acuity or in visible lesions in the posterior segment was recorded. The results suggest that a complex interaction between chloroquine and O. volvulus takes place in vivo, which can be beneficial to the patient over a long period.
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33.) The reduction in microfilariae loads in the skin and eye after nodulectomy in Ecuadorian onchocerciasis.
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Trop Med Parasitol 1987 Dec;38(4):275-8
Guderian RH, Proano R, Beck B, Mackenzie CD
Health Care Division, Hospital Vozandes, H.C.J.B., Quito, Ecuador, South America.
This study is concerned with the relationship between palpable onchocercal nodules and Onchocerca volvulus microfilarial loads in the skin. The number of microfilariae in clinically normal skin decreases as the distance from the nodule increases. Surgical removal of nodules reduces the microfilarial loads in 40 of 46 patients studied over a period of five months, with an average reduction of 65.4% of the prenodulectomy microfilarial load at the iliac crest. Complete elimination of detectable parasites was seen in some patients. Five individuals had increased microfilarial loads, all of which had developed new palpable nodules. Also, nodulectomy had a significant effect on ocular tissue, reducing the levels of parasites in the cornea and anterior chamber in 10 of 15 patients observed with no new nodules developing during the observation period. Both dermal and ocular clinical manifestations of onchocerciasis were reduced in a proportion of the patients. These parasitological and clinical findings provide evidence that nodulectomy is a beneficial procedure to O. volvulus infected patients in Ecuador by reducing both microfilarial loads and the degree of pathology.
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34.) Onchocerciasis in southwestern Sudan: parasitological and clinical characteristics.
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Am J Trop Med Hyg 1987 Mar;36(2):371-82
Mackenzie CD, Williams JF, O'Day J, Ghalal I, Flockhart HA, Sisley BM
Parasitological and clinical observations were made on residents of Pongo Nuer, a village in the province of Bahr El Ghazal, southwestern Sudan. Of 202 skin biopsies, 189 (94%) were positive for microfilariae of Onchocerca volvulus. Nodules were most common around the pelvic girdle and rare on the limbs or head. Microfilarial intensities, ranging up to 1,094 mf/mg of skin, were highest at the iliac crest and shoulder; they increased rapidly in childhood but then appeared to reach a plateau maintained through adult life. Nodule presence and number, especially at multiple sites, was significantly related to skin microfilarial intensity. Dermal manifestations of O. volvulus infection were widespread and severe, ranging from acute maculopapular eruptions to chronic, diffuse, and degenerative changes, even in young adults. However, high skin microfilarial intensities were found in asymptomatic individuals; conversely, lowest intensities were in those with severest maculopapular lesions, suggesting that host response was a major determinant of disease outcome. Microfilariae were detected in the cornea or anterior chamber of the eyes of one third of those examined in all age groups, but lesions of the posterior segment, including optic neuritis, chorioretinitis, and pigmentary abnormalities, were considered responsible for visual deficits in the population sample. Some pathologic changes in the anterior segment attributable to microfilariae were more common in the young than in adults but there was no preponderance of sclerosing keratitis in adults, contrary to expectations in hyperexposed individuals in a Sudan savannah zone. The best correlate of the presence of microfilariae in the eye was the intensity of infection in shoulder skin snips. Little value could be derived from data on outer canthus samples, either in terms of severity of ocular infection or disease. Microfilaremia was common (76%) but in only one case was attributed to O. volvulus; the remainder were due to Mansonella perstans.
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35.) Onchocerciasis in Ecuador. II. Epidemiology of the endemic foci in the province of Esmeraldas.
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Tropenmed Parasitol 1983 Sep;34(3):149-54
Guderian RH, Swanson D, Carrillo R, Proano R, Molea J, Swanson WL
The epidemiology of infection was studied in all endemic foci of onchocerciasis in the province of Esmeraldas in Ecuador. The incidence of infection and the density of microfilariae in the skin, both greater in males than females, increased with age, reaching highest levels at 40-45 years in males and at 60 years and older in females. In the hyperendemic area males and females had the same rate of infection, but the microfilarial density in males exceeded that in females. In the hypoendemic areas males had a higher infection rate than females, but females registered a higher density of microfilariae in the skin. The incidence and location of the onchocercal nodules correlated closely with the density of microfilariae. Adults, aged 50-54 had the highest prevalence of onchocercal nodules, which occurred primarily in the thorax and pelvic regions. Children aged 0-14 years showed a low prevalence of nodules, the head region being the primary site. Of the two diagnostic methods used to detect the presence of microfilariae, most of the diagnoses (85.6%) were made by skin biopsies as compared to those made by the Mazzotti test (14.4%).
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36.) [Studies on the Filariidae of Cervidae in southern Germany. 2. Filariidae of the red deer].
===================================================================
Tropenmed Parasitol 1975 Sep;26(3):348-58
Schulz-Key H
In southern Germany many of the red deer are infected with 4 filariid species. The microfilariae of 3 subcutaneous and one intradermal filariae are described. Skin snips were taken according to a regular pattern from the hides of several killed deer. The emerging microfilariae were identified and counted, and the characteristic distribution of each species in the skin was plotted. The adult worms of O. tarsicola are located on the abductor tendons of the tibiotarsal or radiocarpal joints. Some microfilariae are found in the tissues near the adults, but they concentrate at a considerable distance away, in the skin which covers the outer parts of the ears and the nose. The adult worms of O. tubingensis are found in subcutaneous nodules on the caudal part of the back. The microfilariae are distributed on the ventral part of the body with maximum densities in the region of the sternum and with lower densities on the inner sides of the hindlegs. O. flexuosa is also found in nodules on the back and flanks of the deer, while the microfilariae are distributed on the posterior part of the body with maximum densities on the inner sides of the hindlegs. C. wenki lives intradermally on the dorsal part of the trunk. The microfilariae are found in the skin near the adults. The infection rates of 94 red deer investigated during 1907-1974 were high: O. tarsicola 82%, O. tubingensis 23%, O. flexuosa 96%, C. wenki 85%. The prepatent period of all species is no longer than 6 months.
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37.) Biopsy of Onchocerca nodules in the Igbos of Nigeria.
===================================================================
Am J Trop Med Hyg 1975 Jul;24(4):708-9
Onuigbo WI
The occurrence of Onchocerca nodules in the Igbos of Nigeria was studied in a biopsy series. There were 90 cases in approximately 5,000 biopsies received in 4.5 years at a central laboratory. The prevalence of infection in males was 1.5 times that of females. The two youngest patients were both aged 3 years; the oldest was approximately 70 years. Of the 79 single-site biopsies, 14 (17.7%) nodules occurred on the head and 65 (82.3%) were done elsewhere. The nodules above the waist line totalled 42 (53.2%) and those below it 37 (46.8%). The favorite location was the forehead cephalically and the hip caudally. Eyelid and breast nodules were also noteworthy.
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38.) SURAMINa,b (Systemic) the product
====================================================================
VA CLASSIFICATION (Primary/Secondary)¾AP100/AP200
Commonly used brand name(s):
309 F;
Antrypol;
Bayer 205;
Belganyl;
Fourneau 309;
Germanin;
Moranyl;
Naganin;
Naganol;
Naphuride.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).
aNot commercially available in the U.S.
bNot commercially available in Canada.
Category
Antiprotozoal (systemic)1,2,3,4,5,6,7,19; anthelmintic (systemic)1,8,9,11,12,13,19.
Indications
Note: Because suramin is not commercially available in the U.S. or Canada, the bracketed information and the use of the superscript 1 in this monograph reflect the lack of labeled (approved) indications for this medication in these countries.
Accepted
[Trypanosomiasis, African, (treatment)]*¾Suramin is used as a primary agent in the treatment of African trypanosomiasis (African sleeping sickness; trypanosome fever) caused by Trypanosoma brucei gambienseor T. b. rhodesiense in patients with early or hemolymphatic disease without central nervous system (CNS) involvement.1,2,3,4,5,6,7,19,27,36,45
In patients with late stage or chronic trypanosomiasis caused by T. b. gambiense or T. b. rhodesiense involving the CNS, the primary agent is the toxic arsenical compound melarsoprol. Suramin may be administered as a preliminary agent prior to starting melarsoprol therapy in order to reduce the number of trypanosomes in the blood, thereby minimizing the adverse effects of melarsoprol.2,36,42,49,57 For patients who cannot tolerate melarsoprol, an alternative treatment is a combination of suramin and tryparsamide.10,33,34,35,38 These 2 medications are synergistic in action, and good therapeutic results have been obtained with combined administration.33,36 Eflornithine is another agent that has been found to be effective for T. b. gambiense infections.2,10,19,39,40,43,44 However, eflornithine has variable efficacy against T. b. rhodesiense infections.10
[Onchocerciasis (treatment)]*¾Suramin is used as a secondary agent in the treatment of onchocerciasis (river blindness) caused by Onchocerca volvulus.1,2,8,9,11,12,13,34,44,45,55,65 This agent is effective in killing the adult worm (macrofilaricidal)2,29,49,52,53,55 and also has partial microfilaricidal action.33,36,53 However, because of its intrinsic toxicity, suramin is now rarely used for this indication.36,38,51,53Currently, its use is restricted to radical cure of selected individuals in areas without transmission of onchocerciasis, for expatriates leaving the endemic area, and for severe hyperreactive onchodermatitis in patients whose symptoms are not adequately controlled by repeated treatment with ivermectin.38,51,52 Ivermectin is considered the primary agent in the treatment of onchocerciasis as a microfilaricide;10,19,54 it has been shown to have little or no macrofilaricidal effect.10,19,44 For heavily infected patients, ivermectin may be given prior to suramin therapy to reduce the microfilarial load.56
Acceptance not established
Suramin has demonstrated antitumor activity against a variety of neoplasms that are refractory to conventional treatment modalities.36,58,59,60,61,62,63 These neoplasms include metastatic adrenocortical carcinoma,62,63 advanced platinum-resistant ovarian carcinoma,61 and advanced-stage prostatic carcinoma58,59,60. The potential usefulness of suramin as an antineoplastic agent may be due to this agent's ability to inhibit lysosomal enzymes and a wide range of growth factors by interfering with binding at their receptors59,62 or by altering signal transduction.59 However, currently there are insufficient data to establish optimal dose, safety, and efficacy of suramin for these indications.58,59,60,61,62,63,64.
Unaccepted
Suramin alone is not useful in the treatment of late or chronic trypanosomiasis with central nervous system (CNS) involvement2,6,7 because it poorly passes the blood-brain barrier.36
In the past, suramin has been used in the treatment of hereditary angioneurotic edema.3 In this condition there is a lack of complement C1 esterase inhibitors and suramin inhibits complement C1 esterase.31 However, its therapeutic benefit has been found to be very erratic.3 Other effective agents, such as aminocaproic acid or tranexamic acid, are preferred for treatment of this condition.3
Suramin also was found to be ineffective in the treatment of chronic active hepatitis due to infection with viral hepatitis B.24
Although suramin is known to have an effect on deoxyribonucleic acid/ribonucleic acid (DNA/RNA) polymerase and on viral reverse transcriptase of human immunodeficiency virus (HIV) activity (anti-HIV) in vitro,14,20,21,26 this agent has been used unsuccessfully in the treatment of patients with acquired immunodeficiency syndrome (AIDS) and AIDS-related complex.21,22,23
Pharmacology/Pharmacokinetics
Physicochemical characteristics:
Chemical¾
Polysulfonated naphthylamine6,7 derivative of urea36
Molecular weight¾
1429.1618
Mechanism of action/Effect:
Trypanosomiasis, African¾Trypanocidal; the mechanism is unknown, but the trypanocidal activity may be due to the inhibition of enzymes involved with the oxidation of reduced nicotinamide-adenine dinucleotide (NADH), which functions as a co-enzyme in many cellular reactions,3,6,7 such as respiration and glycolysis, in the trypanosome parasite.33
Onchocerciasis¾Suramin is macrofilaricidal and partially microfilaricidal.8,9,13
Absorption:
Poorly absorbed from the gastrointestinal tract; must be given parenterally.3,36,55
Distribution:
Combines with serum proteins2,3 after intravenous administration and a large amount circulates in the blood; some is absorbed by the cells of the reticuloendothelial system, such as the liver, spleen, bone marrow, and connective tissue histiocytes, where it may be detected for more than 12 days after administration3; concentration in the kidney is approximately double the concentration in other tissues; accumulation in the adrenal glands is from 3- to 20-fold higher than that in the other organs;36 it may be present in the bloodstream for as long as 36,7 to 6 months after the last dose.3 Suramin is not concentrated in red blood cells or platelets. It has been assumed that suramin poorly passes the blood-brain barrier due to its large molecular size and its strongly anionic nature at physiological pH.36 Its concentration in the cerebrospinal fluid (CSF) is at most 1% of the corresponding plasma concentration.3,16
Volume of distribution (VolD) during terminal phase¾90±21 L.17
VolDat steady state¾38±8 L.14
Protein binding:
Very high (approximately 99.7%).14,15
Biotransformation:
Undergoes little or no metabolism as shown by its long persistence in the blood,3,17 apparent lack of metabolites found in plasma chromatograms, and high ratio of renal to total body clearance.14
Half-life:
Terminal phase¾About 36 to 60 days.14,17
Peak plasma concentration
> 100 mcg per mL; this concentration persists for several weeks.3,14
Elimination:
Renal¾Accounts for the elimination of most of the medication.2,14,55 Suramin is very slowly excreted in the urine3,13,14,17due to its combination with blood proteins.3,13About 12% of radiolabeled suramin is recovered in the urine over a 40-day period after administration of the medication to patients with onchocerciasis.17
Fecal¾About 4.5% of radiolabeled suramin is recovered in the feces over a 40-day period after administration to patients with onchocerciasis.17
Precautions to Consider
Pregnancy/Reproduction
65Pregnancy¾Adequate and well-controlled studies in humans have not been done.1 Suramin is not recommended for use in pregnant women with a chronic nonfatal condition such as onchocerciasis.2,3,49For a potentially fatal infection such as trypanosomiasis, it has been recommended that suramin be used during pregnancy only when there is no suitable alternative available.49 The potential benefit of using suramin should justify the potential risk to the fetus. Eflornithine should be considered for use in pregnant women with trypanosomiasis.39
Studies in rats have shown that suramin does not cross the placenta into the embryo, but accumulates in the lysosomes of the phagocytic epithelial cells of the umbilical vesicle (which develops from the yolk sac). This interferes with embryonic nutrition resulting in adverse effect on the fetus.3,20
Studies in pregnant rats given doses ranging from 30 mg per kg (mg/kg) of body weight per day (little more than the human therapeutic dose) to 75 mg/kg per day for 12 days have shown that suramin is very toxic, causing the death of 8 to 14% of the mother rats. In rats given higher doses (100 to 170 mg/kg), suramin had abortifacient but not teratogenic effects.3
Studies in pregnant mice given a dose of 25 mg/kg per day have not shown suramin to adversely affect the fetus. However, at doses of 40 to 65 mg/kg per day, suramin caused 64% fetal mortality and teratogenic effects were observed in the surviving fetuses.3
Breast-feeding
It is not known whether suramin is distributed into breast milk. However, problems in humans have not been documented.
Pediatrics
65No information is available on whether the risk of suramin-induced adverse effects is increased in children. However, because of this medication's toxicity, it should be used with caution, after less toxic alternatives have been considered and/or found ineffective. Recommended doses should not be exceeded and the patient should be carefully monitored during therapy.39,41,45,50
Geriatrics
65In one study on the use of suramin in the treatment of onchocerciasis, it was noted that side effects are less well tolerated in this age group, with a longer period of recovery.12,40Because of this medication's toxicity, suramin should be used with caution, after less toxic alternatives have been considered and/or found ineffective. Recommended doses should not be exceeded, and the patient should be carefully monitored during therapy.50
Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)¾not necessarily inclusive (>> = major clinical significance).
Risk-benefit should be considered when the following medical problems exist45
>> Hepatic function impairment2,3¾(because some suramin may be absorbed by the liver, hepatic damage may occur through its action on the lysosomal enzymes; elevations of hepatic enzymes, jaundice, and hepatitis have been reported3,29,56)
>> Hypersensitivity to suramin2,3¾
>> Renal function impairment1,2,3¾(suramin may be deposited as granules in the renal tubules and renal damage may occur2,3,6,25,56)
Suramin should be used with caution in severely debilitated or malnourished patients.1,3,6,29,36¾
Note: In ocular onchocerciasis, prolonged administration of suramin may result in inflammation and subsequent degenerative changes in the optic disk and retina; the World Health Organization (WHO) prescribing information does not recommend treatment with suramin for totally blind patients with onchocerciasis unless they require relief from the intensely itchy lesions [onchodermatitis] unrelieved by safer alternative; WHO also does not recommend treatment with suramin for light to moderately infected patients whose eyes are not at risk.48,65
Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; >> = major clinical significance):
45
>> Complete blood count (CBC)¾(suramin may decrease the concentration of erythrocytes, hemoglobin, or platelets on rare occasion6,10,29,53)
>> Creatinine, serum¾(should be measured regularly to assess renal function40)
>> Urinalysis¾(should be performed before administration of each dose of suramin47,49,56,65 to detect the presence of albumin;49,56 moderate albuminuria indicates the need for a reduction in dose; heavy albuminuria, with the passage of cast cells, calls for immediate discontinuation of treatment2,3,45,53,55)
For onchocerciasis
>> Ophthalmologic examinations, including examinations for visual acuity, visual fields, and ophthalmoscopy¾(ophthalmologic examinations for visual acuity and visual fields may be required prior to, and periodically during, therapy with suramin; slit-lamp examinations may be required before and after treatment, and periodically during treatment, with suramin to detect adverse reactions2,6,12,45,55)
Side/Adverse Effects
Note: Adverse effects of suramin may result either from the intrinsic toxicity of this medication or from its filaricidal action.2,53,65 Side effects are usually seen after the third dose, although some side effects may occur weeks after the completion of therapy. Patients should be monitored even after treatment is completed.53,65
Suramin administration has been associated with a rare (1 person in 20,000) but potentially fatal idiosyncratic reaction (See below). This risk is greater in patients with trypanosomiasis who also have concurrent onchocerciasis.51,56,65
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)¾not necessarily inclusive:
Those indicating need for medical attention
Incidence more frequent
Arthritis (joint pain)25,56; erythematous maculopapular eruptions (skin rash1,28,29,37,46,56); nephrotoxicity with albuminuria, transient (cloudy urine)6,7,11,25,29,56; neurological complications such as headache6,7,32palmar-plantar hyperesthesias1,7,25,29 (tenderness of the palms and soles)paresthesias6,7,29,32 (crawling or tingling sensation of the skin)and peripheral neuropathy6,7,32 (numbness or weakness in arms, hands, legs, or feet); pruritus7,56 (itching); relative adrenal insufficiency (diarrhea; easy fatigability; faintness, especially after missing meals; increased skin pigmentation; irritability; loss of appetite; nausea; vomiting)25,29,36,56; urticaria (stinging sensation on skin; swelling on skin)56
Incidence less frequent
Lymphadenopathy (painful tender glands in the neck, armpits, or groin6,7,8,9,11,25); ocular effects such as lacrimation (watery eyes)29optic atrophy (changes in or loss of vision)6,7,8,9,11,25,29palpebral edema (swelling around eyes)29and photophobia (increased sensitivity of eyes to light)29; prostration (extreme tiredness or weakness)11,25; stomatitis (ulcers or sores in mouth)11,12,25
Incidence rare
Blood dyscrasias such as agranulocytosis (fever and sore throat)anemia (unusual tiredness or weakness)6,10,29or thrombocytopenia (pinpoint red spots on skin; unusual bleeding or bruising)37; exfoliative dermatitis (fever with or without chills; red, thickened, or scaly skin; swollen and/or painful glands; unusual bruising)2,25,56; hepatitis (fever with or without chills; skin rash; swelling and/or tenderness in upper abdominal or stomach area; swollen and/or painful glands; unusual bleeding or bruising; unusual tiredness or weakness; yellow eyes or skin)56; idiosyncratic reaction including collapse (loss of consciousness)nauseaseizuresshock (cold and clammy skin; decreased blood pressure; difficulty in breathing; increased heart rate; pale skin)and/or vomiting1,6,7,11,25,29,30,32,56; jaundice (yellow eyes or skin)56
Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
Anorexia (loss of appetite)56; fatigue (weakness)32; fever25,32; gastrointestinal disturbances (abdominal pain32; diarrhea25,32 ; nausea6,7,32; vomiting6,11); malaise6,7,32 (general feeling of discomfort); metallic taste6,7,32
Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Suramin (Systemic).
In providing consultation, consider emphasizing the following selected information (>> = major clinical significance):
Before receiving this medication
>> Conditions affecting use, especially:
Hypersensitivity to suramin; importance of receiving a test dose for hypersensitivity prior to receiving the full dose
Pregnancy¾Not recommended for chronic non-fatal onchocerciasis; recommended during pregnancy for potentially life-threatening trypanosomiasis only if there are no suitable alternatives available; use should justify the potential risk to the fetus
Use in children¾Use with caution at recommended doses after less toxic alternatives have been considered and/or found ineffective
Use in the elderly¾Use with caution at recommended doses after less toxic alternatives have been considered and/or found ineffective
Other medical problems, especially hepatic function impairment and renal function impairment
Proper use of this medication
>> Importance of receiving this medication in the hospital and on a regular schedule
>> Proper dosing
Precautions after receiving this medication
Importance of regular visits with the physician after the end of therapy to check progress or adverse effects
Side/adverse effects
Signs of potential side effects, especially arthritis; erythematous maculopapular eruptions; nephrotoxicity; neurological complications such as headache, palmar-plantar hyperesthesias, paresthesias, and peripheral neuropathy; pruritus; relative adrenal insufficiency; urticaria; lymphadenopathy; ocular effects such as lacrimation, optic atrophy, palpebral edema, and photophobia; prostration; stomatitis; blood dyscrasias such as agranulocytosis, anemia, or thrombocytopenia; exfoliative dermatitis; hepatitis; idiosyncratic reaction including collapse, nausea, seizures, shock, and/or vomiting; and jaundice
General Dosing Information
Because suramin is highly toxic, it should be given only under medical supervision.2 Patients being treated with suramin should receive this medication in the hospital2,51,52They should be observed for 24 hours after administration of each dose of the medication.50 A careful assessment of the patient's capacity to withstand the effects of treatment should be done both before and during the administration of suramin.52
Suramin should be reconstituted with sterile water for injection and should be administered within 30 minutes56as a 10% solution by slow intravenous injection.2
Because of the risk of severe reactions, it is advisable to give an initial test dose of 100 to 200 mg (0.1 to 0.2 gram) in 2 mL of sterile water for injection before starting treatment.2,6,10,49 This test dose should be administered by slow intravenous injection. After injecting the first few microliters, wait at least 1 minute, then inject the next 0.5 mL over 30 seconds and wait one minute. Finally, inject the remainder of the dose over several minutes. Epinephrine (1:1000 solution), parenteral antihistamines, and corticosteroids should be available immediately to deal with any adverse reaction that may arise.2 A patient who experiences an anaphylactic reaction after the first injection should never receive suramin again.55
For treatment of adverse effects
Recommended treatment consists of the following
· For hypersensitivity reactions¾Epinephrine (1:1000 solution), parenteral antihistamines, and corticosteroids.2
· For thrombocytopenia¾Intravenous injection of gammaglobulin.37
· Reduction in dosage or discontinuation of treatment.3
Parenteral Dosage Forms
Note: Because suramin is not commercially available in the U.S. or Canada, the bracketed uses and the use of superscript 1 in the Dosage Forms section reflect the lack of labeled (approved) indications for this product in these countries.
SURAMIN SODIUM FOR INJECTION1,33
Usual adult dose
[Trypanosomiasis, African (treatment)]*¾
Early stage: Intravenous, 100 to 200 mg (0.1 to 0.2 gram) administered slowly as a test dose for hypersensitivity. This is followed after twenty-four hours46,50,64 by a dose of 20 mg per kg of body weight per day to a maximum of 1 gram42,56 on days one, three, seven, fourteen, and twenty-one,10,32,34,56 or weekly, until a total dose of 5 grams is achieved.56 Patients in poor general condition should receive approximately one-quarter of the normal dose.1,46
Late stage: Intravenous, 100 to 200 mg (0.1 to 0.2 gram) administered slowly as a test dose for hypersensitivity.45 This is followed after twenty-four hours46,48,50 by a dose of 10 mg per kilogram (kg) of body weight per day every five days for a total of twelve injections. This is given in combination with tryparsamide at a dose of 30 mg per kg of body weight (maximum of 2 grams) per day, also administered intravenously every five days, for a total of twelve injections. One month after completion of therapy, a second course of this combined treatment may be repeated, if necessary.10,34
Note: The following table provides the World Health Organization (WHO) prescribing information for suramin. Doses are for both adults and children (in mg per kg of body weight per day), for cure of early or hemolymphatic stage (A) and for administration before melarsoprol treatment in the late stage (B) of the disease.2
Dose (mg/kg of body weight) per Day
Treatment 1 3 5 11 17 23 30
A 5 10 20 20 20 20 20
B 5 10 20
[Onchocerciasis (treatment)]*¾
Intravenous, 100 to 200 mg (0.1 to 0.2 gram) administered slowly as a test dose for hypersensitivity. Treatment with the full dose may then be started after one week.48 A total of 66.7 mg per kg of body weight should be administered in six incremental weekly doses apportioned as follows: 3.3 mg/kg week one, 6.7 mg/kg week two, 10 mg/kg week three, 13.3 mg/kg week four, 16.7 mg/kg week five, and 16.7 mg/kg week six.2
Usual adult prescribing limits
Up to 142,56 to 1.51,28,39,41,47 grams per day.
Usual pediatric dose
[Trypanosomiasis, African (treatment)]*¾
Early stage: Intravenous, 100 to 200 mg (0.1 to 0.2 gram) administered slowly as a test dose for hypersensitivity. This is followed after twenty-four hours by a dose of 10 to 20 mg per kg of body weight per day on days one, three, seven, fourteen, and twenty-one.7,10,34,46,48
Note: See also table based on the WHO prescribing information in Usual adult dose for the treatment of both early and late stage trypanosomiasis in children.
[Onchocerciasis (treatment)]*¾
Not usually recommended unless no safer alternative is available.39,41,43,50
Usual pediatric prescribing limits
Up to 20 mg per kg of body weight per day.10,48
Strength(s) usually available
U.S.¾
Not commercially available.
Note: Although suramin is not commercially available in the U.S., it can be obtained from the Parasitic Disease Drug Service, Centers for Disease Control (CDC), Atlanta, Georgia 30333 (telephone nos.: 404-639-3670; 404-639-2888 on evenings, weekends, or holidays [emergencies only]).10,19
Canada¾
Not commercially available.
Note: Although suramin is not commercially available in Canada, it is made available with authorization from the Bureau of Human Prescription Drugs (BHPD), Health Protection Branch (HPB), Health Canada, Tower B, 3rd Floor, 1600 Scott Street, Ottawa, Ontario K1A 0L2 (telephone no.: 613-941-2108).40
Other¾
1 gram (Rx)[Antrypol].[Bayer 205 (Germany) (South Africa)].[Belganyl].[309 F].[Fourneau 309].[Germanin (Germany) (South Africa)].[Moranyl].[Naganin].[Naganol].[Naphuride1,7,15,33,65].
Packaging and storage:
Store below 25 °C (77 °F), unless otherwise specified by manufacturer. Protect from light.1
Preparation of dosage form:
The solution for injection should always be freshly prepared.1,33. Using a sterile technique, slowly inject 10 mL sterile water for injection into the vial containing suramin. The mixture should then be shaken vigorously to dissolve the powder in the solution.1
Stability:
Suramin should be used immediately (preferably within 30 minutes)56 after reconstitution with sterile water for injection.33
*Not included in Canadian product labeling.
References
1Suramin package insert (Bayer¾Germany), Rev 5/91, Rec 10/93.
2WHO Model Prescribing Information: Drugs used in parasitic diseases. Geneva: World Health Organization, 1990: 64-5, 67-8, 70, 105-7, 110-12.
3Hawking F. Suramin: With special reference to onchocerciasis. Adv Pharm and Chemoth 1978; 289-322.
4Kleine FK, Fischer W. Dtsch Med Wochenschr 1923; 49: 1039. Cited by Hawking 1978.
5Van Hoof L, Henrard C, Peel E, Wanson M. (1947). Cited by Hawking 1978.
6Van Voorhis WC. Therapy and prophylaxis of systemic protozoan infections. Drugs 1990; 40(20): 176-202.
7Gutteridge WE. Existing chemotherapy and its limitations. Br Med Bull 1985; 41(2): 162-8.
8Rougemont A, Thylefors B, Ducam M, Prost A, Ranque P, Delmont J. Treatment of onchocerciasis in hyperendemic communities in West Africa with small gradually increasing doses of suramin. 1. Parasitological results and opthalmological surveillance in a region where transmission has not been interrupted. Bull World Health Organ 1980; 58(6): 917-22.
9Thylefors B, Rolland A. The risk of optic atrophy following suramin treatment of ocular onchocerciasis. Bull World Health Organ 1979; 57(3): 479-80.
10Abramowicz M, editor. Drugs for parasitic infections. Med Lett Drugs Ther 1993; 35(911): 111-22.
11Anderson J, Fuglsang H. Further studies on the treatment of ocular onchocerciasis with diethylcarbamazine and suramin. Br J Ophthalmol 1978; 62(7): 450-7.
12Anderson J, Fuglsang H. Effects of suramin on ocular onchocerciasis. Tropenmed Parasitol 1976; 27: 279-96.
13Duke BOL. The effects of drugs on Onchocerca volvulus. 3. Trials of suramin at different dosages and a comparison of the brands Antrypol, Moranyl, and Naganol. Bull World Health Organ 1968: 39: 157-67.
14Collins JM, Klecker RW, Yarchoan R, Lane HC, Fauci AS, Redfield RR, et al. Clinical pharmacokinetics of suramin in patients with HTLV-III/LAV infection. J Clin Pharmacol 1986; 26: 22-6.
15Spinks A. The persistence in the blood stream of some compounds related to suramin. Biochem J 1948; 42: 109-16.
16Van Boxtel CJ, Schattenkerk EFK, Van Den Berg M, de Graaf YP, Danner SA. Therapeutic monitoring of suramin treatment in patients with AIDS. Acta Pharmacol et Toxicol 1986; 59(suppl 5 pt 2): 196.
17Edwards G, Rodick CL, Ward SA, Awadzi K, Orme ML, Breckenridge AM. Disposition of suramin in patients with onchocerciasis. Acta Pharmacol et Toxicol 1986; 59(suppl 5 pt 2): 222.
18Fleeger CA, editor. USAN 1994. USAN and the USP dictionary of drug names. Rockville, MD: The United States Pharmacopeial Convention, Inc., 1993: 634.
19Goldsmith RS. Antiprotozoal drugs/Anthelmintic drugs. In: Katzung BG, editor. Basic and clinical pharmacology. Norwalk: Appleton and Lange, 1992: 723-47, 748-65.
20Freeman SJ, Lloyd JB. Evidence that suramin and aurothiomalate are teratogenic in rat by disturbing yolk sac-mediated embryonic protein nutrition. Chem Biol Interact 1986; 58: 149-60.
21Chandra P, Vogel A, Gerber T. Inhibitors of retroviral DNA polymerase: their implication in the treatment of AIDS. Cancer Res (Suppl) 1985; 46: 4677-84.
22Busch W, Brodt R, Ganser A, Helm EB, Stille W. Suramin treatment for AIDS. Lancet 1985; 2: 1247.
23Kaplan LD, Wolfe PR, Volberding PA, Feorino P, Levy JA, Abrams DI, et al. Lack of response to suramin in patients with AIDS and AIDS-related complex. Am J Med 1987; 82: 615-22.
24Loke RHT, Anderson MG, Coleman JC, Tsiquaye KN, Zuckerman AJ, Murray-Lyon IM. Suramin treatment for chronic active hepatitis B - toxic and ineffective. J Med Virol 1987; 21: 97-9.
25Fuglsang H, Anderson A. Side effects of suramin. Paho Scientific Publication 1974; 298: 54-7.
26Mitsuya H, Popovic M, Yarchoan R, Matsushita S, Gallo RC, Broder S. Suramin protection of T cells in vitro against infectivity and cytopathic effect of HTLV-III. Science 1984; 226: 172-4.
27Cochran R, Rosen T. African trypanosomiasis in the United States. Arch Dermatol 1993; 119: 670-4.
28Manufacturer's comment {Bayer¾Germany}, 6/94.
29Dukes MNG, editor. Meyler's side effects of drugs. An encyclopedia of adverse reactions and interactions. Amsterdam: Elsevier, 1994: 770-80.
30Thibault A, Figg WD, Cooper MR, Prindiville SA, Sartor AO, Headlee DJ, et al. Anaphylactoid reaction with suramin. Pharmacotherapy 1993; 13(6): 656-7.
31Eisen V, Loveday C. Effects of suramin on complement, blood clotting, fibrinolysis and kinin formation. Br J Pharmacol 1973; 49: 678-87.
32Gilman AG, Rall TW, Nies AS, Taylor P, editors. Goodman and Gilman's the pharmacological basis of therapeutics. 8th ed. New York: Pergamon Press, 1990: 1014-6.
33Bayer 205 product monograph (Bayer¾Germany), Rec 10/93.
34Wilson JD, Braunwald E, Isselbacher KJ, Petersdorf RG, Martin JB, Fauci AS, et al, editors. Harrison's principles of internal medicine. 12th ed. New York: McGraw-Hill, Inc., 1991: 793-5, 811-2.
35WHO Tech Rep Ser 1962; 247: 28.
36Voogd TE, Vansterkenburg ELM, Wilting J, et al. Recent research on the biological activity of suramin. Pharmacol Rev 1993; 45(2): 177-203.
37Seidman AD, Schwartz M, Reich L, et al. Immune-mediated thrombocytopenia secondary to suramin. Cancer 1993; 71: 851-4.
38Merkus FWHM. WHO/OMS revised list of essential drugs. Intl Pharm J 1994; 8(2): 83-5.
39Panel comment, 9/94.
40Panel comment, 9/94.
41Panel comment, 9/94.
42Buyst H. The treatment of T. rhodesiense sleeping sickness, with special reference to its physio-pathological and epidemiological basis. Ann Soc Belge Med Trop 1975; 55(2): 95-104.
43Markell EK, Voge M, John DT. Medical parasitology. 7th ed. Philadelphia: WB Saunders Co., 1992: 134.
44Orme M, Awadzi K, Edwards G, et al. Drug treatment of onchocerciasis. Q J Med 1988; 66(251): 195-201.
45Reviewers consensus on monograph revision of 6/94.
46Manufacturer's comment {Bayer (Pty) Ltd¾South Africa}, 9/94.
47Panel comment, 9/94.
48Panel comment, 9/94.
49Reynolds JEF, editor. Martindale, the extra pharmacopeia. 29th ed. London: The Pharmaceutical Press, 1989: 515, 527-8.
50Panel comment, 9/94.
51Panel comments, 9/94.
52WHO Expert Committee Report on the Control of Onchocerciasis (TRS 1993): in press.
53WHO Expert Committee Report on African Trypanosomiasis (TRS739 1986): 72-3.
54Suramin box label (Bayer¾Germany), Rec 10/93.
55Suramin data sheet from WHO Model Prescribing Information: Drugs used in Parasitic Diseases Rev. 1 (1994): in press.
56Strickland GT, editor. Hunter's Tropical Medicine. 7th ed. Philadelphia: W. B. Saunders Co, 1991: 625; 742-3.
57Pepin J, Guerin C, Ethier L, et al. Trial of prednisolone for the prevention of melarsoprol-induced encephalopathy in gambiense sleeping sickness. Lancet 1989; 1246-50.
58Eisenberger MA, Reyno LM, Jodrell DI, et al. Suramin, an active drug for prostate cancer: interim observations in a phase 1 trial. J Nat Can Inst 1993; 85(8): 611-20.
59Myers C, Cooper M, LaRocca R, et al. Suramin: a novel growth factor antagonist with activity in hormone-refractory metastatic prostate cancer. J Clin Oncol 1992; 10(6): 881-9.
60Rapoport BL, Falkson G, Raats JI, et al. Suramin in combination with mitomycin C in hormone-resistant prostate cancer. A phase II clinical study. Ann Oncol 1993; 4: 567-73.
61Reed E, Cooper MR, LaRocca, RV, et al. Suramin in advanced platinum-resistant ovarian cancer. Eur J Cancer 1992; 28A (4/5): 864-6.
62Stein CA, LaRocca RV, Thomas R, et al. Suramin: an anticancer drug with a unique mechanism of action. J Clin Oncol 1989; 7(4): 499-508.
63Vierhapper H, Nowotny P, Mostbeck G, et al. Effect of suramin in a patient with adrenocortical carcinoma. Lancet 1989; 1207-8.
64Panel comment, 2/95.
65Parasitic Disease Advisory Panel Meeting, 11/94.
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39.) DIETHYLCARBAMAZINE (Systemic) the product
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Revised: 08/11/95
VA CLASSIFICATION (Primary/Secondary)¾AP200
Commonly used brand name(s):
Hetrazan.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).
Category
Anthelmintic (systemic)16.
Indications
Accepted
Filariasis, Bancroft's (treatment)¾Diethylcarbamazine is indicated as a primary agent in the treatment of Bancroft's filariasis caused by Wuchereria bancrofti.1,3 8,12
Loiasis (treatment)¾Diethylcarbamazine is indicated as a primary agent in the treatment of loiasis caused by Loa loa.1,3,12
Onchocerciasis (treatment)¾Diethylcarbamazine is indicated as a secondary agent in the curative treatment, given before and after suramin therapy, of onchocerciasis (river blindness) caused by Onchocerca volvulus.Ivermectin is considered to be the primary agent in the treatment of onchocerciasis.1,2,5,6,12
Tropical eosinophilia (treatment)¾Diethylcarbamazine is indicated as a primary agent in the treatment of tropical eosinophilia (eosinophilic lung; tropical pulmonary eosinophilia).1,12
Unaccepted
Diethylcarbamazine has been used for the treatment of ascariasis. However, in the opinion of most USP medical experts, it has been superseded by newer, safer, and more effective anthelmintics.12
Pharmacology/Pharmacokinetics
Mechanism of action/Effect:
Filariasis; loiasis¾Microfilaricidal and macrofilaricidal.3,6
Onchocerciasis¾Microfilaricidal; diethylcarbamazine reduces the number of intrauterine Onchocerca volvulus microfilariae by inhibiting the rate of embryogenesis; this agent also increases the rate of loss of O. volvulus microfilariae from nematodes and nodules; diethylcarbamazine has no sterilizing effect on adult worms.5,6,7,12
Absorption:
Readily absorbed following oral administration.6,7
Distribution:
Widely distributed throughout all body compartments, except adipose tissue.19
Biotransformation:
Partially metabolized to diethylcarbamazine N-oxide.4
Half-life:
Approximately 8 hours.19
Time to peak serum concentration
1 to 2 hours.4,19
Peak serum concentration
80 to 200 nanograms per mL after a single 50-mg dose.4
Elimination:
Renal¾Excreted in urine, largely unchanged and as N-oxide metabolite, within 48 hours.6
Fecal¾Approximately 4 to 5% eliminated in feces.4
Precautions to Consider
Pregnancy/Reproduction
Treatment of pregnant patients with diethylcarbamazine should be deferred until after delivery.6,12 However, problems in humans have not been documented.
Breast-feeding
It is not known whether diethylcarbamazine is distributed into breast milk. However, problems in humans have not been documented.
Pediatrics
Appropriate studies on the relationship of age to the effects of diethylcarbamazine have not been performed in the pediatric population. However, no pediatrics-specific problems have been documented to date.1,17,18
Geriatrics
No information is available on the relationship of age to the effects of diethylcarbamazine in geriatric patients.
Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)¾not necessarily inclusive (>> = major clinical significance).
Risk-benefit should be considered when the following medical problem exists
Hypersensitivity to diethylcarbamazine¾
Note: In ocular onchocerciasis, prolonged administration of diethylcarbamazine may result in inflammation and subsequent degenerative changes in the optic disc and retina.2,6
Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; >> = major clinical significance):
For Bancroft's filariasis and loiasis
Microfilarial blood concentrations¾(may be required prior to and periodically during therapy with diethylcarbamazine; in loiasis, retinal hemorrhage and encephalopathy may occur with very high microfilarial blood concentrations12)
For onchocerciasis
>> Ophthalmologic examinations, including examinations for visual acuity, visual fields, and ophthalmoscopy¾(ophthalmologic examinations for visual acuity and visual fields may be required routinely prior to and12 periodically during therapy with diethylcarbamazine; slit-lamp examinations may be required prior to, periodically during, and following treatment with diethylcarbamazine to assess the number of intraocular microfilariae and adverse reactions such as iridocyclitis2,6 12)
>> Skin snips¾(may be required prior to and every 6 to 1212 months following treatment with diethylcarbamazine to assess the number of intradermal microfilariae2)
Side/Adverse Effects
Note: In heavily infected patients with onchocerciasis, severe reactions may occur following a single dose of diethylcarbamazine. The Mazzotti reaction, a complex, acute inflammatory response characterized by fever, tachycardia, hypotension, adenitis, and an ocular inflammatory response, usually results from the death of microfilariae. The intensity of the reaction depends on the dose and the microfilarial load. However, it is sometimes difficult to determine whether these reactions are caused by the death of microfilariae or by diethylcarbamazine itself.1,3,6
In very heavily infected patients with loiasis, encephalopathy and retinal hemorrhage may occur following treatment with diethylcarbamazine.12
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)¾not necessarily inclusive:
Those indicating need for medical attention
Incidence more frequent
Itching and swelling of face, especially eyes1
Incidence less frequent
Fever2,6; lymphadenopathy (painful and tender glands in neck, armpits, or groin)6; skin rash1,2,6
With prolonged use in onchocerciasis6
Visual disturbances (loss of vision; night blindness; tunnel vision)
Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
Arthralgia (joint pain)2,6; headache1,2,6; malaise (unusual tiredness or weakness)1
Incidence less frequent
Dizziness2,6; nausea or vomiting1
Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Diethylcarbamazine (Systemic).
In providing consultation, consider emphasizing the following selected information (>> = major clinical significance):
Before using this medication
>> Conditions affecting use, especially:Pregnancy¾Treatment of pregnant patients should be deferred until after delivery; however, problems in humans have not been documented
Proper use of this medication
Taking immediately after meals
>> Compliance with full course of therapy; second course may be required in some patients
>> Proper dosingMissed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses
>> Proper storage
Precautions while using this medication
Checking with physician if no improvement within a few days
For river blindness
Regular visits to physician to check progress, as well as ophthalmologic examinations
>> Caution if dizziness, loss of vision, night blindness, or tunnel vision occurs
Concurrent administration with systemic corticosteroids to reduce inflammatory response to death of microfilariae
Side/adverse effects
Signs of potential side effects, especially itching and swelling of face, particularly eyes; fever; lymphadenopathy; skin rash; and visual disturbances
General Dosing Information
Diethylcarbamazine should be taken immediately after meals.1
Diethylcarbamazine should be administered with caution (e.g., gradually increasing doses) to prevent or minimize allergic reactions. Most side effects of diethylcarbamazine are not serious and do not generally require discontinuation of therapy. However, it may be necessary to discontinue therapy if severe allergic reactions, in conjunction with skin rash, occur.1
Patients who are more heavily infected may require more prolonged treatment.1,3
For Bancroft's filariasis, loiasis, or onchocerciasis
In the acute and chronic stages of these infections, treatment should be continued for 2 to 4 weeks. Recurrences require retreatment.1,12
In Bancroft's filariasis, treatment should preferably be given before irreparable damage is done to the lymphatic system and its valves.3
In the curative treatment of onchocerciasis, diethylcarbamazine is administered before and after suramin therapy. Diethylcarbamazine is recommended in low initial doses concurrently with systemic corticosteroids to suppress the inflammatory response to the death of microfilariae caused by diethylcarbamazine, especially in moderate to heavy infections with ocular involvement.2,5,6,12
In severe onchocerciasis, severe allergic reactions may develop following the administration of a single dose of diethylcarbamazine. Gradually increasing doses are recommended as follows: 25 mg daily, gradually increased to the usual maintenance dose over a period of 7 to 14 days.13 If very severe allergic reactions occur, diethylcarbamazine should be discontinued and corticosteroids should be given.12If severe allergic reactions occur again, diethylcarbamazine should not be used in these patients.1,12
In the suppressive treatment of onchocerciasis, diethylcarbamazine is recommended in low, intermittent doses to preserve eyesight and to relieve pruritus by reducing the microfilarial load.6,12
For treatment of adverse effects
Recommended treatment consists of the following:
· Systemic corticosteroids for very severe allergic reactions.1,2 5,6,12
Oral Dosage Forms
DIETHYLCARBAMAZINE CITRATE TABLETS USP
Usual adult dose
Bancroft's filariasis; or
Loiasis; or
Onchocerciasis¾
Oral, 2 to 3 mg per kg of body weight three times a day.1,3,12
Tropical eosinophilia¾
Oral, 6 mg per kg of body weight once a day for four to seven days.1,12
Usual adult prescribing limits
Onchocerciasis¾Up to 9 mg per kg of body weight a day.5,12
Tropical eosinophilia¾Up to 13 mg per kg of body weight a day.1
Usual pediatric dose
Dosage has not been established in the treatment of Bancroft's filariasis, loiasis, onchocerciasis, or tropical eosinophilia. However, doses of 50 mg to 250 mg daily, based on the patient's age, have been used in children between the ages of 1 and 15 years of age.17 18
Strength(s) usually available
U.S.¾
50 mg (Rx)[Hetrazan1,9,10,14].200 mg (Rx) [Generic]11400 mg (Rx) [Generic]11
Note: The 50-mg tablet is available only through the manufacturer upon request (tel. no.: 914-735-2815).9,10,14
Canada¾
50 mg (Rx)[Hetrazan (scored)15].
Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight container.
Auxiliary labeling:
· Take immediately after meals.
· May cause dizziness or vision problems.
· Continue medication for full time of treatment.
References
1Hetrazan package insert (Lederle¾US), Rev 2/82, Rec 9/87, Rec 6/95.
2Rivas-Alcala AR, Taylor HR, Ruvalcaba-Macias AM, et al. Chemotherapy of onchocerciasis: a controlled comparison of mebendazole, levamisole, and diethylcarbamazine. Lancet 1981; 485-90.
3Duke BOL. Lymphatic and other filariases. Br Med J 1981; 283: 1036-7.
4Edwards G, Awadzi K, Breckenridge AM, et al. Diethylcarbamazine disposition in patients with onchocerciasis. Clin Pharmacol Ther 1981; 30(4): 551-7.
5Langham ME, Beltranena F. The Onchocerca volvulus micro- and macrofilarial responses in onchocerciasis patients to increased dosage of diethylcarbamazine. Trop Med Parasitol 1985; 36: 175-9.
6Diethylcarbamazine. WHO Drug Info 1987; 1(2): 83-5.
7Taylor HR, Greene BM. Ocular changes with oral and transepidermal diethylcarbamazine therapy of onchocerciasis. Br J Ophthalmol 1981; 65: 494-502.
8Partono F, Purnomo, Oemijati S, et al. The long term effects of repeated diethylcarbamazine administration with special reference to microfilaraemia and elephantiasis. Acta Tropica 1981; 38: 217-25.
9Lederle letter to Mark Bonner, 4/2/84.
10Sklaver L, Murray C. Availability of diethylcarbamazine citrate. Am J Hosp Pharm 1986; 43: 2987.
11Diethylcarbamazine (generic). In: Red book 1991. Montvale, NJ: Medical Economics Data, 1991: 246.
12Panel comments, Diethylcarbamazine (Systemic), 3/31/88.
13Review comments, Diethylcarbamazine (Systemic), Vol. 9, No. 1.
14Katzung BG, editor. Basic and clinical pharmacology. Norwalk, CT: Appleton and Lange, 1992: 763.
15Hetrazan (Lederle). In: Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 23rd ed. Ottawa: Canadian Pharmaceutical Association, 1988: 389.
16Fleeger CA, editor. USAN 1989. USAN and the USP dictionary of drug names. Rockville, MD: The United States Pharmacopeial Convention, Inc., 1988: 180.
17Wijers DJB, Kaleli N. Bancroftian filariasis in Kenya, V. Mass treatment given by members of the local community. Ann Trop Med Parasitol 1984; 78(4): 383-94.
18Dreyer G, de Andrade L. Inappropriateness of the association of diphenhydramine with diethylcarbamazine for the treatment of lymphatic filariasis. J Trop Med Hygiene 1989; 92: 32-4.
19Mandell GL, Douglas RG, Bennett JE, editors. Principles and practice of infectious diseases. New York: Churchill Livingstone, Inc., 1990: 418-9, 2142-4.
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DATA-MEDICOS/DERMAGIC-EXPRESS No (74) 21/09/99 DR. JOSE LAPENTA R.
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