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****** DATA-MEDICOS **********
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LA PENTOXIFILINA / THE PENTOXIFYLLINE
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****** DERMAGIC-EXPRESS No.37 ******* 
****** 09 FEBRERO DE 1.999 ********* 
09 FEBRUARY 1.999
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EDITORIAL ESPANOL
=================
Saludos, amigos de la red, DERNAGIC en esta ocasion con una revision de LA PENTOXIFILINA (TRENTAL), medicamento muy utilizado en numerosas patologias dermatologicas y no dermatologicas. Estas 56 referencias nos hablan sobre sus mecanismos de accion y algunas de las enfermedades donde se esta utilizando. Al final una monografia del producto.

Bienvenidos a DEMAGIC: Dr. pedro Pinto, (ESPAñA), Armando Mocci (PANAMA), David Rosenfeld (PARAGUAY),

Saludos a TODOS,,, 

PROXIMA EDICION: CARCINOMA DE MERKEL !!

Dr. Jose Lapenta R.,,,


EDITORIAL ENGLISH
=================
Greetings, friends of the net, DERMAGIC in this occasion with a revision of THE PENTOXIFILINA (TRENTAL), medication very used in numerous pathologies dermatologic and non dermatologic. These 56 references talk us about their action mechanisms and some of the illnesses where they are using it. At the end a monograph of the product. 

Welcome to DERMAGIC: Dr. Bruce Bennin (USA), Robert E. Kalb (USA), Dominic F. Schreer (BELGIUM), John F. Kaiser (USA), Catalin Popescu (ROMANIA), Klaus Helm (USA), Fabio Zorzi (ITALY), Andrea G. Di Stefano, (ITALY), enzo berardesca (ITALY), Sandra Johnson (USA)

Greetings to ALL, 
NEXT EDITION: THE MERKEL CELL CARCIMONA !!!
Dr. José Lapenta,

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DERMAGIC/EXPRESS(37)
======================================================================
LA PENTOXIFILINA / THE PENTOXIFYLLINE
======================================================================
1.) New developments in the treatment of systemic vasculitis. 
2.) Chilblain lupus erythematosus (lupus pernio): clinical review of the
Mayo Clinic experience and proposal of diagnostic criteria. 
3.) [Vernet's syndrome as an early manifestation of systemic erythematous
lupus] 
4.) [Favorable in vitro effect of pentoxifylline on damaged lymphocyte
migration in arteriosclerosis obliterans and systemic lupus erythematosus
(see comments)] 
5.) Effect of pentoxifylline on decreased in vitro mononuclear leucocyte
chemotaxis in vascular and polysystemic autoimmune diseases. 
6.) Effect of pentoxifylline on the course of systemic Candida albicans
infection in mice. 
7.) [Current status and trends in treatment of scleroderma] 
8.) [New properties of trental as an inhibitor of viral activity with a
wide range of activity] 
9.)[Lymphotropic therapy with trental in the treatment of chronic herpetic
stomatitis] 
10.) A double-blind, randomized, placebo-controlled, crossover trial of
pentoxifylline for the prevention of chemotherapy-induced oral mucositis. 
11.) Vasculitis. 
12.) Improvement of acral circulation in a patient with systemic sclerosis
with stellate blocks. 
13.) Effects of pentoxifylline on hemodynamics and oxygenation in septic
and nonseptic patients. 
14.) Antiproliferative effect of pentoxifylline on psoriatic and normal
epidermis. In vitro and in vivo studies. 
15.) Antineoplastic effect of the xanthine derivative Trental. 
16.) Treatment of experimental frostbite with pentoxifylline and aloe vera
cream.
17.) High-dose pentoxifylline in patients with AIDS: inhibition of tumor
necrosis factor production. National Institute of Allergy and Infectious
Diseases AIDS Clinical Trials Group.
18.) Pentoxifylline as a supportive agent in the treatment of cerebral
malaria in children.
19.) Pentoxifylline inhibits tumor necrosis factor-alpha (TNF
alpha)-induced T-lymphoma cell adhesion to endothelioma cells.
20.) Pharmacotherapy of Raynaud's phenomenon. 
21.) Severe idiopathic recurrent aphthous stomatitis: treatment with
pentoxifylline [letter]
22.) Pentoxifylline for Sweet's syndrome [letter; comment]
23.) Urticarial vasculitis syndrome effectively treated with dapsone and
pentoxifylline.
24.) Schamberg's purpura: association with persistent hepatitis B surface
antigenemia and treatment with pentoxifylline.
25.) The use of pentoxifylline in the treatment of systemic sclerosis and
lipodermatosclerosis: a unifying hypothesis? [letter; comment]
26.) Pentoxifylline [see comments]
27.) Toxic epidermal necrolysis. Treatment with pentoxifylline [letter]
28.) Pentoxifylline for the treatment of infection with human
immunodeficiency virus.
29.) Inhibition of collagen lattice contraction by pentoxifylline and
interferon-alpha, -beta, and -gamma.
30.) Long-term pretreatment with pentoxifylline increases random skin flap
survival.
31.) Angiolymphoid hyperplasia with eosinophilia may respond to
pentoxifylline.
32.) Chronic balanitis with palisading granuloma: an atypical genital
localization of necrobiosis lipoidica responsive to pentoxifylline.
33.) Pentoxifylline for ischemic pain in pseudoxanthoma elasticum.
34.) Pentoxifylline suppresses irritant and contact hypersensitivity
reactions.
35.) Ulcerating necrobiosis lipoidica effectively treated with pentoxifylline.
36.) Generalised granuloma annulare successfully treated with pentoxifylline.
37.) Intractable chronic furunculosis: prevention of recurrences with
pentoxifylline.
38.) Successful treatment of Kasabach-Merritt syndrome with pentoxifylline.
39.) Pentoxifylline inhibits the proliferation of human fibroblasts derived
from keloid, scleroderma and morphoea skin and their production of
collagen, glycosaminoglycans and fibronectin.
40.) Effects and limitations of pentoxifylline therapy in various stages of
peripheral vascular disease of the lower extremity.
41.) Enhancement of the treatment of experimental candidiasis with vascular
decongestants.
42.) Treatment of sickle cell leg ulcers with pentoxifylline.
43.) Oxpentifylline treatment of venous ulcers of the leg [see comments]
44.) Oxpentifylline in endotoxaemia [see comments]
45.) Pentoxifylline inhibits normal human dermal fibroblast in vitro
proliferation, collagen, glycosaminoglycan, and fibronectin production, and
increases collagenase activity.
46.) Pentoxifylline increases extremity blood flow in diabetic
atherosclerotic patients.
47.) Treatment of peripheral gangrene due to systemic sclerosis with
intravenous pentoxifylline.
48.) Therapy of livedo vasculitis with pentoxifylline.
49.) Pentoxifylline therapy in dermatology. A review of localized
hyperviscosity and its effects on the skin.
50.) Augmentation of skin flap survival by parenteral pentoxifylline.
51.) Synergistic effects of pentoxifylline and hyperbaric oxygen on skin
flaps.
52.) Pentoxifylline inhibits granulocyte and platelet function, including
granulocyte priming by platelet activating factor.
53.) Livedo vasculitis. Therapy with pentoxifylline [published erratum 
54.) Pentoxifylline inhibits T-cell adherence to keratinocytes.
55.) Pentoxifylline promotes replication of human cytomegalovirus in vivo
and in vitro. 
56.) PENTOXIFYLLINE (Systemic), the product
========================================================================
1.) New developments in the treatment of systemic vasculitis. 
========================================================================
Author 
Gross WL 
Address 
Universit¨at zu L¨ubeck, Germany. 
Source 
Curr Opin Rheumatol, 6(1):11-9 1994 Jan 
Abstract 
Although precise diagnosis of the systemic vasculitides can provide general
prognostic information and help to guide initial therapy, recent studies on
the long-term clinical course have revealed considerable variation in
clinical severity. Therefore, anatomic distribution of involvement and
speed of progression should be the principle determinants of the intensity
of immunosuppressive therapy. In progressive pulmonary or renal disease,
eg, Wegener's granulomatosis, aggressive "standard" therapy is obligatory,
eg, daily cyclophosphamide and glucocorticoids. Such regimens, however,
should be applied with caution in chronic or indolent and abortive forms of
systemic vasculitis, because follow-up studies (eg, in Wegener's
granulomatosis) have revealed treatment-associated morbidity rates of up to
42%, disease-related morbidity, and a high incidence of relapse under
treatment. Moreover, less toxic therapeutic strategies are being pursued
with remarkable success: low-dose weekly methotrexate, monthly intravenous
or oral pulses of cyclophosphamide plus glucocorticoids, and high-dose
intravenous immunoglobulin. Long-term remission of intractable
(non-antineutrophil cytoplasmic antibody-associated) systemic vasculitis
has been achieved using humanized monoclonal antibodies (ie,
anti-CD4/anti-CDw52); and amelioration of glomerulonephritis in immune
complex diseases (eg, systemic lupus erythematosus) has been achieved with
nafamostat mesilate, an inhibitor of complement serine proteases. In
addition, leukocytoclastic vasculitis has been effectively controlled with
pentoxifylline, presumably by neutralizing proinflammatory cytokines, and
hepatitis C virus-associated mixed cryoglobulinemia has been successfully
treated with interferon alfa. 

========================================================================
2.) Chilblain lupus erythematosus (lupus pernio): clinical review of the
Mayo Clinic experience and proposal of diagnostic criteria. 
========================================================================
Author 
Su WP; Perniciaro C; Rogers RS 3rd; White JW Jr 
Address 
Department of Dermatology, Mayo Clinic, Rochester, Minnesota 55905. 
Source 
Cutis, 54(6):395-9 1994 Dec 
Abstract 
Five cases of chilblain lupus erythematosus were retrospectively reviewed
regarding their clinical, histopathologic, serologic, and
immunofluorescence findings. Ages at onset of chilblain lupus erythematosus
varied from 26 to 73 years, with a female-to-male ratio of 3:2. Since other
entities can be confused with this disorder, we propose the following
diagnostic criteria. The two major criteria are skin lesions in acral
locations induced by exposure to cold or a drop in temperature, and
evidence of lupus erythematosus in the skin lesions by results of
histopathologic examination or direct immunofluorescence study. The three
minor criteria are coexistence of systemic lupus erythematosus or other
skin lesions of discoid lupus erythematosus, response to anti-lupus
erythematosus therapy, and negative results of cryoglobulin and cold
agglutinin studies. We conclude that chilblain lupus erythematosus can be
diagnosed and treated. Discoid lupus erythematosus lesions respond more
quickly to treatment than chilblain lupus erythematosus lesions. Treatment
with antimalarial agents, prednisone, pentoxifylline, or dapsone was of
benefit to our patients. 

========================================================================
3.) [Vernet's syndrome as an early manifestation of systemic erythematous
lupus] 
========================================================================
Author 
Leache Pueyo JJ; Campos del Alamo MA; Gil Para´iso P; Ortiz Garc´ia A 
Address 
Servicio de O.R.L., Hospital Miguel Servet, Z´aragoza. 
Source 
An Otorrinolaringol Ibero Am, 24(2):135-41 1997 
Abstract 
Report of one case of Vernet's syndrome (involving the IX, X and XIth
cranial nerves) in a young woman, as early sing of SEL. The patient
presented the 4 criteria suggested by the American Society in order to
diagnose SEL: arthritis, serositis, positive anti-nuclear antibodies and
anemia. The AA. carry out a study in search of other cases sitting in the
larynx and a perusal about etiopathogenical theories as well. Hinting, for
the clinical picture, of being it due to a localised vasculitis of vasa
nervorum, a treatment with corticoids and pentoxifylline was ordered, being
the outcome, after 3 weeks, the eradication of ENT syndrome. 

========================================================================
4.) [Favorable in vitro effect of pentoxifylline on damaged lymphocyte
migration in arteriosclerosis obliterans and systemic lupus erythematosus
(see comments)] 
========================================================================
Author 
Szekanecz Z; Szab´o G; Sonkoly I; Bed¨o Z; Szegedi G 
Address 
Debreceni Orvostudom´anyi Egyetem III. sz. Belgy´ogy´azati Klinika. 
Source 
Orv Hetil, 134(7):349-53 1993 Feb 14 
Abstract 
Decreased blood cell--e.g. lymphocyte--motility is seen in a number of
vascular and autoimmune diseases. Pentoxifylline (Pf) shows a well-known
therapeutic effect in several vascular alterations by causing the
redistribution of blood cell cytoskeleton and increased microcirculation.
As most literary data on Pf concern red blood cells and granulocytes
authors here investigated the effect of Pf on previously decreased
lymphocyte migration and chemotaxis. Results of in vitro studies suggest
that Pf enhances impaired lymphocyte motility in obliterative
arteriosclerosis and systemic lupus erythematosus and thus may also be
introduced in the treatment of polysystemic autoimmune diseases. 

========================================================================
5.) Effect of pentoxifylline on decreased in vitro mononuclear leucocyte
chemotaxis in vascular and polysystemic autoimmune diseases. 
========================================================================
Author 
Szekanecz Z; Szab´o G; Sonkoly I; Bed¨o Z; Szegedi G 
Address 
3rd Department of Medicine, University Medical School of Debrecen, Hungary. 
Source 
Agents Actions, 33(3-4):254-9 1991 Jul 
Abstract 
Impaired mononuclear leucocyte (MNL) motility can be found both in vascular
and autoimmune diseases. Pentoxifylline (PTX) has a well-known therapeutic
effect in vascular diseases, which is based on the rearrangement of blood
cell cytoskeleton and thus increased microcirculatory flow. Most data on
PTX concern red blood cells and granulocytes so now the effect of PTX on
previously decreased MNL migration and chemotaxis was investigated in
vitro. The results of MNL chemotaxis studies described here suggest that
this drug enhances impaired MNL motility in obliterative atherosclerosis
and systemic lupus erythematosus and thus may also be introduced in the
treatment of certain polysystemic autoimmune diseases with decreased in
vitro MNL chemotaxis. 

========================================================================
6.) Effect of pentoxifylline on the course of systemic Candida albicans
infection in mice. 
========================================================================
Author 
Louie A; Baltch AL; Franke MA; Ritz WJ; Smith RP; Singh JK; Gordon MA 
Address 
Infectious Disease Section, Stratton Veterans Affairs Medical Center,
Albany, New York 12208, USA. 
Source 
J Antimicrob Chemother, 37(5):943-54 1996 May 
Abstract 
Pentoxifylline can decrease the production of tumour necrosis factor alpha
(TNF alpha) by endotoxin-stimulated macrophages and may improve survival in
animals with overwhelming bacterial sepsis. In this study various doses of
pentoxifylline were administered to mice with systemic Candida albicans
infection to determine its effect on serum TNF alpha levels, organ fungal
burden, and host survival. Intraperitoneal injections of pentoxifylline at
20 mg/kg every 8 h did not affect these endpoints. However, fungal counts
were significantly higher in kidneys of animals that received 30 and 60
mg/kg of pentoxifylline every 8 h when compared to controls. Injection of
60 mg/kg of pentoxifylline at 8 h intervals also significantly shortened
mean survival from 5.8 to 3.8 days (P = 0.01). Pentoxifylline did not
affect peripheral WBC counts, serum TNF alpha and interleukin-6 levels, or
the density of neutrophils in tissues. In vitro, pentoxifylline decreased
the production of TNF alpha by C. albicans-stimulated macrophages in a
dose-dependent manner, but only at concentrations greater than 100 mg/L. In
contrast, pentoxifylline suppressed TNF alpha production by
endotoxin-stimulated macrophages at concentrations as low as 10 mg/L. Thus,
higher doses of pentoxifylline are detrimental in systemic C. albicans
infection. However, the detrimental effect is not mediated by alterations
in serum TNF alpha or interleukin-6 levels or the aggregation of
neutrophils in tissues. 

========================================================================
7.) [Current status and trends in treatment of scleroderma] 
========================================================================
Author 
Haustein UF 
Address 
Klinik f¨ur Hautkrankheiten, Universit¨at Leipzig. 
Source 
Hautarzt, 43(7):409-16 1992 Jul 
Abstract 
Owing to the wide variety of symptoms, the long clinical course, the
inadequate knowledge of the points at which therapeutic action is
appropriate and the difficulty of obtaining objective measurements of the
treatment results, therapy for systemic sclerosis has to be planned
individually. Besides basic recommendations (avoidance of noxious
substances, sensible diet, keeping warm, active exercises), physiotherapy
and psychological guidance, the therapy is directed at three pathogenetic
complexes. Among the vasoactive substances the prostacyclins, calcium
channel blockers and angiotensin-converting-enzyme inhibitors (in the case
of complicated renal involvement) are recommended. They inhibit the
thrombocyte hyperaggregation and lead to vasodilatation. The
anti-inflammatory substances prednisolone and azathioprine also exert
immunosuppressant (and cytotoxic) effect. Their use is indicated in
inflammatory, immunologically active forms of systemic sclerosis.
Antifibrotic agents inhibit cross-link formation, prolylhydroxylase,
extrusion of collagen from fibroblasts and, thus, collagen synthesis. In
addition, they favour the degradation of collagen via the activation of
collagenase. Good results have been reported with penicillamine and
penicillin G. Pentoxyphyllin leads to vasodilatation and also inhibits
collagen metabolism. Promising agents and procedures for future use include
cyclosporin A, CD4 antibodies, photopheresis, interferon gamma and factor
XIII. A critical attitude to therapy and a great deal of patience are
necessary to avoid harming the patients, especially as it is often some
months before any effects of the treatment are seen. 

========================================================================
8.) [New properties of trental as an inhibitor of viral activity with a
wide range of activity] 
========================================================================
Author 
Amvros'eva TV; Votiakov VI; Andreeva OT; Vladyko GV; Nikolaeva SN; Orlova
SV; Azarova IA; Zgirovskaia AA 
Source 
Vopr Virusol, 38(5):230-3 1993 Sep-Dec 
Abstract 
Experimental investigations on the spectrum and degree of the expression of
trental antiviral activity were carried out. The investigations were done
in cell cultures and laboratory animals using laboratory strains (including
drug-resistant ones) of 13 viruses, causative agents of human and animal
infections. The drug demonstrated its activity against 8 viruses of 7
families. It was highly active against 5 viruses: herpes simplex virus
(including its acyclovir-resistant strain), vaccinia virus (including its
methisazone-resistant strain), rotavirus and tick-borne encephalitis virus.
As regards other viruses, its activity was less pronounced (hepatitis JA
virus) or low (vesicular stomatitis virus, West Nile virus). It was
concluded that, being a cardiovascular drug, trental was an effective broad
spectrum virus inhibitor. 

========================================================================
9.)[Lymphotropic therapy with trental in the treatment of chronic herpetic
stomatitis] 
========================================================================
Author 
Shumski¨i AV 
Source 
Stomatologiia (Mosk), 76(1):15-7 1997 
Abstract 
Lymphotropic therapy with trental was administered to patients with chronic
herpetic stomatitis. Trental was injected near the mastoid process after
preinjection with lidase (total dose no more than 1 ml on each side, 6
sessions per course). The treatment normalized the immune status, clinical
symptoms regressed sooner than after treatment with an antiviral agent
bonafton, remissions were prolonged, and in 5 out of 18 patients no more
relapses occurred. 

========================================================================
10.) A double-blind, randomized, placebo-controlled, crossover trial of
pentoxifylline for the prevention of chemotherapy-induced oral mucositis. 
========================================================================
Author 
Verdi CJ; Garewal HS; Koenig LM; Vaughn B; Burkhead T 
Address 
Section of Hematology/Oncology, Tucson Veteran's Affairs Medical Center,
Ariz., USA. 
Source 
Oral Surg Oral Med Oral Pathol Oral Radiol Endod, 80(1):36-42 1995 Jul 
Abstract 
Oral mucositis is a frequent side effect of cancer therapy. No effective
method of prophylaxis is currently available. We conducted a randomized,
double-blind, placebo-controlled, crossover trial of pentoxifylline to
evaluate its potential in preventing mucositis in cancer patients receiving
chemotherapy. Ten cancer patients were randomized for treatment with a
15-day course of 400 mg of pentoxifylline given orally four times daily.
Concurrent chemotherapy consisted of bolus cisplatin and infusional
5-fluorouracil. Mucositis was evaluated with the use of the Oral Assessment
Guide developed at the University of Nebraska. Patients completing two
cycles of chemotherapy--one with pentoxifylline and one with placebo--were
evaluated for prophylaxis efficacy. Comparison of the oral assessment
scores of the two cycles with a two-sided Student's t test failed to
demonstrate a cytoprotective effect for pentoxifylline over placebo. We
conclude that pentoxifylline as given in this study is ineffective for
preventing mucositis in patients receiving cisplatin and 5-FU. 

========================================================================
11.) Vasculitis. 
========================================================================

Author 
Smith JG Jr 
Address 
University of South Alabama, Mobile, USA. 
Source 
J Dermatol, 22(11):812-22 1995 Nov 
Abstract 
Many cutaneous and systemic disorders are associated with inflammation and
necrosis of blood vessels. Several classifications of vasculitis have been
used. Internists tend to utilize the classification of Fauci with
modifications such as those by Cupps. Gibson and Ryan, who are
dermatopathologists, have classified vasculitis based on vessel size,
leukocyte type, and presence of granulomas. A more recent classification
has been developed by Jennette, a pathologist, and colleagues. The etiology
of vasculitis is varied; it includes bacteria, viruses, chemicals,
autoimmune disease, malignancy and abnormal exogenous and endogenous
proteins. Leukocytoclastic vasculitis can be experimentally reproduced by
the Arthus phenomenon. IgM and C3 are found in cutaneous blood vessels and
associated with circulating immune complexes. CH50, C3 and C4 may be
reduced in serum. Increased incidence of nasal carriage of staphylococci is
associated with higher relapse rates in Wegener's granulomatosis and toxic
shock syndrome toxin from staphylococci is associated with the Kawasaki
syndrome. Additionally, at least four systemic vasculitic drug reactions
can be confirmed with patch testing. Antineutrophil cytoplasmic antibodies
(ANCA) are found in association with certain systemic vasculitides. These
may be tested with indirect immunofluorescence and enzyme linked
immunosorbent assays (ELISA) with radioimmunoassays. Originally cytoplasmic
ANCA (cANCA) was identified with proteinase 3 as the antigen and
perinuclear ANCA (pANCA) was related to myeloperoxidase. While cANCA is
very specific for proteinase 3, pANCA is associated with a number of
antigens other than myeloperoxidase. pANCA is found with alcohol fixed but
not formalin-fixed neutrophils. cANCA is particularly sensitive and
specific for Wegener's granulomatosis and predicts prognosis and response
to therapy. pANCA is not so specific and is associated with a number of
other vasculitic syndromes. Cutaneous vasculitis is managed primarily with
colchicine, dapsone and prednisone, with recent studies indicating that
there may be a synergistic effect of pentoxifylline with dapsone. Systemic
vasculitis involves treatment with various agents. Recently it has been
observed that co-trimoxazole (trimethoprim/sulfamethoxazole) is useful in
many cases of Wegener's granulomatosis along with other more toxic
chemotherapeutic agents. 

========================================================================
12.) Improvement of acral circulation in a patient with systemic sclerosis
with stellate blocks. 
========================================================================
Author 
Klyscz T; J¨unger M; Meyer H; Rassner G 
Address 
Department of Dermatology, University of T¨ubingen, Germany. 
Source 
Vasa, 27(1):39-42 1998 Feb 
Abstract 
We report on a 77-year-old male patient with systemic sclerosis. He
suffered from secondary Raynaud's phenomenon on the basis of systemic
sclerosis. Medical treatment in the past, including the administration of
calcium-channel blockers, pentoxifylline and intravenous prostaglandin
therapy, was unsuccessful and the clinical situation became worse. In a
final effort stellate blocks were performed over a period of several weeks
and, for the first time, there was lasting clinical benefit. Complaints and
Raynaud's attacks abated significantly, as documented by local cold
exposure tests. Therapeutic benefit from stellate blocks in a patient with
systemic sclerosis is described here for the first time. 

========================================================================
13.) Effects of pentoxifylline on hemodynamics and oxygenation in septic
and nonseptic patients. 
========================================================================
Author 
Bacher A; Mayer N; Klimscha W; Oism¨uller C; Steltzer H; Hammerle A 
Address 
Department of Anesthesiology and General Intensive Care, University of
Vienna, Austria. 
Source 
Crit Care Med, 25(5):795-800 1997 May 
Abstract 
OBJECTIVE: To evaluate the effects of pentoxifylline on hemodynamics and
systemic oxygenation in septic and nonseptic critically ill patients.
DESIGN: Prospective clinical investigation. SETTING: Intensive care unit
(ICU) of a university hospital. PATIENTS: Nineteen critically ill patients
were included in the study 1 to 4 days after their admission to the ICU. A
systemic inflammatory response syndrome was present in 12 patients,
fulfilling at least two of the American College of Chest Physicians/
Society of Critical Care Medicine Consensus Conference criteria. The other
seven patients did not fulfill these criteria and were classified as
nonseptic. INTERVENTIONS: All patients were mechanically ventilated. The
dosage of catecholamines was kept constant during the entire study period
and at least during 15 mins before the start of the study. In both study
groups, pulmonary and radial artery catheters were inserted and 5 mg/kg of
pentoxifylline (diluted in 300 mL of physiologic saline) was intravenously
administered over a period of 180 mins at a rate of 100 mL/hr. MEASUREMENTS
AND MAIN RESULTS: Hemodynamic variables, oxygen transport (DO2), oxygen
uptake (VO2), and oxygen extraction ratio were determined before
pentoxifylline, after 2.5 mg/kg of pentoxifylline, after 5 mg/kg of
pentoxifylline, and 60 mins after the termination of pentoxifylline.
Repeated-measures analysis of variance and Mann-Whitney test were used for
statistical analysis. At baseline, there were significant differences
between the septic and the nonseptic groups in mean pulmonary arterial
pressure (septic: 31 +/- 5 mm Hg; nonseptic: 26 +/- 7 mm Hg, p < .05), and
pulmonary vascular resistance index (PVRI) (septic: 344 +/- 121 dyne.sec/
cm5.m2; nonseptic: 233 +/- 100 dyne.sec/cm5.m2, p < .05). In the septic
group, significant increases in heart rate and cardiac index were observed.
Systemic vascular resistance index and PVRI decreased. No significant
changes in hemodynamic variables occurred in the nonseptic group. In both
groups, DO2 and VO2 increased significantly, while oxygen extraction ratio
remained unchanged. CONCLUSIONS: The administration of pentoxifylline to
septic patients results in a significant improvement in hemodynamic
performance compared with critically ill nonseptic patients. The better
hemodynamic state is accompanied by an increase in DO2 and VO2 with
unchanged oxygen extraction ratio. 

========================================================================
14.) Antiproliferative effect of pentoxifylline on psoriatic and normal
epidermis. In vitro and in vivo studies. 
========================================================================
Author 
Gilhar A; Grossman N; Kahanovicz S; Reuveni H; Cohen S; Eitan A 
Address 
Skin Research Laboratory, Bruce Rappaport Faculty of Medicine,
Technion-Israel Institute of Technology, Haifa, Israel. 
Source 
Acta Derm Venereol, 76(6):437-41 1996 Nov 
Abstract 
Psoriasis is characterized by abnormal cell proliferation, inflammation and
increased biosynthesis of various cytokines. The inhibitory effect of
pentoxifylline on some cell functions has been reported widely. This
property of pentoxifylline prompted an investigation of its possible role
in controlling psoriasis. In the in vitro study normal human keratinocytes
proliferation was determined and formation of cornified envelopes was
assayed following treatment with pentoxifylline. The in vivo experiment
consisted of nude mice grafted with psoriatic or normal skin treated with
tetradecanyl phorbol 13 acetate. At the end of the treatment period, the
grafts were excised and assessed for acanthosis and labelling index. The in
vitro study showed that continuous exposure of normal human keratinocyte
cultures to pentoxifylline resulted in a significant dose-dependent
inhibition of proliferation, and in induction of cornified envelope
formation. The in vivo experiments showed a significant reduction of
epidermal thickness and of labeling index in psoriatic and tetradecanyl
phorbol 13 acetate-treated normal skin, as compared to the initial values. 

========================================================================
15.) Antineoplastic effect of the xanthine derivative Trental. 
========================================================================
Author 
Biddle W; Ambrus CM; Gastpar H; Ambrus JL 
Source 
J Med, 15(5-6):355-66 1984 
Abstract 
The xanthine derivative, Trental (pentoxifylline) was found to inhibit
several human leukemic and lymphoma cell lines in tissue cultures. Optimal
concentrations were less inhibitory for a normal B-lymphocyte cell line
then for the neoplastic cell lines. In fact, small concentrations
stimulated DNA synthesis in the normal cell line. Trental and
beta-interferon appeared to be additive synergists at certain dosages.
Possible mechanisms are discussed. 

========================================================================
16.) Treatment of experimental frostbite with pentoxifylline and aloe vera
cream.
========================================================================
SO - Arch Otolaryngol Head Neck Surg 1995 Jun;121(6):678-80
AU - Miller MB; Koltai PJ
AD - Division of Otolaryngology, Albany (NY) Medical College, USA.
AB - OBJECTIVE: To compare the therapeutic effects of systemic
pentoxifylline and topical aloe vera cream in the treatment of frostbite.
DESIGN: The frostbitten ears of 10 New Zealand white rabbits were assigned
to one of four treatment groups: untreated controls, those treated with
aloe vera cream, those treated with pentoxifylline, and those treated with
aloe vera cream and pentoxifylline. MAIN OUTCOME MEASURES: Tissue survival
was calculated as the percent of total frostbite area that remained after 2
weeks. RESULTS: The control group had a 6% tissue survival. Tissue survival
was notably improved with pentoxifylline (20%), better with aloe vera cream
(24%), and the best with the combination therapy (30%). CONCLUSION:
Pentoxifylline is as effective as aloe vera cream in improving tissue
survival after frostbite injury.

========================================================================
17.) High-dose pentoxifylline in patients with AIDS: inhibition of tumor
necrosis factor production. National Institute of Allergy and Infectious
Diseases AIDS Clinical Trials Group.
========================================================================
SO - J Infect Dis 1995 Jun;171(6):1628-32
AU - Dezube BJ; Lederman MM; Spritzler JG; Chapman B; Korvick JA; Flexner
C; Dando S; Mattiacci MR; Ahlers CM; Zhang L; et al
AD - Department of Medicine, Beth Israel Hospital, Boston, MA 02215, USA.
AB - Tumor necrosis factor-alpha (TNF) may activate human immunodeficiency
virus (HIV), antagonize zidovudine activity, and contribute to AIDS wasting
syndrome. Pentoxifylline decreases TNF production. In cell culture,
pentoxifylline decreases HIV replication and gene expression. Since an AIDS
Clinical Trial Group study suggested that pentoxifylline (400 mg thrice
daily) is safe in AIDS patients and decreases TNF mRNA levels in peripheral
blood mononuclear cells (PBMC), a second cohort received 800 mg thrice
daily for 8 weeks. During treatment, the median decrease in TNF production
by PBMC cultured with 0.1 microgram/mL lipopolysaccharide (LPS) was 40%.
The median change in TNF mRNA was a 34% decrease. Pentoxifylline did not
affect HIV levels as detected by quantitative microculture or serum p24
antigen measurements, nor did it alter zidovudine pharmacokinetics. The
most common toxicity was gastrointestinal. Pentoxifylline at dosages of
less than thrice-daily 800 mg is well tolerated and may decrease TNF mRNA
levels and LPS-induced TNF production.

========================================================================
18.) Pentoxifylline as a supportive agent in the treatment of cerebral
malaria in children.
========================================================================
SO - J Infect Dis 1995 May;171(5):1317-22
AU - Di Perri G; Di Perri IG; Monteiro GB; Bonora S; Hennig C; Cassatella
M; Micciolo R; Vento S; Dusi S; Bassetti D; et al
AD - Institute of Immunology, University of Verona, Italy.
AB - In an open, randomized, controlled therapeutic trial, 56 children
with cerebral malaria (CM) were randomly assigned to receive standard
quinine regimen with or without pentoxifylline (10 mg/kg/day by continuous
intravenous infusion). Pentoxifylline exerted an inhibitory effect on the
synthesis of tumor necrosis factor (TNF), a possible mediator of CM. The 26
children who received pentoxifylline had significantly shorter comas than
controls (median, 6 vs. 46 h; P .001) Pentoxifylline recipients showed a
trend toward a lower mortality, with a borderline significant difference (P
= .055). The better outcome in the pentoxifylline group was associated with
a decline in TNF serum levels on the third day of treatment in a few
subjects that was not seen in controls. While alternative or concurrent
mechanisms of action may be of some relevance, larger double-blind trials
are needed to determine whether pentoxifylline has a therapeutic role in CM.

========================================================================
19.) Pentoxifylline inhibits tumor necrosis factor-alpha (TNF
alpha)-induced T-lymphoma cell adhesion to endothelioma cells.
========================================================================
SO - J Invest Dermatol 1995 May;104(5):824-8
AU - Weiss JM; Vanscheidt W; Pilarski KA; Weyl A; Peschen M; Schopf E;
Vestweber D; Simon JC
AD - Department of Dermatology, University of Freiburg, Germany.
AB - Pentoxifylline, a methylxanthine derivative, has been shown to
inhibit T-cell-mediated cutaneous immune response by yet ill-understood
mechanisms. Because cell adhesion to endothelial cells is a critical step
in the initiation of such immune responses, we analyzed whether
pentoxifylline would affect this process. To address this issue, adhesion
of mouse T-lymphoma cells (TK-1) to mouse endothelioma cells (eEnd.2),
either untreated or stimulated with tumor necrosis factor-alpha (TNF
alpha), was studied. Pentoxifylline reduced the ability of endothelioma
cells stimulated with different concentrations of TNF alpha, but not of
untreated endothelioma cells, to bind T-lymphoma cells in dose-dependent
(10(-5)-10(-3) M) fashion. Selective incubation of either endothelioma
cells or T-lymphoma cells revealed that pentoxifylline acted exclusively on
the endothelioma cells, even when added after TNF alpha stimulation. We
questioned whether pentoxifylline suppressed T-lymphoma cell/endothelioma
cell interactions by interfering with adhesion molecules expressed by
either cell. However, as determined by flow cytometry, pentoxifylline did
not alter TNF alpha-induced upregulation of intercellular adhesion
molecule-1 or vascular cellular adhesion molecule-1 on endothelioma cells
nor did it affect constitutive CD11a, CD18, or alpha 4-integrin expression
on T-lymphoma cells, suggesting that rather than affecting quantitative
expression of these adhesion molecules, pentoxifylline might modulate their
avidity. We conclude that pentoxifylline in therapeutically achievable
concentrations is a potent inhibitor of TNF alpha-induced T-lymphoma cell
adhesion to endothelioma cells. This finding may account, at least in part,
for the recently discovered anti-inflammatory action of pentoxifylline.

========================================================================
20.) Pharmacotherapy of Raynaud's phenomenon. 
========================================================================
Author 
Belch JJ; Ho M 
Address 
Department of Vascular Medicine, Ninewells Hospital and Medical School, Dundee, Scotland. [email protected] 
Source 
Drugs, 52(5):682-95 1996 Nov 
Abstract 
Primary Raynaud's phenomenon is common, particularly in younger women, and may be familial. Vasospasm is not confined to the digits and may involve, for example, the tongue and nose, and also visceral organs like the heart, oesophagus or lung and cerebral circulation. Symptoms tend to be milder in primary compared with secondary Raynaud's phenomenon, which is associated with other disorders such as the connective tissue diseases. Indeed, the severity of symptoms often acts as the predictor for the much later onset of the associated systemic disease. Occupational Raynaud's phenomenon is related to the use of vibrating instruments, and a significant proportion of patients may be cured by an early change in job. In those over 60 years of age, Raynaud's phenomenon is commonly a result of atherosclerotic obstructive arterial disease, and screening for and treatment of the risk factors is appropriate. The best-studied mechanisms in Raynaud's phenomenon involve the blood and vascular endothelium. Microcirculatory flow may be impeded by activated platelet clumps, rigid red and white blood cells and damaged endothelium. These platelet clumps, white blood cells and damaged endothelium also release vasoactive/vasoconstrictive compounds which may additionally trigger the clotting cascade and thrombosis. Initial management for mild disease should focus on support and advice regarding avoidance of known precipitating factors, including vasospastic drugs. Cold protection with warming agents, 'Abel' shoes and also electrically heated gloves and socks is effective, but may be too cumbersome and inconvenient for some patients. Simple vasodilators like naftidrofuryl, inositol nicotinate and possibly pentoxifylline (oxpentifylline) are useful in mild disease, with adverse effects like headache and flushing being less problematic. The 'gold standard' of Raynaud's phenomenon treatment is nifedipine, a calcium channel antagonist/blocker. Full dosage, however, can be limited by ankle swelling, headache and flushing, but adverse effects may be reduced by using the 'retard' or long-acting preparations. Adverse effects are also reduced with the newer calcium channel antagonists like diltiazem but at the expense of efficacy. Useful, enhanced benefit is also achieved by combination therapy with vasodilators. Newer treatments include the prostaglandin analogues which are effective but disadvantaged by their parenteral route of administration, and lack of licence in some countries. Oral preparations are, however, being studied and are in the pipeline. Essential fatty acid supplementation is mildly effective, while ketanserin and calcitonin gene-related peptide both look promising. Lumbar sympathectomy retains its important role in the treatment of Raynaud's phenomenon involving the lower limbs. Satisfactory symptomatic relief is now possible for many patients with Raynaud's phenomenon and this should certainly be the aim for all patients seeking medical help. 

========================================================================
21.) Severe idiopathic recurrent aphthous stomatitis: treatment with
pentoxifylline [letter]
SO - Acta Derm Venereol 1995 Mar;75(2):157
AU - Wahba-Yahav AV
========================================================================

========================================================================
22.) Pentoxifylline for Sweet's syndrome [letter; comment]
CM - Comment on: J Am Acad Dermatol 1994 Apr; 30(4):603-21; Comment on: J
Am Acad Dermatol 1994 Apr; 30(4):639-42
SO - J Am Acad Dermatol 1995 Mar;32(3):533-5
AU - Cohen PR; Holder WR
========================================================================

========================================================================
23.) Urticarial vasculitis syndrome effectively treated with dapsone and
pentoxifylline.
========================================================================
SO - Acta Derm Venereol 1995 Jan;75(1):54-6
AU - Nurnberg W; Grabbe J; Czarnetzki BM
AD - Department of Dermatology, University Clinics Rudolf Virchow,
FU-Berlin, Germany.
AB - Urticarial vasculitis is difficult to treat. We report here on a
40-year-old woman with a 16-year history of idiopathic hypocomplementemic
urticarial vasculitis syndrome. Her disease had been resistant to treatment
with H1- and H2-blockers, indomethacin, dapsone and interferon alpha but
responded to 25 mg/day prednisolone. Monotherapy with pentoxifylline was
also of only minor benefit. Using a combination of dapsone (100 mg/day) and
pentoxifylline (1,200 mg/day), we observed a gradual improvement resulting
in a complete remission within 8 weeks. Complete control of symptoms could
be maintained for 18 months without any serious side-effects. This type of
treatment may be of benefit in other therapy-resistant cases of
hypocomplementemic urticarial vasculitis syndrome, particularly in view of
its excellent tolerance.

========================================================================
24.) Schamberg's purpura: association with persistent hepatitis B surface
antigenemia and treatment with pentoxifylline.
========================================================================
SO - Cutis 1994 Sep;54(3):205-6
AU - Wahba-Yahav AV
AB - A 54-year-old man experienced an extensive asymptomatic purpuric
eruption on both his legs consistent with Schamberg's purpura. Three months
before, he had had an episode of acute viral hepatitis. Nine months later,
the purpura was unchanged despite administration of a topical
corticosteroid. Results of serologic evaluation revealed hepatitis B
surface antigen. The patient was treated orally with pentoxifylline, 400 mg
three times daily. After one month of therapy, the purpuric elements of his
eruption had disappeared, and after two additional months most of the
pigmentation had also faded.

========================================================================
25.) The use of pentoxifylline in the treatment of systemic sclerosis and
lipodermatosclerosis: a unifying hypothesis? [letter; comment]
CM - Comment on: J Am Acad Dermatol 1993 Apr; 28(4):525-47; Comment on: J
Am Acad Dermatol 1993 Apr; 28(4):623-7
SO - J Am Acad Dermatol 1994 Jul;31(1):135-6
AU - Goldman MP
========================================================================

========================================================================
26.) Pentoxifylline [see comments]
========================================================================
CM - Comment in: J Am Acad Dermatol 1994 Apr; 30(4):639-42; Comment in: J
Am Acad Dermatol 1995 Mar; 32(3):533-5; Comment in: J Am Acad Dermatol 1995
Jul; 33(1):143
SO - J Am Acad Dermatol 1994 Apr;30(4):603-21
AU - Samlaska CP; Winfield EA
AD - Dermatology Service, Tripler Army Medical Center, Honolulu, Hawaii.
AB - Pentoxifylline (oxpentifylline) is a methylxanthine derivative with
potent hemorrheologic properties. In the United States it is marketed for
the treatment of intermittent claudication. Human and animal studies have
shown that pentoxifylline therapy results in a variety of physiological
changes at the cellular level, which may be important in treating a diverse
group of human afflictions. Immune modulation includes increased leukocyte
deformability and chemotaxis, decreased endothelial leukocyte adhesion,
decreased neutrophil degranulation and release of superoxides, decreased
production of monocyte-derived tumor necrosis factor, decreased leukocyte
responsiveness to interleukin 1 and tumor necrosis factor, inhibition of T
and B lymphocyte activation, and decreased natural killer cell activity.
Hypercoagulable states improve through decreased platelet aggregation and
adhesion, increased plasminogen activator, increased plasmin, increased
antithrombin III, decreased fibrinogen, decreased alpha 2-antiplasmin,
decreased alpha 1-antitrypsin, and decreased alpha 2-macroglobulin. Wound
healing and connective tissue disorders may respond to an increase in
fibroblast collagenases and decreased collagen, fibronectin, and
glycosaminoglycan production. Fibroblast responsiveness to tumor necrosis
factor is also diminished. Potential medical uses of pentoxifylline are
reviewed.

========================================================================
27.) Toxic epidermal necrolysis. Treatment with pentoxifylline [letter]
SO - Br J Dermatol 1994 May;130(5):688-9
AU - Redondo P; Ruiz de Erenchun F; Iglesias ME; Monedero P; Quintanilla E
========================================================================
========================================================================
28.) Pentoxifylline for the treatment of infection with human
immunodeficiency virus.
========================================================================
SO - Clin Infect Dis 1994 Mar;18(3):285-7
AU - Dezube BJ
AD - Department of Medicine, Beth Israel Hospital, Boston, Massachusetts
02215.
AB - Cytokine dysregulation in human immunodeficiency virus type 1 (HIV-1)
infection has been documented in numerous studies and has been cited as an
important component in the pathogenesis of this retroviral infection.
Pharmacological modification of cytokine dysregulation, therefore, has been
suggested as a therapeutic modality for HIV-1 infection. Dr. Dezube of Beth
Israel Hospital (Boston) concisely reviews the state of our knowledge
regarding the effects of pentoxifylline on expression of tumor necrosis
factor-alpha, a cytokine known to influence HIV-1 replication and to play a
possible role in the clinical manifestations of advanced infection with
this virus. Pentoxifylline, a trisubstituted xanthine derivative, has been
used to decrease blood viscosity and is reasonably well tolerated by most
recipients of the drug. Results of preliminary studies, many of which were
conducted by Dr. Dezube, suggest that use of this agent in combination with
antiretroviral compounds may prove useful in the treatment of patients with
HIV-1 infection.

========================================================================
29.) Inhibition of collagen lattice contraction by pentoxifylline and
interferon-alpha, -beta, and -gamma.
========================================================================
SO - J Invest Dermatol 1994 Jan;102(1):118-21
AU - Dans MJ; Isseroff R
AD - Department of Dermatology, University of California, Davis 95616.
AB - The ability to control wound contraction is important in preventing
disfiguring scarring in burn and trauma patients. Fibroblasts within the
wound generate the mechanical forces that cause this contraction, and their
interactions with various extracellular matrix components are thought to
regulate this process. Because pentoxifylline and the interferons are
believed to moderate fibroblast production of such matrix components, we
assessed the effects of these agents on wound contraction in vitro, using a
model wherein dermal fibroblasts are incorporated into a collagen lattice.
Pentoxifylline and interferon-alpha, -beta, and -gamma inhibited lattice
contraction in a dose-dependent manner and showed no effect on cell number
or cell viability. These results suggest that pentoxifylline and the
interferons may retard wound contraction in vivo and thus reduce scarring
associated with severely contracted wounds. Further study is needed to
determine the mechanism of action of these agents on the collagen lattice
model.

========================================================================
30.) Long-term pretreatment with pentoxifylline increases random skin flap
survival.
========================================================================
SO - Arch Otolaryngol Head Neck Surg 1994 Jan;120(1):65-71
AU - Williams PB; Hankins DB; Layton CT; Phan T; Pratt MF
AD - Department of Pharmacology, Eastern Virginia Medical School, Norfolk.
AB - Optimizing survival of random skin flaps is essential to ensure
successful rehabilitation of patients in whom flap reconstruction is
necessary. This study tested the hypothesis that pentoxifylline improves
random skin flap survival in porcine dorsal flank flaps when administered
for at least 2 weeks preoperatively. Specific aims included establishing
the mechanisms by which pentoxifylline enhanced survival. Treatment with
pentoxifylline (25 mg/kg per day) for 14 days before surgery and for 7 days
thereafter significantly increased mean flap survival to 73.2% +/- 4.5%
compared with mean flap survival of 49.6% +/- 2.2% in untreated pigs.
Increased flap survival was associated with a parallel increase in red
blood cell flexibility. Plasma concentration of pentoxifylline ranged from
92.9 to 122.7 ng/mL but did not correlate directly with the improved flap
survival. Likewise, pentoxifylline decreased platelet aggregation; there
was a trend toward increased flap survival in those pigs with the least
amount of aggregation. Thus, pentoxifylline improves random flap survival
but only after a sufficient pretreatment period of at least 14 days.

========================================================================
31.) Angiolymphoid hyperplasia with eosinophilia may respond to
pentoxifylline.
========================================================================
SO - J Am Acad Dermatol 1994 Jul;31(1):117-8
AU - Person JR
AD - Fallon Clinic, Worcester, Massachusetts.

========================================================================
32.) Chronic balanitis with palisading granuloma: an atypical genital
localization of necrobiosis lipoidica responsive to pentoxifylline.
========================================================================
SO - Dermatology 1994;188(3):222-5
AU - Espana A; Sanchez-Yus E; Serna MJ; Redondo P; Robledo A; Quintanilla E
AD - Department of Dermatology, University Clinic of Navarra, Pamplona,
Spain.
AB - We report a case of necrobiosis lipoidica located on the glans penis
of a patient without diabetes mellitus. Both clinical and histologic
features favor the diagnosis of necrobiosis lipoidica, even though the
location is unusual. Treatment with pentoxifylline was effective. The
differential diagnosis is discussed.

========================================================================
33.) Pentoxifylline for ischemic pain in pseudoxanthoma elasticum.
========================================================================
SO - West J Med 1993 Dec;159(6):689-90
AU - Takaro TK; Coodley GO
AD - Division of Internal Medicine, Oregon Health Sciences University
School of Medicine, Portland 97201-3098.

========================================================================
34.) Pentoxifylline suppresses irritant and contact hypersensitivity
reactions.
========================================================================
SO - J Invest Dermatol 1993 Oct;101(4):549-52
AU - Schwarz A; Krone C; Trautinger F; Aragane Y; Neuner P; Luger TA;
Schwarz T
AD - Department of Dermatology, University Munster, Germany.
AB - Pharmacologic suppression of the effector phase of contact
hypersensitivity appears to have major relevance with regard to treatment
of type IV reactions like contact dermatitis. Recently, tumor necrosis
factor alpha has been shown to be a critical mediator in hapten-induced
irritant and contact hypersensitivity reactions, thus offering new
possibilities, for therapeutic intervention. Pentoxifylline, a
methylxanthine derivative used in the treatment of vascular disorders,
currently has been found to suppress the production of tumor necrosis
factor alpha by human and murine leukocytes. Therefore, the effect of
pentoxifylline on the elicitation phase of contact hypersensitivity was
studied. Intraperitoneal injection of pentoxifylline into sensitized Balb/c
and C3H/HeN mice before application of the challenging hapten dose resulted
in a significant reduction of the outcome of the contact hypersensitivity
reaction. The suppressive effect of pentoxifylline was dose dependent and
maximally pronounced upon injection 3 h before hapten application. In
contrast to the effector phase of contact hypersensitivity, induction of
contact hypersensitivity was not affected by pentoxifylline when injected
into naive mice before performance of sensitization. In addition, irritant
dermatitis induced by 1% croton oil or 5% benzalkonium chloride was
suppressed by pentoxifylline as well. These data suggest a potential
pharmacologic intervention, with pentoxifylline as a means to treat contact
dermatitis.

========================================================================
35.) Ulcerating necrobiosis lipoidica effectively treated with pentoxifylline.
========================================================================
SO - Clin Exp Dermatol 1993 Jan;18(1):78-9
AU - Noz KC; Korstanje MJ; Vermeer BJ
AD - Department of Dermatology, Academic Hospital Leiden, The Netherlands.
AB - A 30-year-old man had suffered from persistent ulceration within an
area of necrobiosis lipoidica diabeticorum for 13 months. The ulcerating
necrobiosis lipoidica was resistant to topical therapy and oral therapy
with acetylsalicylic acid. However, the ulcers healed completely within 8
weeks of administration of 400 mg pentoxifylline twice daily.

========================================================================
36.) Generalised granuloma annulare successfully treated with pentoxifylline.
========================================================================
SO - Australas J Dermatol 1993;34(3):103-8
AU - Rubel DM; Wood G; Rosen R; Jopp-McKay A
AD - Department of Dermatology, Prince of Wales Hospital, Randwick, NSW.
AB - Generalised granuloma annulare (GA) is a chronic disease of unknown
aetiology and is recalcitrant to many treatment regimes. Some investigators
have suggested that an immune medicated vasculitis may be involved in the
pathogenesis of GA. We describe a patient with a ten year history of
generalised GA, who showed dramatic clearing of the majority of papules
after four weeks of treatment with pentoxifylline. This drug has shown
promising results in the treatment of many dermatologic disorders including
necrobiosis lipoidica diabeticorum, leukocytoclastic vasculitis and
Raynaud's phenomenon. Pentoxifylline is thought to reduce blood viscosity
via effects on all major blood components, and its clinical effectiveness
in generalised GA lends support to a model of immune-medicated vasculitis
in the pathogenesis of this disorder. Thus, pentoxifylline offers a
well-tolerated and effective alternative to the treatment options available
for patients with granuloma annulare.

========================================================================
37.) Intractable chronic furunculosis: prevention of recurrences with
pentoxifylline.
========================================================================
SO - Acta Derm Venereol 1992 Nov;72(6):461-2
AU - Wahba-Yahav AV
AB - A 60-year-old HIV-negative man with known noninsulin-dependent
diabetes mellitus and glucose 6-phosphate-dehydrogenase deficiency anemia
suffered from chronic recurrent furunculosis since the age of 30. In recent
years, his condition had become increasingly severe and the recurrences
increasingly frequent. Different measures including continuous therapy with
large doses of systemic antibiotics for a period of 6 months failed to
prevent the recurrences. Oral treatment with pentoxifylline 400 mg t.i.d.
was prescribed, and 2 months later the patient experienced a dramatic and
complete remission of his furunculosis. Six months later he was still
totally free of lesions while continuing to take the same medication.
Pentoxifylline may provide a new and effective approach to the previously
difficult and often disappointing problem of the management of patients
with chronic recurrent furunculosis.

========================================================================
38.) Successful treatment of Kasabach-Merritt syndrome with pentoxifylline.
SO - J Am Acad Dermatol 1991 Nov;25(5 Pt 1):854-5
AU - de Prost Y; Teillac D; Bodemer C; Enjolras O; Nihoul-Fekete C; de
Prost D
AD - Department of Dermatology, Hopital Necker Enfants Malades, Paris,
France.
========================================================================

========================================================================
39.) Pentoxifylline inhibits the proliferation of human fibroblasts derived
from keloid, scleroderma and morphoea skin and their production of
collagen, glycosaminoglycans and fibronectin.
========================================================================
SO - Br J Dermatol 1990 Sep;123(3):339-46
AU - Berman B; Duncan MR
AD - Department of Dermatology, University of California, Davis School of
Medicine.
AB - Pentoxifylline, an analogue of the methylxanthine theobromine,
inhibits the proliferation and certain biosynthetic activities of
fibroblasts derived from normal human skin. Fibroblasts from the skin of
patients with keloids, scleroderma and morphoea were cultured in vitro in
the presence and absence of pentoxifylline (100-1000 micrograms/ml) to
determine whether it inhibits fibroblast proliferation and the production
of collagen, glycosaminoglycans (GAG), fibronectin and collagenase
activity. The exposure of subconfluent fibroblast cultures to
pentoxifylline resulted in non-lethal, dose-dependent reductions in
serum-driven fibroblast proliferation, with 1000 micrograms/ml
pentoxifylline virtually negating the proliferative effect of serum on the
cells. The fibroblasts assayed as confluent cultures produced reduced
amounts, by up to 95%, of collagen and GAG, dependent on the concentration
of pentoxifylline, both in the presence and absence of serum.
Pentoxifylline similarly inhibited the fibronectin production by keloid and
scleroderma fibroblasts, but had no effect on collagenase activity.

========================================================================
40.) Effects and limitations of pentoxifylline therapy in various stages of
peripheral vascular disease of the lower extremity.
========================================================================
SO - Am J Surg 1990 Sep;160(3):266-70
AU - Abu Rahma AF; Woodruff BA
AD - Department of Surgery, West Virginia University Health Sciences
Center, Charleston.
AB - One hundred one patients with peripheral vascular disease of the
lower extremity were entered into a study of the efficacy of oral
pentoxifylline to determine if the response to therapy varied with the
severity of disease. Ninety-three patients were evaluated before and after
8 weeks of therapy with pentoxifylline, while 8 did not complete the entire
course due to adverse drug reactions. Resting and post-stress ankle/arm
Doppler indices (AAIs) were measured and, in those patients who could walk
on a treadmill, treadmill walking distances were measured. Patients were
classified according to pretreatment clinical and treadmill measurements
and according to pretreatment resting AAIs. Resting and post-stress AAIs,
as well as treadmill walking distances, increased in patients with
moderately severe claudication. Patients in this group responded better to
therapy than did patients with rest pain or ischemic ulcers, severe
claudication, or mild claudication. Patients with a pretreatment resting
AAI greater than or equal to 0.5 responded better than those with an AAI
less than 0.5. Only 5% of patients reported satisfaction with the results
of treatment. These results support the findings that pentoxifylline may be
useful only in selected patients with moderately severe peripheral vascular
disease of the lower extremity and may not be useful in those with severe
or mild disease.

========================================================================
41.) Enhancement of the treatment of experimental candidiasis with vascular
decongestants.
========================================================================
SO - J Infect Dis 1990 Jul;162(1):211-4
AU - Luke DR; Wasan KM; McQueen TJ; Lopez-Berestein G
AD - Department of Pharmaceutics, University of Houston.
AB - The mechanism of amphotericin B (AmB) nephrotoxicity may be related
to changes in vascular flow within the kidney, resulting in significant
decreases in glomerular filtration rate and tubular integrity. The toxic
and antifungal effects of AmB with and without the vascular decongestants
pentoxifylline (PTX) and a methylxanthine analog, HWA-138, were compared in
the murine model of candidiasis. At 48 h after inoculation with Candida
albicans, half of the rats received a single intravenous 0.8 mg/kg dose of
AmB whereas the others were administered sterile water. After 1 h, rats
were randomized to receive three doses of 45 mg/kg PTX intraperitoneally, 5
mg/kg HWA-138 intravenously, or saline every 12 h. Renal function and
Candida cell counts were estimated 24 h after AmB administration. Mean
inulin clearances were significantly greater in rats coadministered AmB and
PTX or HWA-138 than in AmB controls. Candida counts in kidneys of rats
administered HWA-138 were similar independent of AmB therapy and markedly
reduced compared with other groups. Whereas both vascular decongestants
prevented drug-associated renal toxicity, the coadministration of AmB with
HWA-138 resulted in a profound antifungal effect.

========================================================================
42.) Treatment of sickle cell leg ulcers with pentoxifylline.
========================================================================
SO - Int J Dermatol 1990 Jun;29(5):375-6
AU - Frost ML; Treadwell P
AD - Department of Dermatology, Indiana University Medical Center,
Indianapolis.
AB - A 58-year-old black man with leg ulcers of 43 years duration
responded to pentoxifylline 400 mg tid in 8 months. The ability of
pentoxifylline to increase erythrocyte flexibility and decrease blood
viscosity was the basis for our use of this agent. Oral pentoxifylline may
be a useful adjunct in healing sickle cell leg ulcers and preventing their
recurrence.

========================================================================
43.) Oxpentifylline treatment of venous ulcers of the leg [see comments]
========================================================================
CM - Comment in: BMJ 1990 Jun 9; 300(6738):1528; Comment in: BMJ 1990 Jun
30; 300(6741):1725
SO - BMJ 1990 Apr 14;300(6730):972-5
AU - Colgan MP; Dormandy JA; Jones PW; Schraibman IG; Shanik DG; Young RA
AD - Vascular Laboratories, St James's Hospital, Dublin.
AB - OBJECTIVE--To determine the effect of oxpentifylline on the healing
of venous ulcers of the leg. DESIGN--Double blind, randomised, prospective,
placebo controlled, parallel group study. SETTING--Four outpatient clinics
treating leg ulcers in England and the Republic of Ireland. PATIENTS--80
Consecutive patients with clinical evidence of venous ulceration of the leg
in whom appreciable arterial disease was excluded by the ratio of ankle to
brachial systolic pressure being greater than 0.8. INTERVENTIONS--All
patients received either oxpentifylline 400 mg three times a day by mouth
or a matching placebo for six months (or until their reference ulcer healed
if this occurred sooner) in addition to a locally standardised method of
compression bandaging. MAIN OUTCOME MEASURES--The primary end point was
complete healing of the reference ulcer within six months. The secondary
end point was the change in the area of the ulcer over the six month
observation period. RESULTS--Complete healing of the reference ulcer
occurred in 23 of the 38 patients treated with oxpentifylline and in 12 of
the 42 patients treated with a placebo. Life table analysis showed that the
proportion of ulcers healed at six months was 64% in the group treated with
oxpentifylline compared with 34% in the group treated with a placebo (log
rank test chi 2 = 4.78, p = 0.03), which was significant (odds ratio =
1.81, 95% confidence interval 1.20 to 2.71). CONCLUSION--Oxpentifylline
used in conjunction with compression bandaging improves the healing of
venous ulcers of the leg.

========================================================================
44.) Oxpentifylline in endotoxaemia [see comments]
========================================================================
CM - Comment in: Lancet 1990 Mar 3; 335(8688):543
SO - Lancet 1989 Dec 23-30;2(8678-8679):1474-7
AU - Zabel P; Wolter DT; Schonharting MM; Schade UF
AD - Forschungsinstitut Borstel, Medizinische Klinik, Federal Republic of
Germany.
AB - Oxpentifylline (pentoxifylline), which is known to have
pharmacological effects in animal models of respiratory distress syndrome,
multiorgan failure, and shock, was tested in human beings after injection
of endotoxin. Of ten healthy volunteers, nine met the inclusion criterion
of a rise in body temperature of at least 1.0 degrees C after 100 ng
endotoxin (Salmonella abortus equi) as a bolus injection. Serum levels of
tumour necrosis factor alpha (TNF) and interleukin-6 (IL-6) were both
significantly higher than baseline levels 2 h and 3 h after endotoxin
injection. 3 weeks later the nine volunteers were again injected with 100
ng endotoxin and oxpentifylline (500 mg over 4 h) was also infused. There
was no rise in TNF levels, though IL-6 levels rose in parallel with body
temperature. These data suggest that oxpentifylline blocks the
endotoxin-induced synthesis of TNF in man and, therefore, could possibly
have beneficial effects in clinical endotoxaemia.

========================================================================
45.) Pentoxifylline inhibits normal human dermal fibroblast in vitro
proliferation, collagen, glycosaminoglycan, and fibronectin production, and
increases collagenase activity.
========================================================================
SO - J Invest Dermatol 1989 Apr;92(4):605-10
AU - Berman B; Duncan MR
AD - Department of Dermatology, University of California, Davis School of
Medicine.
AB - Fibroblasts from normal human adult skin were cultured in vitro in
the presence and absence of different concentrations of pentoxifylline or a
pentoxifylline analog, A81-3138 (10(-1)-10(3) micrograms/ml). Similar
concentration dependent reductions in normal proliferation of fibroblasts
in fetal calf serum-driven subconfluent cultures were detected following
treatment with pentoxifylline or A81-3138. Fibroblasts assayed as confluent
cultures produced sub-normal amounts of collagen, glycosaminoglycans
(GAGs), and fibronectin in a fashion dependent upon the concentration of
pentoxifylline. In contrast, fibroblasts exposed to pentoxifylline
elaborated double the collagenase activity produced by normal, untreated
fibroblasts. The reduced proliferation and reduced synthetic activities
were not due to a lethal toxic effect on fibroblasts by pentoxifylline and
A81-3138, nor was the reduction in collagen synthesis simply due to an
inability to secrete newly synthesized intracellular collagen. Unlike
pentoxifylline-induced inhibition of collagen and fibronectin production,
which was detected only in cultures supplemented with serum, pentoxifylline
inhibits, to a similar degree, both constitutive and serum-driven
production of GAGs. The addition of IL1 beta (2.5 and 10.0 U/ml) to
serum-driven fibroblast cultures resulted in greater proliferation, which
was inhibitable by the presence of pentoxifylline and A81-3138 as
anti-fibrotic agents in certain disorders of fibrosis.

========================================================================
46.) Pentoxifylline increases extremity blood flow in diabetic
atherosclerotic patients.
========================================================================
SO - Arch Surg 1989 Apr;124(4):434-7
AU - Schwartz RW; Logan NM; Johnson PJ; Strodel WE; Fine JG; Kazmers A;
Hyde GL
AD - Department of Surgery, University of Kentucky, Chandler Medical
Center, Lexington 40536-0084.
AB - Pentoxifylline, a new trisubstituted methylxanthine derivative known
for its hemorrheologic action, has been shown to improve exercise tolerance
in atherosclerotic patients. We examined the responses of diabetic
atherosclerotic patients to pentoxifylline administration, measured by
Doppler waveform analysis and exercise tolerance. Standard exercise
tolerance and Doppler waveform analytic studies of the lower extremity,
specifically the right dorsalis pedis artery, were performed before and
after three months of pentoxifylline administration (400 mg three times a
day). The study group comprised ten subjects (six men and four women) with
a mean (+/- SD) age of 60 +/- 3.3 years. Data were analyzed using a paired
Student t test. All ten subjects showed a significant increase in exercise
tolerance after pentoxifylline treatment. Eight of ten subjects
demonstrated a significant increase in right dorsalis pedis arterial flow.

========================================================================
47.) Treatment of peripheral gangrene due to systemic sclerosis with
intravenous pentoxifylline.
========================================================================
SO - Clin Exp Dermatol 1989 Mar;14(2):161-2
AU - Goodfield MJ; Rowell NR
AB - Vascular problems are very common in systemic sclerosis with 95% of
patients suffering with Raynaud's phenomenon at some stage in their
illness. Acute ischaemic lesions are much less common, but when they occur
are a serious complication, and are often difficult to treat. Many drugs
have been used in this situation, including both oral and intravenous
vaso-dilators and low molecular weight dextran, each with varying degrees
of success. The phospho-diesterase inhibitor, pentoxifylline, is reported
to be useful in peripheral vascular disease, and in Raynaud's phenomenon,
and the intravenous form is indicated for acute peripheral ischaemia,
though its use in the context of connective tissue disease has not so far
been reported. We now report the use of intravenous pentoxifylline in two
patients with acute peripheral gangrene due to systemic sclerosis.

========================================================================
48.) Therapy of livedo vasculitis with pentoxifylline.
========================================================================
SO - Cutis 1988 Nov;42(5):448-53
AU - Ely H; Bard JW
AD - University of California, Davis.
AB - Two patients with idiopathic livedo vasculitis responded favorably to
therapy with pentoxifylline. One patient had responded to fibrinolytic
therapy with phenformin and ethylestrenol before phenformin was taken off
the market. Pentoxifylline (Trental) has multiple mechanisms of action,
including stimulation of prostacyclin synthesis, decreased aggregation of
platelets, increased deformability of red blood cells, increased mobility
of neutrophils, and increased fibrinolysis. All of these factors may
contribute to its successful use in the treatment of idiopathic livedo
vasculitis.

========================================================================
49.) Pentoxifylline therapy in dermatology. A review of localized 
hyperviscosity and its effects on the skin.
========================================================================
SO - Dermatol Clin 1988 Oct;6(4):585-608
AU - Ely H
AD - Department of Dermatology, University of California, Davis.
AB - The conditions treatable with PTX are limited only by our
understanding of disease pathogenesis. Surely the reader will think of new
applications. I would caution at this point that PTX is not the primary
treatment for any cutaneous condition but may be a valuable therapeutic
adjunct.

========================================================================
50.) Augmentation of skin flap survival by parenteral pentoxifylline.
========================================================================
SO - Br J Plast Surg 1988 Sep;41(5):515-20
AU - Roth AG; Briggs PC; Jones EW; Heckler FR
AD - Allegheny-Singer Research Institute, University of Pittsburgh,
Pennsylvania.
AB - One prime factor implicated in flap necrosis is diminished blood
flow. A known corollary of morbid ischaemia is an energy-dependent
reduction in red blood cell deformability associated with an increase in
whole blood viscosity. The newly available drug pentoxifylline is alleged
to improve this red cell membrane defect in the low flow state, thereby
improving the rheologic characteristics of blood. We studied its effect in
a flap model with an ischaemic component and also measured changes in blood
viscosity. A caudally-based dorsal flap in a rat model was used. Control
(saline-treated) animals exhibited 74.8 +/- 9.8% flap survival. Three
groups of animals were treated at different times with pentoxifylline with
respect to date of surgery; all groups showed a statistically significant
increase in flap survival compared to controls, ranging from 92.3 to 94.3%
(p less than .01). Simultaneous viscometric measurements with a cone-plate
viscometer were performed. The observed increase in flap survival did not,
as suggested by other investigators, correlate dependably with viscosity
reduction. Reasons for this are discussed.

========================================================================
51.) Synergistic effects of pentoxifylline and hyperbaric oxygen on skin
flaps.
========================================================================
SO - Arch Otolaryngol Head Neck Surg 1988 Sep;114(9):977-81
AU - Nemiroff PM
AD - Department of Surgery, Southern Illinois University School of
Medicine, Springfield.
AB - This study investigated the effects of pentoxifylline and hyperbaric
oxygen (HBO) on experimental skin flaps in rats under four conditions.
Sixty animals were randomly divided into one of four groups: (1) a control
group, (2) a pentoxifylline- or (3) an HBO-treated group, and (4) a
pentoxifylline- plus HBO-treated group. Cranially based skin flaps were
elevated on the dorsum. The surviving length was evaluated with fluorescein
dye seven days after the operation. Rats that were treated with
pentoxifylline received 20 mg/kg intraperitoneally at 24, 12, and 1 hour(s)
before flap elevation and every 12 hours after the operation for seven
days. Rats that were treated with HBO received a total of 14 two-hour
treatments at 2.5 absolute atmospheres in divided doses. Results indicated
that the surviving length of flaps in the pentoxifylline- or HBO-treated
groups was significantly greater than those in the control group, but were
not significantly different from each other. Animals treated with both
pentoxifylline and HBO had significantly greater flap survival than animals
in any of the other three groups. This reflected a 30% to 39% improvement
over pentoxifylline alone- or HBO alone-treated animals, and an 86%
improvement over control animals. Mechanisms of action for this apparent
synergistic effect on flap survival are discussed.

========================================================================
52.) Pentoxifylline inhibits granulocyte and platelet function, 
including granulocyte priming by platelet activating factor.
========================================================================
SO - J Lab Clin Med 1988 Aug;112(2):254-63
AU - Hammerschmidt DE; Kotasek D; McCarthy T; Huh PW; Freyburger G;
Vercellotti GM
AD - Department of Medicine, University of Minnesota Medical School,
Minneapolis.
AB - Pentoxifylline has been claimed to work a beneficial effect in
arterial insufficiency by improving erythrocyte deformability and thus
improving blood flow. A number of observations, including the drug
concentrations required to work the red cell effect, suggested that this
was not likely to be a complete explanation. We therefore examined the
effect of pentoxifylline on several granulocyte and platelet functions.
Pentoxifylline inhibited platelet aggregation in response to 4 mumol/L
adenosine diphosphate; although statistically significant inhibition was
seen at 1 mumol/L pentoxifylline, over 200 mumol/L was required for 50%
inhibition. The adherence of unstimulated platelets to cultured endothelial
cells was not strongly inhibited by pentoxifylline; however, the additional
increment in adherence seen in the presence of thrombin was strongly
inhibited (50% attenuative dose [AD50] = 18 mumol/L). Granulocyte
aggregation in response to C5a was modestly inhibited (AD30 approximately
equal to 8 mumol/L; AD50 greater than 1 mmol/L), and the adherence of
unstimulated polymorphonuclear neutrophils (PMNs) to endothelium was
uninhibited. The C5a-mediated augmentation of PMN adherence to endothelium
was mildly inhibited (AD50 = 240 mumol/L). Inhibition of PMN chemotaxis to
N-Formyl-methionyl-leucyl-phenylalanine (FMLP) or C5a (AD50 = 12 mumol/L)
and inhibition of superoxide production in response to FMLP-cytochalasin B
(AD50 = 24 mumol/L) were seen at more clinically credible concentrations.
Perhaps most important, pentoxifylline blocked the ability of platelet
activation factor to prime neutrophils for enhanced response to subsequent
stimuli (AD50 approximately equal to 8 mumol/L; AD60 = 10 mumol/L when
production was the indicator system); in vivo, this could broaden the
drug's effect to include functions that it does not inhibit potently in a
primary fashion. Although pentoxifylline is known to be a phosphodiesterase
inhibitor, and we found it to elevate intracellular cyclic adenosine
monophosphate in stimulated PMNs, we found it to be only marginally more
potent than theophylline in this regard; therefore, the failure of
theophylline to inhibit PMN priming suggests that this enzyme inhibition is
not a complete explanation of the pharmacologic action of pentoxifylline.
We suggest that the effects of pentoxifylline on platelet and granulocyte
function are likely to contribute to the drug's clinical efficacy.

========================================================================
53.) Livedo vasculitis. Therapy with pentoxifylline [published erratum
========================================================================
appears in Arch Dermatol 1989 Mar; 125(3):368]
SO - Arch Dermatol 1988 May;124(5):684-7
AU - Sams WM Jr
AD - Department of Dermatology, University of Alabama, Birmingham 35294.
AB - Eight patients with livedo vasculitis of four to 30 years' duration
that was unresponsive to a variety of medications were treated with
pentoxifylline. Three patients experiences complete healing and remained
free of active lesions while receiving the drug, four noted much
improvement, and one had no change.

========================================================================
54.) Pentoxifylline inhibits T-cell adherence to keratinocytes.
========================================================================
SO - J Invest Dermatol 1995 Jun;104(6):1004-7
AU - Bruynzeel I; van der Raaij LM; Stoof TJ; Willemze R
AD - Department of Dermatology, Free University Hospital, Amsterdam, The
Netherlands.
AB - In many inflammatory dermatoses leukocyte function-associated
antigen-1/intercellular adhesion molecule-1 mediated T-cell/keratinocyte
adhesion is considered to play an important role. Pentoxifylline (PTX), a
methylxanthine derivative widely used for the symptomatic treatment of
various vascular disorders, was recently found to have anti-inflammatory
effects. PTX can suppress tumor necrosis factor-alpha production and
function, and inhibits leukocyte-endothelial cell adherence. The aim of the
present study was to investigate whether PTX also interferes with
T-cell/keratinocyte binding. Peripheral blood T cells were activated with
phorbol myristate acetate and co-incubated with interferon-gamma- or tumor
necrosis factor-alpha-stimulated keratinocytes (SVK 14 cells) in the
presence or absence of PTX. Using an enzyme-linked immuno cell adhesion
assay PTX was found to inhibit T-cell/keratinocyte adhesion in a
dose-dependent manner. A similar inhibition was found when PTX was replaced
by isobutylmethylxanthine, another methylxanthine derivative, or by a
combination of two cyclic adenosine monophosphate analogues. No major
effect on T-cell/keratinocyte adherence was observed when PTX was present
during the pre-incubation of keratinocyte monolayers with tumor necrosis
factor-alpha or interferon-gamma prior to the adhesion assay. In
keratinocyte monolayers the interferon-gamma or tumor necrosis factor-alpha
induced intercellular adhesion molecule-1 expression could not be inhibited
by PTX. However, when PTX was added to short-term organ cultures of normal
human skin biopsies, the lipopolysaccharide- and tumor necrosis
factor-alpha-induced keratinocyte intercellular adhesion molecule-1
expression was blocked completely. The interferon-gamma-induced ICAM-1
expression was not blocked by PTX. The results presented herein suggest
that impaired T-cell/keratinocyte binding may be one of the mechanisms by
which PTX exerts a beneficial effect in certain inflammatory dermatoses.

========================================================================
55.) Pentoxifylline promotes replication of human cytomegalovirus in vivo
and in vitro. 
========================================================================
Author 
Staak K; Prosch S; Stein J; Priemer C; Ewert R; Docke WD; Kruger DH; Volk
HD; Reinke P 
Address 
Institute of Medical Virology, Medical Clinic V-Nephrology, Medical Faculty
(Charite), Humboldt Universitat zu Berlin, Germany. 
Source 
Blood, 89(10):3682-90 1997 May 15 
Abstract 
OKT3 monoclonal antibody (MoAb) therapy is well established in the
prevention and therapy of acute rejection in transplant patients.
Unfortunately, this therapy is associated with several short-term (cytokine
release syndrome) and long-term (infections, EBV-related lymphoma) side
effects. Recently, we were able to demonstrate an association between the
TNF alpha release following the first OKT3 MoAb infusions and the
appearance of human cytomegalovirus (HCMV) reactivation several days later.
In order to prevent this TNF alpha associated HCMV reactivation patients
were additionally treated with pentoxifylline (PTX), a methylxanthine
derivative that has been shown to suppress TNF alpha induction. Although
the TNF alpha peak plasma level following OKT3 MoAb treatment was markedly
reduced, the incidence of HCMV reactivation and HCMV disease was not
influenced. In transient transfection experiments using HCMV immediate
early enhancer/promoter CAT reporter gene constructs PTX enhanced the
promoter activity independently from TNF alpha in premonocytic cells.
Furthermore, PTX acted synergistically with TNF alpha. In virus-infected
human embryonal lung fibroblasts HCMV replication was triggered in the
presence of both PTX and TNF alpha, while either substance alone had only
marginal effects. The stimulatory effect of PTX on the immediate early (IE)
enhancer/promoter was mediated via CREB/ ATF, a eukaryotic transcription
factor that binds to the 19 bp sequence motif in the enhancer region, while
TNF alpha stimulation was mediated by activation of the transcription
factor NF-kappaB and its binding to the 18 bp sequence motif in the
enhancer. These data suggest a potential side effect of cAMP-elevating
drugs such as PTX. 
Language 

========================================================================
56.) intravenous and oral pentoxifylline in the treatment of peripheral vascular disease. A clinical trial.
==========================================================================
Int Angiol. 1990 Oct-Dec;9(4):266-70.

Thomson GJ1, Thomson S, Todd AS, Vohra RK, Carr MH, Walker MG.
Author information

1
Department of Vascular Surgery, Manchester Royal Infirmary, Gran Bretagna.

Abstract

Sixteen patients with severe occlusive vascular disease of the lower extremities were randomised to receive a five day course of combined intravenous and oral Pentoxifylline followed by three months oral treatment only, or identical treatment with a matching placebo. Nine patients received active Pentoxifylline, and 7 placebo, Follow-up by regular clinical examination and haemoreological assessment revealed a marked improvement in claudication distance and an increase in red cell deformability in those receiving Pentoxifylline, there being no change in those receiving placebo. Although both of the above parameters were improved by the treatment, there did not appear to be a direct correlation between red cell deformability and claudication distance in individual patients. A combination of intravenous and oral Pentoxifylline therapy results in an increase in both claudication distance and red cell deformability, but the former may not te a direct consequence of the latter.

==========================================================================
57.) Targeting inflammation in diabetic kidney disease: early clinical trials.
==========================================================================
Expert Opin Investig Drugs. 2016 Sep;25(9):1045-58. doi: 10.1080/13543784.2016.1196184. Epub 2016 Jun 13.

Perez-Gomez MV1,2, Sanchez-Niño MD1,2, Sanz AB1,2, Zheng B1, Martín-Cleary C1,2, Ruiz-Ortega M1,2, Ortiz A1,2, Fernandez-Fernandez B1,2.
Author information

1
a Division of Nephrology and Hypertension and FRIAT, IIS-Fundacion Jimenez Diaz, School of Medicine , UAM , Madrid , Spain.
2
b REDINREN , Madrid , Spain.

Abstract
INTRODUCTION:

The age-standardized death rate from diabetic kidney disease increased by 106% from 1990 to 2013, indicating that novel therapeutic approaches are needed, in addition to the renin-angiotensin system (RAS) blockers currently in use. Clinical trial results of anti-fibrotic therapy have been disappointing. However, promising anti-inflammatory drugs are currently on phase 1 and 2 randomized controlled trials.
AREAS COVERED:

The authors review the preclinical, phase 1 and 2 clinical trial information of drugs tested for diabetic kidney disease that directly target inflammation as a main or key mode of action. Agents mainly targeting other pathways, such as endothelin receptor or mineralocorticoid receptor blockers and vitamin D receptor activators are not discussed.
EXPERT OPINION:

Agents targeting inflammation have shown promising results in the treatment of diabetic kidney disease when added on top of RAS blockade. The success of pentoxifylline in open label trials supports the concept of targeting inflammation. In early clinical trials, the pentoxifylline derivative CTP-499, the CCR2 inhibitor CCX140-B, the CCL2 inhibitor emapticap pegol and the JAK1/JAK2 inhibitor baricitinib were the most promising drugs for diabetic kidney disease. The termination of trials testing the anti-IL-1β antibody gevokizumab in 2015 will postpone the evaluation of therapies targeting inflammatory cytokines.
==========================================================================
58.) Pentoxifylline for Diabetic Nephropathy: an Important Opportunity to Re-purpose an Old Drug?
===========================================================================
Curr Hypertens Rep. 2016 Jan;18(1):8. doi: 10.1007/s11906-015-0612-7.

Bhanot S1, Leehey DJ2,3.
Author information

1
George Washington University School of Medicine, Washington, DC, USA.
2
Loyola University Stritch School of Medicine, Maywood, IL, USA. [email protected].
3
Hines VA Hospital, 111L, Hines, IL, 60141, USA. [email protected].

Abstract

Diabetic nephropathy, or diabetic kidney disease (DKD), is the most serious complication of diabetes mellitus (DM). Despite recent advances in therapy, DKD still often progresses to end-stage renal disease (ESRD). Recent studies have suggested that pentoxifylline (PTX) may be efficacious in the treatment of DKD. PTX is a rheologic modifier approved for use in the USA for the symptomatic relief of claudication. It competitively inhibits phosphodiesterase (PDE), resulting in increased intracellular cyclic AMP (cAMP), activation of protein kinase A (PKA), inhibition of interleukin (IL) and tumor necrosis factor (TNF) synthesis, and reduced inflammation. PTX improves red blood cell deformability, reduces blood viscosity, and decreases platelet aggregation. In combination with renin-angiotensin-aldosterone (RAAS) blockers, PTX may help prevent progression to ESRD in patients with DKD. This review focuses on the possible mechanisms of action of PTX in DKD and studies suggesting possible efficacy of this old drug for a new indication.
==========================================================================
59.) Improvements in the Management of Diabetic Nephropathy.
==========================================================================
Rev Diabet Stud. 2015 Spring-Summer;12(1-2):119-33. doi: 10.1900/RDS.2015.12.119. Epub 2015 Aug 10.

Dounousi E1, Duni A1, Leivaditis K2, Vaios V2, Eleftheriadis T2, Liakopoulos V2.
Author information

1
University of Ioannina, School of Health Siences, Department of Internal Medicine, Division of Nephrology, Ioannina, Greece.
2
Division of Nephrology and Hypertension, 1st Department of Internal Medicine, AHEPA Hospital, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece.

Abstract

The burden of diabetes mellitus is relentlessly increasing. Diabetic nephropathy is the most common cause of end-stage renal disease (ESRD) worldwide and a major cause of morbidity and mortality in patients with diabetes. The current standard therapy of diabetic nephropathy involves intensive treatment of hyperglycemia and strict blood pressure control, mainly via blockade of the renin-angiotensin system (RAS). Attention has been drawn to additional beneficial effects of oral hypoglycemic drugs and fibrates on other aspects of diabetic nephropathy. On the other hand, antiproteinuric effects of RAS combination therapy do not seem to enhance the prevention of renal disease progression, and it has been associated with an increased rate of serious adverse events. Novel agents, such as bardoxolone methyl, pentoxifylline, inhibitors of protein kinase C (PKC), sulodexide, pirfenidone, endothelin receptor antagonists, vitamin D supplements, and phosphate binders have been associated with controversial outcomes or significant side effects. Although new insights into the pathogenetic mechanisms have opened new horizons towards novel interventions, there is still a long way to go in the field of DN research. The aim of this review is to highlight the recent progress made in the field of diabetes management based on the existing evidence. The article also discusses novel targets of therapy, with a special focus on the major pathophysiologic mechanisms implicated in the initiation and progression of diabetic nephropathy.
==========================================================================
60.) Improvements in the Management of Diabetic Nephropathy.
==========================================================================
Rev Diabet Stud. 2015 Spring-Summer;12(1-2):119-33. doi: 10.1900/RDS.2015.12.119. Epub 2015 Aug 10.

Dounousi E1, Duni A1, Leivaditis K2, Vaios V2, Eleftheriadis T2, Liakopoulos V2.
Author information

1
University of Ioannina, School of Health Siences, Department of Internal Medicine, Division of Nephrology, Ioannina, Greece.
2
Division of Nephrology and Hypertension, 1st Department of Internal Medicine, AHEPA Hospital, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece.

Abstract

The burden of diabetes mellitus is relentlessly increasing. Diabetic nephropathy is the most common cause of end-stage renal disease (ESRD) worldwide and a major cause of morbidity and mortality in patients with diabetes. The current standard therapy of diabetic nephropathy involves intensive treatment of hyperglycemia and strict blood pressure control, mainly via blockade of the renin-angiotensin system (RAS). Attention has been drawn to additional beneficial effects of oral hypoglycemic drugs and fibrates on other aspects of diabetic nephropathy. On the other hand, antiproteinuric effects of RAS combination therapy do not seem to enhance the prevention of renal disease progression, and it has been associated with an increased rate of serious adverse events. Novel agents, such as bardoxolone methyl, pentoxifylline, inhibitors of protein kinase C (PKC), sulodexide, pirfenidone, endothelin receptor antagonists, vitamin D supplements, and phosphate binders have been associated with controversial outcomes or significant side effects. Although new insights into the pathogenetic mechanisms have opened new horizons towards novel interventions, there is still a long way to go in the field of DN research. The aim of this review is to highlight the recent progress made in the field of diabetes management based on the existing evidence. The article also discusses novel targets of therapy, with a special focus on the major pathophysiologic mechanisms implicated in the initiation and progression of diabetic nephropathy.
==========================================================================
61.) Renoprotective effect of combining pentoxifylline with angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker in advanced chronic kidney disease.
==========================================================================
J Formos Med Assoc. 2014 Apr;113(4):219-26. doi: 10.1016/j.jfma.2014.01.002. Epub 2014 Feb 7.

Chen PM1, Lai TS2, Chen PY3, Lai CF1, Wu V1, Chiang WC4, Chen YM1, Wu KD1, Tsai TJ1.
Author information

1
Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
2
Department of Internal Medicine, National Taiwan University Hospital, Bei-Hu Branch, Taipei, Taiwan.
3
Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Department of Internal Medicine, Chi Mei Medical Center, Chiali Campus, Tainan, Taiwan.
4
Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan. Electronic address: [email protected].

Abstract
BACKGROUND/PURPOSE:

Several studies have shown the renoprotective effects of pentoxifylline in the treatment of chronic kidney disease (CKD). This study was conducted to examine whether there was an increased benefit of including pentoxifylline with angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) in the treatment of CKD.
METHODS:

A single-center retrospective analysis was conducted. A total of 661 Stage 3B-5 CKD patients who received ACEI or ARB treatment were recruited. The patients were divided into the pentoxifylline use group and the no pentoxifylline group. Renal survival analysis of the two groups was compared. Subgroup analysis was performed by dividing the patients into lower [urine protein to creatinine ratio (UPCR)<1 g/g] and higher (UPCR ≥ 1 g/g) proteinuria subgroups.
RESULTS:

There was no between-groups difference regarding mortality and cardiovascular events. Addition of pentoxifylline showed a better renal outcome (p = 0.03). The protective effect of add-on pentoxifylline was demonstrated in the higher proteinuria subgroup (p = 0.005). In the multivariate Cox regression model, pentoxifylline use also showed a better renal outcome [hazard ratio (HR): 0.705; 95% confidence interval (CI): 0.498-0.997; p = 0.048]. This effect was more prominent in the higher proteinuria subgroup (HR: 0.602; 95% CI: 0.413-0.877; p = 0.008).
CONCLUSION:

In the advanced stages of CKD, patients treated with a combination of pentoxifylline and ACEI or ARB had a better renal outcome than those treated with ACEI or ARB alone. This effect was more prominent in the higher proteinuria subgroup. More large randomized control trials are needed to provide concrete evidence of the add-on effect of pentoxifylline.
==========================================================================
62.) Diagnosis and Management of Alcoholic Liver Disease.
==========================================================================
J Clin Transl Hepatol. 2015 Jun 28;3(2):109-16. doi: 10.14218/JCTH.2015.00008. Epub 2015 Jun 15.

Dugum M1, McCullough A2.
Author information

1
Department of Internal Medicine, Medicine Institute, Cleveland Clinic, Cleveland, Ohio, USA;
2
Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio, USA.

Abstract

Alcohol is a leading cause of liver disease and is associated with significant morbidity and mortality. Several factors, including the amount and duration of alcohol consumption, affect the development and progression of alcoholic liver disease (ALD). ALD represents a spectrum of liver pathology ranging from fatty change to fibrosis to cirrhosis. Early diagnosis of ALD is important to encourage alcohol abstinence, minimize the progression of liver fibrosis, and manage cirrhosis-related complications including hepatocellular carcinoma. A number of questionnaires and laboratory tests are available to screen for alcohol intake. Liver biopsy remains the gold-standard diagnostic tool for ALD, but noninvasive accurate alternatives, including a number of biochemical tests as well as liver stiffness measurement, are increasingly being utilized in the evaluation of patients with suspected ALD. The management of ALD depends largely on complete abstinence from alcohol. Supportive care should focus on treating alcohol withdrawal and providing enteral nutrition while managing the complications of liver failure. Alcoholic hepatitis (AH) is a devastating acute form of ALD that requires early recognition and specialized tertiary medical care. Assessment of AH severity using defined scoring systems is important to allocate resources and initiate appropriate therapy. Corticosteroids or pentoxifylline are commonly used in treating AH but provide a limited survival benefit. Liver transplantation represents the ultimate therapy for patients with alcoholic cirrhosis, with most transplant centers mandating a 6 month period of abstinence from alcohol before listing. Early liver transplantation is also emerging as a therapeutic measure in specifically selected patients with severe AH. A number of novel targeted therapies for ALD are currently being evaluated in clinical trials.
==========================================================================
63.) Advances in alcoholic liver disease: An update on alcoholic hepatitis.
==========================================================================
World J Gastroenterol. 2015 Nov 14;21(42):11893-903. doi: 10.3748/wjg.v21.i42.11893.

Liang R1, Liu A1, Perumpail RB1, Wong RJ1, Ahmed A1.
Author information

1
Randy Liang, Department of Medicine, Santa Clara Valley Medical Center, San Jose, CA 95128, United States.

Abstract

Alcoholic hepatitis is a pro-inflammatory chronic liver disease that is associated with high short-term morbidity and mortality (25%-35% in one month) in the setting of chronic alcohol use. Histopathology is notable for micro- and macrovesicular steatosis, acute inflammation with neutrophil infiltration, hepatocellular necrosis, perivenular and perisinusoidal fibrosis, and Mallory hyaline bodies found in ballooned hepatocytes. Other findings include the characteristic eosinophilic fibrillar material (Mallory's hyaline bodies) found in ballooned hepatocytes. The presence of focal intense lobular infiltration of neutrophils is what typically distinguishes alcoholic hepatitis from other forms of hepatitis, in which the inflammatory infiltrate is primarily composed of mononuclear cells. Management consists of a multidisciplinary approach including alcohol cessation, fluid and electrolyte correction, treatment of alcohol withdrawal, and pharmacological therapy based on the severity of the disease. Pharmacological treatment for severe alcoholic hepatitis, as defined by Maddrey's discriminant factor ≥ 32, consists of either prednisolone or pentoxifylline for a period of four weeks. The body of evidence for corticosteroids has been greater than pentoxifylline, although there are higher risks of complications. Recently head-to-head trials between corticosteroids and pentoxifylline have been performed, which again suggests that corticosteroids should strongly be considered over pentoxifylline.
==========================================================================
64.) Use of pentoxifylline and tocopherol in radiation-induced fibrosis and fibroatrophy.
==========================================================================

Br J Oral Maxillofac Surg. 2017 Apr;55(3):235-241. doi: 10.1016/j.bjoms.2016.11.323. Epub 2016 Dec 24.

Patel V1, McGurk M2.
Author information

1
Oral Surgery Dept, Floor 23, Guys Dental Hospital, London Bridge, London, SE1 9RT. Electronic address: [email protected].
2
Department of Oral and Maxillofacial Surgery, Atrium 3, 3rd Floor, Bermondsey Wing, Guy's Hospital, London, SE1 9RT. Electronic address: [email protected].

Abstract

Radiation-induced fibrosis in the head and neck is a well-established pathophysiological process after radiotherapy. Recently pentoxifylline and tocopherol have been proposed as treatments to combat the late complications of radiation-induced fibrosis and a way of dealing with osteoradionecrosis. They both have a long history in the management of radiation-induced fibrosis at other anatomical sites. In this paper we review their use in sites other than the head and neck to illustrate the potential benefit that they offer to our patients.
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65.) Prophylactic use of pentoxifylline (Trental) and vitamin E to prevent capsular contracture after implant reconstruction in patients requiring adjuvant radiation.
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Cook M1, Johnson N2, Zegzula HD3, Schray M4, Glissmeyer M5, Sorenson L6.
Author information

1
Oncology Clinical Research, Legacy Health, Portland, OR, USA.
2
Legacy Medical Group- Surgical Oncology, NW 1040 22nd Ave, Portland, OR, 97210, USA. Electronic address: [email protected].
3
Portland Plastic Surgery Group, Portland, OR, USA.
4
Legacy Medical Group- Radiation Oncology, Portland, OR, USA.
5
Legacy Medical Group- Surgical Oncology, NW 1040 22nd Ave, Portland, OR, 97210, USA.
6
Oncology Clinical Research, Legacy Health, Portland, OR, USA; Legacy Medical Group- Surgical Oncology, NW 1040 22nd Ave, Portland, OR, 97210, USA.

Abstract
BACKGROUND:

The combination of pentoxifylline (Trental) and vitamin E has been reported to reverse significant consequences of radiation after mastectomy with immediate reconstruction, such as severe capsular contracture or loss of implants. We questioned whether prophylactic use could prevent these consequences.
METHODS:

Thirty women with implants or tissue expanders after mastectomy that underwent adjuvant radiation were treated with Trental and vitamin E for 180 days. All subjects then entered a 12-month observational phase.
RESULTS:

Of the 26 evaluable subjects, 3 subjects required implant revisions. One due to malposition of the nonradiated breast and 2 were due to contracture (7.7%). There were no implant losses.
CONCLUSIONS:

The combination of Trental and vitamin E can prevent severe contracture and implant losses allowing for immediate reconstruction with implant or tissue expander even if radiation is planned after mastectomy.
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