EDITORIAL ESPAÑOL 
================= 
Hola Amigos DERMAGICOS de la red, EN ESTE CORTO PERO INTERESANTE DERMAGIC, quiero mostrarles la existencia REAL de donde provienen algunos de los PRODUCTOS QUE UTILIZAMOS día a día. 

Lean estas dos interesantes referencias y entraran en ese MARAVILLOSO MUNDO DEL ORIGEN DE ALGUNAS MOLÉCULAS. y su historia. Tema fascinante para nosotros quienes las prescribimos. Léanlo y descubrirán las NUEVAS MOLÉCULAS QUE ESTÁN POR SALIR AL MERCADO. Y LAS QUE ESTÁN EN ESTUDIO. 

Tambien Invito muy cordialmente a LOS LABORATORIOS que comercializan el producto NIMESULIDE (AINE) que si CONSIDERAN QUE LOS EFECTOS ADVERSOS publicados en el DERMAGIC DE AYER no son verdaderos, que LO DEMUESTREN CON SOPORTE BIBLIOGRÁFICO. 

Atentamente 

Dr. José lapenta.R. 

EDITORIAL ENGLISH: 
================= 
Hello DERMAGIC'S friends of the net, IN THIS SHORT BUT INTERESTING DERMAGIC, I want to show you the REAL existence of where some of the PRODUCTS THAT we USE day by day come. 

Read these two interesting references and entered in that WONDERFUL WORLD OF THE ORIGIN OF SOME MOLECULES, and their history. Fear fascinating for us who prescribe them.. read it and You will discover the NEW MOLECULES THAT are to LEAVE TO THE MARKET. And THOSE THAT are IN STUDY. 

I also Invite very cordially to THE LABORATORIES that market the product NIMESULIDE (AINE) that if they CONSIDER THAT THE ADVERSE EFFECTS published in YESTERDAY'S DERMAGIC are not true that DEMONSTRATE IT WITH BIBLIOGRAPHICAL SUPPORT 

Sincerely 

Dr. José lapenta R. 

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REFERENCIAS BIBLIOGRÁFICAS / BIBLIOGRAPHICAL REFERENCES 
================================================================== 
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1.) After roller coaster ride, Sepracor has a new prescription 
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2.) WHO IS SEPRACOR, And THEIR PRODUCTS in study and DEVELOPED. 
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============================================================ 
1.) After roller coaster ride, Sepracor has a new prescription 
Biomed Report 
-------------- 
source: BOSTON BUSINESS JOURNAL 

Ted Griffith 

Sepracor Inc. last year vaulted into the ranks of stock market high fliers, but this year life on Wall Street has been more rocky for the Marlborough company. 

On March 8, Sepracor's stock climbed as high as $140.87, but then a few months later fell to a 52-week low of $55 on May 25. News that New Brunswick, N.J.-based Johnson & Johnson had decided not to help Sepracor sell an allergy drug contributed to Sepracor's stock tumble in the spring. 

In 1998, Sepracor's stock performance was stellar, with shares increasing more than 100 percent from $39.75 to $82.81. Just four years ago, stock in Sepracor was going for under $10. Media attention and the announcement of deals with major pharmaceutical companies helped drive the stock up in 1998. 

David Southwell, Sepracor's chief financial officer, now suggests the company is picking up momentum again. 

Southwell said he is optimistic about the coming months and investors will soon see plenty of good news from the company. At least some analysts agree with Southwell's sunny forecast for Sepracor, which specializes in developing improved versions of existing medicines. 

"The risk is decreasing going forward," said Sergio Traversa, an analyst with Mehta Partners, an investment research firm in New York City. "The news we're expecting is good news." 

A recent positive development for Sepracor was the announcement that Madison, N.J.-based Schering-Plough Corp. filed an application with the U.S. Food and Drug Administration for approval to sell what the company expects would be an improved version of the popular allergy drug Claritin. 

Sepracor developed the upgraded allergy drug, which is known as desloratadine, and would receive an undisclosed amount of royalties from Schering-Plough, provided the New Jersey company gets clearance to sell the drug. Claritin is one of the best-selling prescription medicines ever and generated $2.3 billion in revenue last year. 

The FDA is expected to announce its decision in about a year on whether desloratadine can be marketed in the United States. Schering Plough's announcement helped push Sepracor's stock higher, with investors betting the drug will get FDA approval. Sepracor shares opened last week at $72.75 and closed Friday at $83.18, up 14 percent. 

Southwell said the improved version of Claritin is just one reason to be hopeful about Sepracor. 

"It's going to be an action-packed time for us," the chief financial officer said. "The disappointments we had earlier in the year have largely been resolved. The middle of the year was disappointing. Now, though, we're expecting a good balance of the year and a great next year." 

Among other things, Sepracor is involved with developing an improved version of the antidepressant Prozac. 

There is a catch with the Prozac deal, however--the U.S. Federal Trade Commission is looking into the agreement between Sepracor and the maker of Prozac, Indianapolis-based Eli Lilly & Co. Back in December, Eli Lilly announced it would pay Sepracor as much as $90 million for Sepracor's modified version of Prozac. Sepracor's version is supposed to cause fewer side effects than Prozac. 

But the FTC has requested information about the agreement between Sepracor and Eli Lilly, apparently to determine if Eli Lilly is improperly using the patent process to extend its exclusive rights to Prozac. Southwell said he is confident that the FTC will ultimately allow Eli Lilly's deal with Sepracor to go forward. 

Aside from the improved Prozac that's under development, Southwell said the company will work on developing other compounds. He said Sepracor plans to test a number of new drugs on people throughout next year. The company is also selling an asthma drug called Xopenex, which was approved by the FDA in early 1999. 

In theory, Sepracor's business plan appears to be a brilliant one. The company takes highly popular prescription drugs, such as Prozac and Claritin, and alters them so that they are potentially better than the originals. The new version could be more powerful or have fewer side effects than its predecessor. 

In addition, the improved version offers a company a new way of extending exclusive rights to a lucrative market for a popular drug. In the case of Claritin, for instance, Schering-Plough has a series of patents, the first of which expires in 2002. But Sepracor's improved version has patent protection until 2014, according to Reuters. 

"If the business model works, Sepracor will be a $10 billion company," said Traversa, the Mehta Partners analyst. 

So far, however, Sepracor has yet to translate its good idea into profits. 

In the first nine months of 1999, Sepracor reported a net loss of $122.7 million, or $3.73 per share, compared with a net loss of $58.9 million, or $2.10 per share, during the same period last year. 

TED GRIFFITH, health care and biotechnology reporter for the Boston Business Journal, can be reached by e-mail at [email protected]. 

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2.) WHO IS SEPRACOR, And THEIR PRODUCTS in study and DEVELOPED. 
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SOURCE: SEPRACOR HOME PAGE 
https://www.corporatewindow.com/annuals/sepr99/index.html

To Our Shareholders: 
====================== 

Nineteen Hundred and Ninety- Nine was a momentous year for Sepracor. With the launch of XOPENEX™ (levalbuterol HCI) inhalation solution sold through Sepracor's specialty sales force, we began the transition to a fully-integrated pharmaceutical company. The success of XOPENEX™ demonstrates our capability as an organization to execute in the areas of preclinical and clinical development, process development, manufacturing, regulatory, as well as direct marketing and sale of a proprietary drug. 
Direct Sales and Marketing of ICE™ Pharmaceuticals Last May, Sepracor launched its first directly-marketed drug, XOPENEX™ (levalbuterol HCI) inhalation solution, in two dosage strengths for nebulizer use. XOPENEX™ is currently indicated for the treatment or prevention of bronchospasm in patients 12 years of age and older with reversible obstructive airway disease, such as asthma. XOPENEX™ is a proprietary, single-isomer version of the best-selling bronchodilator, racemic albuterol. 

XOPENEX™ 
======== 
is commercialized through a co-promotion agreement 
with the Ross Products Division of Abbott Laboratories. Sepracor's 65-person respiratory sales force calls on pulmonologists, allergists and primary care physicians in U.S. hospitals and clinics. Ross adds over 300 product specialists providing coverage to pediatric physicians in the U.S. The Sepracor sales force is also complemented in the field by a dedicated contract sales force of 155 territory representatives from Innovex, a division of Quintiles Transnational Corporation. 

Today, over 500 sales representatives are promoting XOPENEX™ to physicians in offices, clinics and hospitals in the U.S. At the end of the first quarter 2000, we are approaching a 10 percent market share of new prescriptions written for beta-agonist unit dose vials. 

Commercialization of ICE Pharmaceuticals 
As Sepracor's ICE Pharmaceutical pipeline continues to expand, and our candidates progress into late-stage trials, we will seek additional co-promotion alliances modeled after the XOPENEX™ commercialization strategy. The 

co-promotion approach to sales and marketing makes it possible for us to achieve the required detailing levels need- ed to successfully market and sell pharmaceutical products. 

As additional ICE Pharmaceuticals reach the market, Sepracor hopes to: (1) expand the focus of its primary care sales organization; (2) add additional sales representatives; and (3) attract new co-promotion partners. 

The earliest potential product launch dates for Sepracor ICE Pharmaceutical direct sale candidates are as follows: ROOI for norastemizole; 2002 for (+)-zopiclone and (R,R)-for- moterol; 2003 for (S)-doxazosin, (+)-desmethylzopiclone, and (S)-oxybutynin; and 2004 for (+)-didesmethyl- sibutramine for depression, (+)-didesmethylsibutramine for attention deficit hyperactivity disorder (A-DHD), (-)-didesmethylsibutramine for erectile dysfunction, and (-)-didesmethylsibutramine for urinary incontinence. Sepracor's direct sales and marketing organization has the potential to launch ten ICE Pharmaceuticals over the next four years. 

Sepracor Out-licensing Agreements 
The Company believes that certain compounds are more appropriate for out-licensing arrangements. Sepracor's existing agreements include the following: 

Eli Lilly and Company plans to develop and globally commercialize (R)-fluoxetine, a single-isomer form of the active ingredient in PR0ZAC®, subject to approval of the Federal Trade Commission. (R)-Fluoxetine is currently in large-scale clinical trials. Sepracor will receive royalties on the (R)-fluoxetine product upon launch. 

Johnson & Johnson is developing (+) -norcisapride, a potentially improved isomer of an active metabolite of PROPULSID®. PROPULSID® (cisapride) is indicated for the symptomatic treatment of patients with nocturnal 

heartburn due to gastroesophageal reflux disease. (+)-Norcisapride is currently in Phase 11 clinical trials. Sepracor will receive royalties on (+)-norcisapride sales upon launch in countries where patents have been issued. 

Schering-Plough has licensed desloratadine, an active- metabolite form of loratadine marketed as CLARITIN®, the world's leading nonsedating antihistamine. In October 1999, Schering's New Drug Application (NDA) for desloratadine was filed with the U.S. Food and Drug Administration (FDA) and it is currently under review. Sepracor "I receive royalties on sales upon launch of desloratadine. 

Sepracor has licensed to UCB Farchim SA all of Sepracor's issued patents and pending patent applications covering levocetirizine in Europe and other countries, except the U.S. and Japan. Levocetirizine is an isomer of ZYRTEC®, Europe's leading antihistamine. UCB intends to file a Marketing Authorization Application (NLAA), the European equivalent of a New Drug Application (NDA), in the first half of 2000. UCB will pay Sepracor royalties upon first product sale. 

ALLEGRA® 
======== 
brand fexofenadine hydrochloride is Hoechst Marion Roussel's nonsedating antihistamine ALLEGRA®. Sepracor and Hoechst Marion Roussel (now Aventis) have settled their patent interference and Sepracor is currently receiving royalties on sales in Europe of the fexofenadine product. Sepracor will receive royalties on sales in the U.S. beginning mid-February 2001. 

Sepracor Primary Care Sales Force Could Be Supported By Co-Promotion Specialty Sales Forces 

Drug Discovery at Sepracor 

We believe that our near-term growth will come from commercialization of the ICE Pharmaceuticals currently under development. However, in the future, Sepracor will need new drug opportunities to complement its ICE Pharmaceutical portfolio. The Company has been broadening its focus to include discovery and development of new chemical entities. The focus of this discovery effort is to identify new drug candidates directed toward serving unmet medical needs. The Company is pursuing compounds in the area of central nervous system disorders, including behavioral disorders and pain management. 

Continued Financial Strength 

For the year ended December 31, 1999, the Company had $336 million in cash and marketable securities. In the first quarter of 2000, the Company issued $460 million in 5 percent Convertible Subordinated Debentures due in 2007- Sepracor's consolidated cash position, as of the first quarter of 2000, has never been stronger. 

We believe that we have a winning business strategy based upon a proven innovative approach to drug development and commercialization. I would like to congratulate Sepracor's shareholders and employees on beginning the transition to a fully-integrated pharmaceutical company. In the coming year, I look forward to reporting on Sepracor's continuing progress. 

Sincerely, 

Timothy J. Barberich 
Chairman of the Board and Chief Executive Officer 


New Drug Applications (NDA) for ALLEGRA® and XOPENEX™ have been approved by the U.S. Food and Drug Administration (FDA). Currently, another pharmaceutical compound is under NDA review; two are in Phase III clinical trials; six are in Phase 11 studies; three are in Phase I studies; and nine pharmaceutical candidates are under preclinical investigation. 

XOPENEX ™(levalbuterol HCI) ... A single- isomer 
========== 
bronchodilatorfor the treatment or prevention of bronchospasm for patients with reversible obstructive airway disease, such as asthma. In May 1999, Sepracor launched its first directly marketed ICE Pharmaceutical, XOPENEX™ (levalbuterol HCI) inhalation solution for use with a nebulizer. XOPENEX™ is currently indicated for use in the treatment or prevention of bronchospasm in patients 12 years of age and older with reversible obstructive airway disease, such as asthma. Asthma affects approximately 17 million Americans, including 5 million children. 

In September 1999, Sepracor entered into a contract with Innovex, a division of Quintiles Transnational Corporation, to supplement the Company's 65-person respiratory sales force with 155 contract sales representatives. In November 1999, Sepracor formed a co-promotion alliance with the Ross Products Division of Abbott Laboratories for XOPENEX™ in the U.S. This arrangement provides expanded coverage for XOPENEX™ with pediatricians and allows Sepracor to focus its own direct selling efforts to hospitals, allergists, pulmonologists and primary care physicians. In total, there are over 500 sales 

Active metabolites… potentially fewer side effects with increased potency 
Many drugs currently on the market are administered in a form that is biochemically modified in the body (metabolized) to become a new therapeutically active form The new active form, an "active metabolite", may be administered as a drug itself, and may exhibit lower side effects, greater efficacy, or improved potency when compared to the parent drug. Sepracor has also shown that some active metabolites offer the opportunity for additional indications. 

For example, (+)-norcisapride is an isomer of the active metabolite of PROPULSIDÓ has the potential to cause cardiac side effects and drug-drug interactions. Based on preclinical studies, we believe (+)-norcisapride will eliminate the risk of these serious side effects and has the potential to increase the efficacy, improve the dosing for gastroesophageal reflux disease, and crate an opportunity for additional indications such as irritable bowel syndrome and bulimia. 

Drug candidates that are active metabolites or isomers of active metabolites include: desloratadine, norastemizole, (+)-norcisapride, (+)-didesmethylsibutramine, (-)didesmethylsibutramine, (+)-desmethylzopiclone, and desmethylvenlafaxine 


Sepracor…a leader in the development of single-isomer drugs 
============================================================ 
Many chiral molecules exist in mirror-image forms called optical isomers. These compounds, which are referred to as "racemic mixtures", contain an equal amount of each isomer. Over 500 racemic drugs are on the market today. 

Although chemically identical, isomers differ in their three-dimensional structures. Therefore, different isomers often interact differently with biological processes in the body. Often only one isomer of the pair in a racemic mixture is responsible for the drug's efficacy, while the other may be inert or may cause undesirable side effects. 

Sepracor's single-isomer ICEä Pharmaceutical have the potential to be purer, safer, and more efficacious versions of the original racemic drug. Since the parent drugs have well-known efficacy and safety profiles, ICE Pharmaceuticals can often be developed with less technical, financial and regulatory risk than new chemical entities. 

Single-isomer compounds in human clinical trials include: levalbuterol, levocetirizine, (R)-fluoxetine, (R,R)-formoterol, (S)-oxybutynin, (S)-fluoxetine, (+)-zopiclone, and (S)-doxazosin. 

representatives from Sepracor, Ross and Innovex detailing XOPENEX™ to physicians' offices. 

Sepracor is developing levalbuterol for use in additional oral and inhaled delivery systems. Levalbuterol delivered in a metered dose inhaler (MDI) is in a Phase 11 clinical study. In addition, a Phase III XOPENEX™ pediatric trial is underway. Sepracor has submitted a Marketing Authorization Application (NLAA) for XOPENEX™ inhalation solution to the United Kingdom. 

ALLEGRA® 
=========== 
(fexofenadine HCI) ... Sepracor's patents relating to fexofenadine are licensed or assigned worldwide to Hoechst Marion Roussel, Inc. The fexofenadine product was developed and marketed by Hoechst Marion Roussel, Inc. as ALLEGRA® brand fexofenadine hydrochloride. 
In September, Sepracor and Hoechst Marion Roussel, Inc., (now Aventis), settled all patent issues between the two companies involving the nonsedating antihistamine developed and marketed by Hoechst Marion Roussel. Under the terms of a U.S. agreement, Sepracor and Hoechst Marion Roussel have settled an ongoing arbitrated patent interference involving their U.S. patent properties, and Hoechst Marion Roussel now owns the Sepracor patent properties. 

Hoechst Marion Roussel has also obtained an exclusive license to various other Sepracor U.S. patent applications related to fcxofenadine. Sepracor will receive royalties on fexofenadine sales in the U.S. upon expiration of Hoechst Marion Roussel's composition of matter patent in mid- February 2001. 

Under the terms of a separate ex-U.S. agreement, Hoechst Marion Roussel has obtained an exclusive license to Sepracor's patents that had been the subject of litigation in Europe, as well as various other patent oppositions between the two companies outside the U.S. Under this 

agreement, all legal actions outside the U.S. have been settled and Sepracor will receive royalties on fexofenadine products effective March 1, 1999, in countries where it has issued patents. 

Desloratadine ... 
================= 
An active metabolite of the world's best-selling nonsedating antihistamine, Schering's CLARITIN®. 
In October 1999, Schering submitted a New Drug Application for desloratadine to the FDA. In addition, Schering-Plough also submitted a centralized Marketing Authorization Application (MAA) for desloratadine to the European Medicines Evaluation Agency of the European Union (EU). Approval of this centralized Marketing Authorization would result in unified labeling for desloratadine that would be valid in all 15 EU member states. 

Schering will pay royalties to Sepracor on sales of desloratadine beginning at product launch in countries where patents have been issued. Royalties will escalate over time and upon achievement of certain sales and other milestones. 

Pharmaceutical Candidates in Phase and Large-Scale Efficacy Studies Phase III trials are conducted with a substantial number of patients to demonstrate the efficacy and safety of a compound. Phase III results will provide the majority of support for marketing approval by the U.S. Food and Drug Administration (FDA). Two pharmaceutical candidates are in Phase III and one candidate is in a large-scale efficacy study. 

Norastemizole 
============= 
... A nonsedating antihistamine with the potential for improved potency, rapid onset, long duration Of action, and reduced side effects. 
Norastemizole, under development by Sepracor, is in Phase III clinical trials. Completed clinical trials have indicated that norastemizole may potentially be a safe and potent nonsedating antihistamine exhibiting both rapid onset and long duration of action, making once-a-day dosing possible. The Company believes that this profile, if reflected in the labeling of the approved drug, would give norastemizole a competitive advantage over currently marketed nonsedating antihistamines. In clinical trials to date, there have been no observed significant differences in incidence and severity of side effects, including cardiac events as measured by an electrocardiogram (ECG), between norastemizole and placebo or loratadine. Sepracor and Janssen Pharmaceutica, N.V., a wholly- owned subsidiary of Johnson &Johnson, have entered into an agreement for norastemizole whereby Sepracor has worldwide rights to all Johnson & Johnson intellectual property covering prescription norastemizole products, including the right, in exchange for royalty payments on sales of norastemizole, to reference data from the New Drug Application (NDA) for astemizole, the parent 


ICETM Pharmaceutical commercialization options 
================================================ 
Sepracor will commercialize its ICE Pharmaceuticals in one of three ways: developing candidates internally and selling them directly through Sepracor's sales force; co-promoting products with large pharmaceutical companies; or out-licensing and receiving royalties on drug sales. 

Sepracor's strong financial position combined with its transition into becoming a fully-integrated pharmaceutical organization, gives the Company flexibility in its choice of commercialization strategies for its ICE Pharmaceutical pipeline. 

Sepracor's decision to internally develop an ICE candidate and market the compound through its sales force is based on Sepracor's proprietary position and the Breadth of the market size to be detailed by sales representatives. 

The potential for partnership is attributable to the possibility of product differentiation with the ICE Pharmaceutical and accelerated introduction of a new drug. These are key factors in determining which compounds to co-promote or out-license. 

Direct sales, an important part of Sepracor's commercialization strategy 
======================================================================= 
With the launch of Sepracor's short-acting bronchodilator, XOPENEXTM (levalbuterol HCI), the Company's sales force is building a strong presence in the respiratory therapy market. Over time, and with the introduction of additional products, Sepracor plans to co-promote in those markets where a partner's specialty sales force will complement the Company's primary care sales organization. Sepracor plans to continue to augment its primary care sales organization over the next four years to support the potential launch of ten ICE pharmaceutical products that re currently under development. 

As the Company continues to build its sales organization, Sepracor's sales force may be supplemented with contract sales personnel and strategic co-promotion alliances with leading pharmaceutical marketers. For example, Sepracor currently has a co-promotion alliance with the Ross Products Division of Abbott Laboratories for XOPENEXTM. 

compound. Sepracor anticipates selling this compound, if approved, through its sales force. 

Levocetirizine ... 
================ 
A single - isomer form of ZYRTEC®, Europe's best-selling antihistamine. 
In June 1999, UCB licensed all of Sepracor's issued and pending patents on levocetirizine for Europe. Sepracor will receive escalating royalties on levocetirizine sales. UCB has announced that it intends to file a Marketing Authorization Application (NLAA), the European equivalent of an NDA, for levocetirizine in 2000. The companies believe, based on preclinical and clinical studies, that the levocetirizine isomer offers the opportunity for an improved treatment for patients with allergies. Sepracor has retained its rights for the U.S. and Japan. Worldwide 1999 sales of ZYRTEC® (racemic cetirizine) approached $1 billion, of which approximately $300 million were European sales. 

(R)-flextime ... 
================= 
The (R) -isomer of Eli Lilly's PROZAC® has the Potential to offer greater flexibility in treating depression compared to currently marketed antidepressants. 
The unique pharmacology of (R)-fluoxetine offers the potential for more rapid onset of relief, greater efficacy for treatment of depression, and fewer side effects such as sexual dysfunction. (R)-Fluoxetine also offers the potential for treatment of additional indications, including anxiety. Improvements in its pharmacokinetic profile should allow for shorter washout and reduced drug- drug interaction. Eli Lilly has independently initiated large- scale efficacy studies with (R) - fluoxetine. 

In December 1998, Sepracor announced a proposed license agreement with Lilly relating to development and commercialization of (R)-fluoxetine. Under the 

terms of the agreement, Lilly shall have the worldwide exclusive right to develop and market products containing (R)-fluoxetine. Lilly will be responsible for all subsequent developmental work on (R)-fluoxetine, regulatory submissions, product manufacturing, marketing, and sales. Upon the effective date of the agreement, Sepracor is entitled to receive a milestone payment and license fee totaling $20 million. Sepracor also may receive up to $70 million in milestone payments based on the progression of (R)-fluoxetine through development. In addition, Sepracor is entitled to royalties on (R)-fluoxetine worldwide sales beginning upon first commercial sale. This license agreement is subject to approval by the Federal Trade Commission. PROZAC® (racemic fluoxetine) marketed by Eli Lilly and Company, with worldwide sales of approximately $2.6 billion in 1999, is a leading selective serotonin reuptake inhibitor for the treatment of depression. 

Phase 11 studies enroll patients for clinical testing and are designed to determine the optimum dose and gather efficacy data. Between Sepracor and its corporate partners, six pharmaceutical candidates are in Phase 11 clinical trials. 

(+)-Zopiclone 
============= 
... Seprocor's single-isomer version of this widely used insomnia medication may offer improved sleep maintenance with a lower incidence Of nocturnal awakening. 
Sepracor has initiated a 400-patient clinical efficacy trial for (+)-zopiclone in the treatment of insomnia. The Company plans to develop two doses of (+)-zopiclone intended for either the maintenance of a full sleep cycle or for the treatment of patients who have difficulty falling asleep. In the higher dose, the duration of action may result in better maintenance of sleep with a lower incidence of nocturnal awakening. Lower doses of (+)-zopiclone have the potential to induce sleep when a shorter duration of action is required. Sepracor has entered into an agreement with Rhone Poulenc-Rorer SA (RPR), now Aventis, where- by Sepracor has exclusively licensed RPR's preclinical clinical and post-marketing surveillance data package relating to zopiclone and its isomers and metabolites, for the U.S. market. Gaining access to the RPR data allows Sepracor to potentially accelerate the (+)-zopiclone program. Racemic zopiclone, marketed by RPR under the brand names of IMOVANE® and AMOBAN®, is available in approximately 80 countries worldwide but has never been submitted for approval in the U.S. According to the National Sleep Foundation, Sleep disorders affect approximately 84 million people in the United States 


Sepracor ICETM Pharmaceuticals… a proven strategy 
================================================== 
The opportunity to improve existing drugs is the cornerstone of Sepracor's ICE Pharmaceutical strategy. The Company selects for development single isomers or active metabolites of widely-sold drugs which have the potential to become compounds that are differentiated from the parent drugs in terms of clinical effectiveness and side-effect profile. 

Sepracor has a pipeline of ICE Pharmaceuticals, each of which the Company believes has a strong probability of regulatory approval and commercial success. The FDA's approval of XOPENEXTM, the first ICE Pharmaceutical developed and sold directly by the Company's sales force, validates Sepracor's business model. 

Sepracor's ICE Pharmaceuticals address large and growing markets. Worldwide 1999 sales for the parent drugs of ICE Pharmaceuticals under development by Sepracor and its partners totaled almost $20 billion. 

Two products are currently on the market, one additional pharmaceutical compound is awaiting regulatory approval, and eleven additional candidates are in human clinical development 

Sepracor capitalizes on ICETM Pharmaceutical intellectual property 
Sepracor's ICE Pharmaceutical patent portfolio is a key component of the Company's valuable business strategy. Sepracor has been granted over 30 ICE patents in the U.S. and has many more pending. Sepracor's intellectual property provides a position from which to partner. 

Sepracor frequently seeks out-licensing agreements with the current marketer of an ICE Pharmaceutical's parent compound in order to accelerate the development and marketing of the new drug. Pharmaceutical companies partner with Sepracor because ICE compounds may provide patients with safety or efficacy advantages as compared to other drugs in the class. Also, the potential for additional indications in some of the ICE compounds, as compared to the parent drug, adds new value to the franchise. 

In addition, partnering with a innovator company provides the opportunity to reference the available preclinical and clinical data in the ICE Pharmaceutical regulatory package. This can reduce the cost of clinical work necessary for regulatory filing and accelerate the introduction of new products. 

(+)-norcisapride ... 
====================== 
A potentially safer active metabolite Of Johnson &Johnson's drug PROPULSID®. 
PROPULSID® is indicated for the symptomatic treatment of patients with nocturnal heartburn due to gastroesophageal reflux disease (GERD). Due to the sometimes serious and potentially fatal side effect of cardiac toxicity, PROPULSID® is only available in a limited access program. Preclinical studies conducted by Sepracor have indicated that (+)-norcisapride has the potential to treat GERD and other indications including ernesis, bulimia, and irritable bowel syndrome without the risk of cardiac toxicity. In July 1998, Sepracor licensed its norcisapride rights to Janssen Pharmaceutical N.V., a wholly-owned subsidiary of Johnson & Johnson, and is entitled to receive royalties on product sales in countries where a patent has issued. Royalties begin upon the first commercial sale and escalate upon achievement of sales volume milestones. (+)-Norcisapride is in Phase 11 clinical development. 

(S) - oxybutynin ... 
==================== 
Seprocor's single-isomer candidate for urinary incontinence has the potential to treat urinary frequency and incontinent episodes. 
In a Phase 11, 186-patient, double blind placebo controlled pilot trial, Sepracor demonstrated that (S)-oxybutynin significantly improved both urinary frequency (18 percent better than placebo) and urinary incontinence (30 percent better than placebo) while being well tolerated (i5 percent incidence of rnoderate/severe dry mouth). Currently, Sepracor is nearing completion of its large-scale 800- patient Phase IIB dose-ranging clinical trial. Urinary incontinence affects approximately 17 million people in the U.S. 

R,R)-formoterol ... 
=================== 
This single- isomer bronchodilator has the Potential of combining the benefits of rapid onset of action with long duration Of action. 
(R,R)-Formoterol is a long-acting, single-isomer bronchodilator that has a rapid onset of action. (R,RY- Formoterol could provide a treatment option presently unavailable to patients with asthma and emphysema. If approved for marketing,, (R,R)-formoterol is expected to be sold through Sepracor's primary care sales force along with Sepracor's short-acting bronchodilator, XOPENEX™. The Company is currently completing a Phase IIB clinical trial on (R,R)-formoterol. 


Phase I clinical studies are designed to demonstrate safety in a small group of healthy volunteers. Sepracor has three ICE- Pharmaceuticals in Phase I clinical studies. In addition, nine more ICE candidates are currently undergoing preclinical testing. 

(S)-doxazosin ... 
================== 
The single-isomer version of Pfizer's best-selling benign prostatic hyperplasia (BPH) drug, CARDURA®, may show reduced orthostatic hypotension leading to more convenient dosing and the potential to improve efficacy. 
Sepracor's preclinical studies indicate that (S)-doxazosin exhibits the potential for a significant reduction in orthostatic hypotension and could be more potent than the parent drug in humans. Sepracor believes that the ICE Pharmaceutical version could reduce the cost of treatment by reducing the number of doctor's visits required for titration. While further extensive studies and clinical work are needed to determine the efficacy and safety profile of this compound, Sepracor believes (S)-doxazosin may offer a significant pharmacoeconomic benefit as compared to other pharmacologic treatments for BPH. (S) -Doxazosin is currently in a Phase I clinical study. 

(+)-didesmethylsibutrarnine ... 
=============================== 
The single isomer of an active metabolite of Knoll Pharmaceutical's MERIDIA® has the potential to provide expanded central nervous system indications with reduced side effects. 
Sepracor has initiated a Phase I clinical study on (+)-didesmethylsibutramine, (+)-DDMS, and plans to commence clinical studies on multiple indications for central nervous system disorders in the second half of 2000. Sepracor's preclinical studies indicate that (+)-DDMS is a potent cartooning, norepinephrine and dopamine reuptake inhibitor. This unique triple mechanism of action 


Commercialization partners extend Sepracor's reach 
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A key ICETM Pharmaceutical commercialization strategy for Sepracor is to out-license compounds to pharmaceutical companies. Sepracor selects out-licensing partners that have development resources and the experience required to expeditiously move the compound through the development cycle. Marketing expertise and infrastructure is also necessary to educate physicians and patients about the new drug. 

For example, Schering-Plough licensed desloratadine, the active metabolite of CLARITIN in December 1997, and filed a New Drug Application (NDA) with the U.S. Food and Drug Administration (FDA) in October 1999. 

Sepracor has agreement with some of the most successful pharmaceutical companies in the world. Sepracor's alliances include agreements for the following: Abbott's Ross Products Division for XOPENEXTM; Eli Lilly for the single isomer of PROZAC (pending Federal Trade Commission approval); Johnson & Johnson for the active metabolite of PROPULSID; Schering-Plough for the active metabolite of CLARITIN; UCB Farchim SA for a single isomer of ZYRTEC; and Aventis for ALLEGRA. 

Increasingly, Sepracor intends to develop drug candidates through the NDA submission and then either market the drug itself or enter into a co-promotion agreement. 

An accelerated pace through clinical trials for ICETM Pharmaceuticals 
Clinical trials for new chemical entities (NCEs) that have the potential to become drugs can cost hundreds of millions of dollars. Before a compound receives regulatory approval, NCE clinical work can be drawn out over a decade or more. Many ICE drug candidates don't make it through strenuous safety and efficacy trials. 

In contrast, the safety and efficacy of the parent drugs of ICE Pharmaceuticals are often well understood before clinical trials begin. Parent drugs have been successfully taken through clinical studies and may have been on the market for years. Therefore, preclinical and clinical development of single-isomer or active-metabolite ICE Pharmaceuticals may be accomplished quickly and at relatively low cost and risk. 

In some cases, the ICE strategy has offered the opportunity for a clinical development timeframe of two years or less. For example, Sepracor received U.S. Food and Drug Admimistration (FDA) approval of its New Drug Application (NDA) in March 1999 for XOPENEXTM. The clinical developement time for XOPENEXTM prior to the NDA filing was approximately two years 

may offer improvement in the treatment of disorders including depression and attention deficit hyperactivity disorder (ADHD). 

(-) - didesmethylsibutramine ... 
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Seprocor is exploring the demethylated opposite isomer of (+) -didesmerthylsibutramine for urology indications. 
(-)-Didesmethylsibutrarnine, (-)-DDMS, is a potent norepinephrine and dopamine reuptake inhibitor that is being investigated for urological disorders such as erectile dysfunction and urinary stress incontinence. A Phase I clinical study of (-)-DDMS is on track for the first half of 2000. 

(+) - desmethylzopiclone ... 
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A single isomer of an active metabolite of zopiclone has the potential for expanded indications. 
Preclinical studies have demonstrated that (+)-desmethylzopiclone, (+)-DMZ, has potent anxiolytic activity without significant sedation. Sepracor plans to develop this com- pound as a treatment for anxiety. The Company plans to file an Investigational New Drug application (IND) in 2000 on (+)-DMZ. 

(S)-lansoprazole ... 
==================== 
A single -isomer form of PREVACID® has the potential for more consistent dosing and improved efficacy. 
PREVACID®, with worldwide sales of approximately $3 billion in 1999, is marketed in the U.S. by TAP Pharmaceuticals. This proton pump inhibitor drug is used to treat diseases associated with excess gastric acid secretions, primarily gastroesophageal reflux disease (GERD). Based on preclinical studies, Sepracor believes that (S)-lansoprazole may offer more consistent dosing and improved efficacy, as compared to PREVACID'. (S)-Lansoprazole is in preclinical studies 


(-)-pantoprazole 
================= 
... A single- isomer form of PANTOZOL™ has the potential for more consistent dosing and improved efficacy. 
PANTOZOL™ is marketed by Byk- Gulden and American Horne Products for the treatment of GERD. Worldwide sales of proton pump inhibitors, a class of drugs used to treat ulcers and GERD, were over $12 billion in 1999. Sepracor's preclinical studies suggest that (-)-pantoprazole has the potential for more consistent dosing and improved efficacy. (-)-Pantoprazole is in preclinical studies. 

Sepracor has many additional single-isomer and active- metabolite compounds under investigation. Sepracor ICE" Pharmaceutical candidates (parent drug in parentheses) in preclinical studies include: hydroxy bupropion (Glaxo Wellcome's ZYBAN™) for depression and ADHD; nefazodone metabolite (Bristol-Myers Squibb's SERZONE®) for anxiety; desmethylvenlafaxine (American Home Products' EFFEXOR®) for CNS indications; (R)-ondansetron (Glaxo Wellcome's ZOFRAN®) for nausea; (-)-amlodipine (Pfizer's NORVASC®) for hypertension; and (S)-salmeterol (Glaxo Wellcome's SEREVENT®) for asthma. 

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DATA-MÉDICOS/DERMAGIC-EXPRESS No 3-(104)  13/08/2.001 DR. JOSÉ LAPENTA R. 
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    Produced by Dr. José Lapenta R. Dermatologist  
Maracay Estado Aragua Venezuela 2.001-2026  
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