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MDI INTRODUCTION

William P. Purcell, Ph.D. founded Molecular Design International, Inc. (MDI) in 1975.  MDI is primarily involved in discovery and out-licensing of innovative pharmaceutical compounds.  We have completed a number of out-licensing arrangements during our existence yet continue to possess a portfolio of very promising proprietary offerings in various stages of development.  Currently MDI has compounds in the fields of oncology, dermatology, female sexual dysfunction and obesity.  Dr. Purcell is the sole shareholder of MDI and serves as its President and Chief Executive Officer. 

MDI is a drug DISCOVERY company.  MDI is NOT a drug development company.  Our business model involves 6 primary steps:

The most qualified scientists in the world conduct our research on a contract basis. We select our collaborators and researchers based on who is identified as THE BEST for the research we need completed.   This approach has allowed us to conduct our research on HMP12 in the laboratories of the recognized experts in pre-clinical study of sexual dysfunction.  We will elaborate on this point later in this document.  Because our approach to drug discovery is primarily contract based, we have the luxury of selecting the best minds and laboratories and can operate as a very cost effective organization.

Key MDI Personnel

Dr. Purcell has had a distinguished career as a Professor of Medicinal Chemistry at The University of Tennessee ( Memphis ).  Dr. Purcell is a recognized expert in the field of molecular modeling and is a pioneer in Quantitative Structure-Activity Relationships (QSAR) with his book, a first in this area, entitled "Strategy of Drug Design:  A Molecular Guide To Biological Activity" (John Wiley and Sons, New York, 1973).  Dr. Purcell has an undergraduate degree in Chemistry from Indiana University and a Masters and Ph.D. degree in Physical Chemistry from Princeton University .

Mr. Dean E. Tozer has had an extraordinary career in the pharmaceutical industry.  During his time in the industry Mr. Tozer has held a wide variety of positions including Cost Accountant, Business Analyst, Sales Representative, Global Brand Manager, Associate Director of Global Commercialization and in his final position he resided in Tokyo Japan as the Director of Marketing for Searle Pharmaceuticals (now Pharmacia Corporation).  Mr. Tozer has been involved in the launch and management of a number of global brands, including Arthrotecâ, Bextraâ, Dynastatâ, and Celebrexâ.  His primary responsibilities within MDI are business development and general business matters.  Mr. Tozer holds a Bachelor of Commerce degree from Saint Mary’s University in Halifax Canada and is a Certified Management Accountant in Canada .

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HMP12 – THE PRODUCT

HMP12 was conceived and created by Duane Miller, Ph.D. (The University of Tennessee at Memphis ) and Seoung-Soo Hong, Ph.D. ( Chungbuk National University in Korea).  Drs. Miller and Hong are recognized experts in their respective fields of medicinal chemistry and chemical synthesis.  Once conceived, Drs. Miller and Hong approached MDI about involvement in realizing the commercial potential of the compound.  MDI subsequently entered into an arrangement with Miller and Hong to transfer the rights and to patent the invention.  The result is that MDI owns all the rights to the HMP12 patent estate which includes an enormous series of novel compounds.  Because of their expertise, Drs. Miller and Hong will remain involved in the development of HMP12. This will be covered in more detail in subsequent sections.

HMP12 is an alpha adrenergic antagonist.  It is being developed for female sexual dysfunction (FSD), a widespread condition with no adequate treatment currently on the market.  Its mechanism of action is based on blocking a₁ and/or a₂ that in turn has an impact on blood flow to the genitalia.

Our Initial research has been conducted by Abdulmaged M. Traish, Ph.D. (Boston University School of Medicine) who is a recognized expert in the field of sexual dysfunction.  Dr. Traish has expressed optimism about the initial results that are provided in the section entitled Pre-Clinical Results To Date.  We have also been fortunate to have input on our development plans from Irwin Goldstein, M.D. (Boston University School of Medicine).  Drs. Goldstein and Traish have provided MDI invaluable guidance.  Their input is the primary reason HMP12 is being developed for FSD as opposed to male sexual dysfunction.

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FSD – THE NEED

Sexual dysfunction is a widespread health problem for both sexes. The Journal of The American Medical Association reported that 31 percent of men had erectile or ejaculatory dysfunction. In women, sexual difficulties were even more common.

Female sexual dysfunction (FSD) is age-related, progressive and highly prevalent affecting 30-43 percent of women.  Based on a National Health and Social Life Survey (JAMA 1999) of 1,749 women, 43 percent experience sexual dysfunction.  The preponderance of those reporting such dysfunctions were not post-menopausal women, but rather such experiences were fairly evenly distributed among women ranging from 18 to 59 years of age. Additionally, U.S. population census data reveal that 9.7 million American women aged 50-74 self-report complaints of diminished vaginal lubrication, pain and discomfort with intercourse, decreased arousal, and difficulty achieving orgasm.  The causes of FSD are broadly defined by the following categories:

If we assume this list represents a reasonable estimate of causality, then we should also assume treatment will need to address each category either individually or in combination.  Currently, treatment is limited to psychological, hormonal and device based approaches. The next section will briefly outline the currently available options (excluding psychological) as well as those pharmacological options under development for treatment of FSD.

FSD is clearly an important women's health issue that affects the quality of life of many. Until recently, there has been little research or attention that focused on female sexual function. As a result, our knowledge and understanding of the anatomy and physiology of the female sexual response is quite limited. Based on improved understanding of the physiology of the male erectile response, recent advances in modern technology, and recent interest in women's health issues, the study of female sexual dysfunction is gradually evolving.  We believe HMP12 is perfectly positioned to take advantage of this emerging tide of interest in the study and treatment of FSD.  Our estimates of market potential are covered in the following section.

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COMPETITIVE LANDSCAPE

As was mentioned in the previous section, the majority of effort to date has been expended on treatments for male sexual dysfunction or erectile dysfunction (ED).  Although female sexual dysfunction (FSD) is generally believed to be more prevalent, the research community appears to have been reluctant to tackle this condition aggressively.

Conservative estimates suggest that 31 million men in the U.S. and 140 million men worldwide are affected with ED. Currently, the worldwide ED treatment market is approximately $1.6 billion with most of those sales going to Pfizer’s Viagra^®. As patient awareness increases with the public's acceptance of open discussion of ED, along with the introduction of new patient friendly treatments and the aging of the world's population, the percentages of men seeking treatment is anticipated to accelerate and spur the growth of a multibillion dollar market.

With this awakening to the market opportunities in sexual dysfunction the interest in this therapeutic category has significantly increased over the last number of years.  However, this increased attention still appears to have been chiefly focused on ED.  Until the approval of Viagra^®, the options available to men were either injection based therapies or some type of implant.  The following represents a sampling of some products that are approved or in development for ED:

Ø      Phosphodiesterase Inhibitors (e.g. Viagra1 – sildenafil citrate, TA1790¹ – PDE5 inhibitor)

Ø      Prostaglandin Analogues (e.g. Alprox-TD¹ - alprostadil)

Ø      Alpha Adrenergic Antagonists (e.g. Vasomax¹ – phentolamine mesylate)

Obviously this list does not represent an exhaustive record of all products either marketed or under development for ED. It is intended to give a general sense of the various approaches being employed. There also appears to be a number of efforts under way to combine different therapeutic approaches in a single product. For example there is research being conducted on combining a prostaglandin analogue with an alpha I blocker.

With an assumed greater occurrence of FSD, our belief is that this condition will be even more lucrative for the companies that successfully compete there.  Our thinking is based on the following simplistic table of contrasts between men and women as it relates to healthcare matters.

 We appreciate the preceding table contains sweeping generalizations.  However, its purpose is to foster consideration of some of the differences that should be evaluated when discussing the market potential for FSD vis-à-vis ED.  If we assume ED is a lucrative market, then success in FSD will be even more so.  FSD education will clearly be required but not to the extent we have seen necessary with ED.

 The options currently identified for FSD bear a striking resemblance to the ED market.  The general categories of treatment for FSD include:

Ø      Hormone Therapy (e.g. estrogen, testosterone)

Ø      Amino-Acid L-Arginine (e.g. Viacreme® - non-prescription)

Ø      Devices (e.g. Eros Therapy¹ - FDA approved device for the treatment of FSD)

Ø      Phosphodiesterase Inhibitors (e.g. UK-369,003[1] - sildenafil citrate, TA1790¹ – PDE5 inhibitor)

Ø      Prostaglandin Analogues (e.g. Femprox¹, Alista¹- alprostadil)

Ø      Alpha Adrenergic Antagonists (e.g. HMP12¹)

This list does not represent an exhaustive record of all products either marketed or under development for FSD. It is intended to give a general sense of the various approaches being considered.

 Although there are significant anatomic and embryologic parallels between men and women, the multifaceted nature of FSD is clearly distinct from that of the male.  We believe HMP12 will become a viable pharmacological intervention for the treatment of FSD.  We believe the FSD market will be an incredibly lucrative one.  The three options currently available (Hormone, L-Arginine & Devices) have had varied and sometimes controversial clinical results.  With the other options mentioned in various stages of development we believe HMP12 can reach the market in time to provide a novel solution to FSD.  With proper development and promotional effort, we estimate HMP12 will achieve blockbuster sales in excess of $1 billion peak year.  The following pages will elaborate on the HMP12 patent estate and our pre-clinical development program for the product.

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PATENT ESTATE

HMP12 is a novel compound protected by US Patent 6,919,357, filed on August 10, 2001.  MDI owns 100% of all rights related to the patent and may enter into an out-license agreement with no reservations.  Currently MDI has synthesized over 50 novel compounds within this patent.  Synthesis is ongoing as we optimize and refine our lead compounds.

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PRE-CLINICAL RESULTS (IN-VITRO)

Initial binding studies were complete at The University of Mississippi in the laboratories of Dr. Dennis Feller.  Based on those results, HMP12 was identified as the appropriate lead compound.  Our research then progressed to Boston University and the laboratories of Dr. Abdulmaged Traish.  Dr. Traish has conducted all in-vitro and in-vivo studies to date.

Functional Activity of the Alpha Adrenergic Antagonist HMP12 in the Penile Corpus Cavernosum (12-10-1999)

Researcher:  Abdulmaged M. Traish

Location:  Urology Research Laboratory, Boston University School of Medicine

Objective:  To assess alpha-blocking and tissue relaxing properties of HMP12

Results Summary:

Contractile responses were assessed in organ bath preparations of isolated rabbit cavernosal tissue strips. All tissue strips were treated with indomethacin to reduce the vasoactive influences of endogenous prostanoids. In cavernosal tissue strips exposed to increasing concentrations of exogenous norepinephrine, HMP12 (50 nM) significantly attenuated the contractile response (n=6). In a separate protocol, cavernosa tissue strips were contracted with 2 mM norepinephrine and then challenged with increasing concentrations of HMP12. HMP12 caused dose-dependent relaxation of these tissue strips with an estimated EC50 of 0.12 mM (n = 8).

Those results indicate that HMP12 is an effective alpha adrenergic antagonist in penile corpus cavernosum, 2.5 times more active than phentolamine mesylate (Vasomaxâ), and provide a rationale for further investigation in the development of this compound as a potential treatment for erectile dysfunction.

Note:

Following our initial in-vitro results, MDI sought guidance from numerous experts regarding the continued development of HMP12.  After discussions with the Boston University team, headed by Dr. Irwin Goldstein, MDI took the decision to focus on the treatment of female sexual dysfunction. Further explanation is considered proprietary.  The following represents our next step, in-vivo analysis of HMP12 for this indication.

PRE-CLINICAL RESULTS (IN-VIVO)

In-Vivo Modulation of Genital Blood Flow by the Alpha Adrenergic Antagonist HMP12 (06-15-2002)

Researcher(s):  Abdulmaged M. Traish, Noel N. Kim, Ricardo Munarriz, Irwin Goldstein

Location:  Urology Research Laboratory, Boston University School of Medicine

Objective:  To assess the effect of HMP12 on female genital blood flow in response to pelvic nerve stimulation.

Materials and Methods:

1.      Animals (3 per group) were sedated by administering ketamine (35 mg/kg) and xylazine (5 mg/kg) intramuscularly.  Anesthesia was maintained as intramuscular injection of this anesthetic agent with 0.5 mL volume and 30 minutes interval. We continuously monitored the systemic blood pressure, respiratory pattern, movement of nose, eye blink reflex.

2.      The ear vein was cannulated using a 23-gauge butterfly needle infusion set. Animals were then placed onto a surgical table in the supine position. And, the neck, lower abdomen and external genitalia regions were saved with caution.

3.      After lidocaine subcutaneous infiltration, midline neck incision was made. The incision was deepened to the trachea. Then carotid artery was mobilized from vagal nerve and surrounding connective tissues just lateral to the trachea. Double black silk was tagged and the vessel was ligated distal to the heart. The carotid artery was then cannulated with 22 Fr. angiocatheter. The angiocatheter was connected to a heparinized line and pressure transducer (PT300 pressure transducer, Grass) to monitor systemic blood pressure throughout the rest of the procedure.

4.   After subcutaneous lidocaine infiltration, the perivesical space was exposed through a 4-cm midline abdominal incision. The bladder was dissected from the surrounding fatty tissues and emptied with needle aspiration. For better surgical field, ipsilateral inguinal ligament was partially cut. The pelvic nerve was identified and carefully dissected under the perivesical fat on the postero-lateral aspect of the upper vagina. The pelvic nerve usually ran along the emerging vein upward.

5.   After exposure of the pelvic nerve, under direct vision, a bipolar platinum wire electrode was hooked onto the nerve without cutting the nerve. Unilateral pelvic nerve stimulation was accomplished with a Grass S9 stimulator set at normal polarity and repeat mode to generate a train of square waves with 10 V pulse amplitude, 0.8 msec pulse width and 2 Hz frequency.  We have chosen this suboptimal frequency in order to assess the effect of the drug during nerve stimulation.  During the nerve stimulation, the clitoris was palpated to evaluate adequate stimulation of the pelvic nerve. If twitch of leg muscle occurred, the electrode was re-positioned.

6.   Then, two 25-guage butterfly needles were inserted into the vaginal cavity intramuscularly. Each needle was filled with the drug or vehicle and tightly fixed to vaginal skin.

7.   After calibration of the oximeter, the probe was positioned longitudinally over the vagina such that the detector fiber was positioned just below the pubic arch. The probe assembly was secured in place by a metal stand. The area over the probe was covered with a black cloth to prevent any interference from natural or artificial ambient light sources. After a sufficient rest to reach equilibrium (at least for 30 minutes), electrical nerve stimulation was accomplished with a stimulator set at normal polarity and repeat mode to generate a 30 sec train of square waves with 10 V pulse amplitude, 0.8 msec pulse width and 2 Hz frequency.

8.      Thirty minutes after the nerve stimulations, intravaginal drug injection was performed gently and slowly. After the oximetry recording stabilized, nerve stimulations were repeated at 2Hz.

Data Analysis.  The genital blood flow response was assessed by measuring the increase in oxyhemoglobin and total hemoglobin concentrations in response to pelvic nerve stimulation, alone or in conjunction with drug or vehicle administration.

Results:

Figure 1 shows that administration of vehicle had no effect in any of the animals on genital blood flow as assessed by laser oximetry.  Administration of 0.5 mg/kg of phentolamine mesylate or 0.5 mg/kg of HMP12 also produced no effect in any of the animals tested (figures 2 & 3).  Figure 4 shows that administration of 1 mg/kg of phentolamine produced a pronounced response in one animal and a moderate response in 2 other animals.  Administration of 1 mg/kg of HMP12 produced marked responses in two out of the three animals tested (Figure 5).  Figures 6 and 7 show the summarized data from each group for oxy and total hemoglobin.  No significant changes in systemic blood pressure were noted for intravaginal administration of phentolamine or HMP12.

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Comments:

These data suggest that HMP12 produces changes in genital blood flow in response to pelvic nerve stimulation.  The changes are greater than that of phentolamine mesylate (Vasomaxâ).  Based upon these results, HMP12 and its many derivatives covered in MDI's provisional patent application will be moved forward for additional biological evaluations.

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CONTINUED PRE-CLINICAL DEVELOPMENT

With our initial results, MDI is committed to continued development on HMP12.  Our plan is to generate the data necessary to obtain an IND as well as optimize the corresponding patent estate.  We must emphasize that FSD research is at a frontier. For example, there is much to learn about mechanism of action.  Additionally, the correlation among molecular structures, biochemical and biological responses, and the clinical environment is virtually unknown.  This is also the good news.  Because little is known and there is almost nothing on the market that is safe and effective, the opportunities are limitless.  We believe we have assembled a team of the finest minds and the best technology available at this point in time.  From MDI’s drug discovery platform technology, the expertise of our chemists, to the finest pharmacological and biological experts, we believe our chances of finding a safe and effective treatment for FSD are excellent. 

Animal Efficacy

We believe the study presented earlier in this document provides the necessary data to demonstrate animal efficacy.

Animal Safety

Standard, well-established toxicological studies will be conducted to provide safety data for the IND application to the FDA.  An outside laboratory will be contracted to conduct standard toxicology consistent with regulatory requirements for safety.

Compound Optimization

As mentioned earlier, over 50 novel compounds inside the patent application have been synthesized.  Some of these compounds have been evaluated for their ability to bind to a₁ and a₂ receptors.  Perhaps surprisingly, but to our advantage, some of these derivatives bind strongly to a₁, some bind strongly to a₂, some bind to both, and some do not bind to either receptor.  These studies are ongoing at the University of Mississippi under the direction of Dr. Dennis Feller, Chair of the Department of Pharmacology and Consultant to MDI.  Armed with the binding profiles of these unique compounds and the physicochemical parameters of the derivatives, Dr. Purcell will use MDI platform technology (QSAR, Molecular Modeling, Computer-Aided Drug Design) to develop models that will predict binding properties. 

Even more important, correlations among a₁ and/or a₂ with the in-vivo rabbit data will provide the information necessary to select the target derivative having the greatest potential of success for FSD.  This technology streamlines the search for the optimum drug candidate by reducing the numbers of compounds synthesized and tested thereby saving time and money in the process.  We believe this work may also represent landmark research in determining if there are correlations among a₁/a₂ binding affinity, in-vivo rabbit data, and/or clinical effectiveness.  The discovery of correlations between any two of these dependant variables would contribute new knowledge in this frontier of research.

Our Scientific Research Team

Abdulmaged M. Traish, Ph.D. is currently Professor of Biochemistry and Urology as well as the Director of Urology Research at Boston University School of Medicine, Boston University.  Dr. Traish has a B.S. in Chemistry and Botany from The University of Tripoli.  He has completed a Ph.D. and Fellowship in Biochemistry as well as an MBA at Boston University.    He has held Assistant and Associate Professor positions in both Urology and Biochemistry at Boston University.  He has authored numerous articles and abstracts.  Dr. Traish has conducted the initial in-vitro and animal research that was presented in previous sections of this document.  He will also be responsible for conducting any additional animal efficacy research on HMP12 should it be necessary.  MDI is convinced that Dr. Traish’s involvement provides a significant research advantage to our development program.

Irwin Goldstein, M.D. has also contributed to our initial animal research on HMP12 as is evidenced by his inclusion as an author on the data presented earlier in this document.  Through his affiliation with Dr. Traish at Boston University, Dr. Goldstein has provided invaluable guidance on the development of HMP12.  He is currently Professor, Department of Urology, Boston University School of Medicine, Boston University. Dr. Goldstein is a global expert in the field of sexual dysfunction for both men and women.  He has published extensively in this field and has been an integral contributor to many successful development programs for various sexual dysfunction treatments.

Duane D. Miller, Ph.D. is currently Van Vleet Professor and Chairman of the Department of Pharmaceutical Sciences at The University of Tennessee (Memphis).  Dr. Miller has a B.S. in Pharmacy from The University of Kansas and a Ph.D. in Medicinal Chemistry from The University of Washington.  He has held various academic positions at Ohio State University including Assistant, Associate and full Professorships.  He was the Department Chairman for the division of Medicinal Chemistry and Pharmacognosy as well as the Kimberly Professor.  He has authored >200 publications and abstracts.  Dr. Miller has an impressive list of achievement as both a teacher and scientist.   His contribution to the development of HMP12 will be especially valuable since he is one of the two scientists who created HMP12.

Seoung-Soo Hong, Ph.D. is currently a Visiting Scientist at the School of Pharmacy, Medical College of Virginia, Virginia Commonwealth University as well as an Associate Professor in the College of Pharmacy at Chungbuk National University in Cheongju, Chungbuk, Korea.  Dr. Hong has a B.S. and M.S. in pharmacy from Yeungnam University in Taegu, Korea and a Ph.D. in Medicinal Chemistry from Ohio State University.  He has held various academic positions at Ohio State University, Virginia Commonwealth University, The University of Tennessee and Chungbuk National University.  He has authored numerous publications and abstracts.  Dr. Hong is a recognized expert in organic chemistry and medicinal chemistry.  His contribution to the development of HMP12 will be especially valuable since he is one of the inventors of HMP12.

Dennis R. Feller, Ph.D. is currently Professor and Chairman of the Pharmacology Department at The University of Mississippi.  Dr. Feller has a B.S., M.S., and Ph.D. in pharmacology from The University of Wisconsin.  He has had a distinguished academic career.  His broad experience includes post-doctoral and professional leave at the NIH.  In the Ohio State University pharmacology department he was an Assistant, Associate, full Professor, and department Chairman.  He has had visiting professorships in Venezuela, Egypt and at The University of Kentucky.  He has authored over 2000 articles, chapters, reviews, patents, and abstracts on various topics.  MDI is thrilled Dr. Feller is willing to lend his scientific expertise to the development of HMP12.

Scientific Responsibilities

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THE OPPORTUNITY

 MDI will consider 3 options for HMP12:

 Option #1 – Immediate Out-License

MDI will consider immediately out-licensing HMP12 and the associated patent estate to an interested drug development company.  Our preference would be an arrangement similar to those in our past.  Our standard agreement contains an up-front signing payment, milestone payments throughout the development program and a royalty percentage on sales of the approved product.

 This option is primarily directed at larger drug development organizations looking to enhance their portfolio of pre-clinical compounds for the female health market.

Option #2 – Purchase Right of First Refusal

MDI will consider partnering with an interested drug development company to continue the pre-clinical development of HMP12.  For a sum, MDI will continue our progress towards an IND at which point our development partner would have the first option to negotiate a licensing agreement with MDI on HMP12 and the associated patent estate.

 This option may best suit a smaller drug development company that does not have the resources to commit to a long-term agreement without more scientific research.  We believe our cost-effective approach allows for a relatively inexpensive, yet scientifically sound, pre-clinical program.

 Option #3 – Equity Investment in Continued Development

MDI will consider an equity investment in the continued development of HMP12.  We have a model established where by an outside investor, particularly one without drug development expertise, can invest in the development of HMP12 in exchange for a percentage ownership in the compound and corresponding patent estate.  Our initial experience leads us to believe a C-corporation or LLC is the optimal way to execute this model.  Details of the arrangement would be determined based on investor preferences and the input of relevant outside expertise.

 This option is directed to venture capital organizations or high net-worth individuals interested in investing in the biopharmaceutical market. An “Investor Information Package” is available from MDI.

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RISKS RELATED TO OUR BUSINESS

This document contains forward-looking statements about the market potential and scientific results that we believe can be attained with HMP12.  These statements and estimates are based on our years of experience in this industry.  As with any estimates, MDI cannot guarantee the outcomes will be exactly as we have proposed.

 Drug discovery and development entail the risk of failure.  Although we believe MDI’s experience and approach minimizes this risk and its track record is exceptional, we cannot guarantee success.  Should a corporation or individual desire to enter into an agreement with MDI related to HMP12 or any other compound from the patent estate, we would encourage a thorough due diligence process on the part of both companies.  

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LeadDiscovery is pleased to announce the completion of it's most recent DiscoveryDossier describing a new licensing or co-development opportunity relating the treatment of erectile dysfunction and female arousal disorder. For free access to this dossier Click here or paste the following address into your browser:

http://www.leaddiscovery.co.uk/dossiers/MDI002/MDI.html