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Title: THE HIGH HARD ONE ,  By: Bie, Tom, Skiing, 00376264, Dec2001, Vol. 54, Issue 4

Section: SKIING SCENE

When planning your next ski trip, you might want to pack some viagra along with your Volkls. A recent study conducted by London’s Hammersmith Hospital shows that the popular impotency drug may also help prevent high altitude pulmonary edema (HAPE). The scientists discovered that the enzyme phosphodiesterasealso can restrict blood flow to the lungs, which can induce HAPE. According to Peter Hackett, high-altitude expert and author of Mountain Sickness: Prevention, Recognition and Treatment, taking viagra helps break down the offending enzyme and allows more oxygen into the lungs.

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By Tom Bie

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Copyright of Skiing is the property of Time4 Media and its content may not be copied or e-mailed to multiple sites or posted to a listserv without the copyright holder`s express written permission. However, users may print, download, or e-mail articles for individual use.
Source: Skiing, Dec2001, Vol. 54 Issue 4, p62, 1p

Title: Establishing Guidelines for Internet-based Prescribing ,  By: Jones, Miles J., Thomasson, William Alvis, Southern Medical Journal, 00384348, Jan2003, Vol. 96, Issue 1

Section: For Debate

Abstract: The American Medical Association called for the establishment of guidelines to allow electronic prescription of medications “for established patients.” Based on experience writing more than 10,000 Interact-based prescriptions, we agree that guidelines are long overdue. Restricting such prescribing to patients with whom a face-to-face relationship has previously been established violates patient autonomy and distorts the physician-patient relationship without improving patient safety or convenience. A study comparing information obtained and used by Internet-based physicians prescribing Sildenafil with that obtained by clinic-based physicians writing similar prescriptions suggests that safety may be greater on the Internet. Data regarding the appropriateness of prescriptions for other medications suggest that the in-office visit is not the panacea it is often assumed to be. Guidelines for electronic prescribing, like guidelines for other aspects of medical practice, need to be based on evidence. Such evidence is currently lacking, and a serious effort to obtain it should be a top priority.

Editor’s Note: Occasionally we receive articles that address controversial issues. We will publish some of these articles under the heading “For Debate.” We hope that the publication of these articles will generate discussion among readers and stimulate the submission of letters to the editor. This article is an example. We emphasize that the Southern Medical Journal’s editor-in-chief and its editorial staff, as well as the Southern Medical Association, neither condone nor condemn the content of this article. We are publishing it because it pertains to a relevant issue in the practice of medicine, and we trust that many of our readers will find it of interest. We look forward to receiving comments about it from our readers.

At its most recent meeting, the American Medical Association’s House of Delegates voted, “That the AMA develop guidelines to assist physicians in using the Interact for legitimate electronic prescribing of pharmaceuticals for established patients.”(n1) Guidelines are in fact long overdue. Much of the controversy that has swirled around online prescribing in recent years rests on the absence of guidelines and the consequent uncertainty about what standards are being applied. More than 10,000 Internet-based prescriptions for Sildenafil written by one of us (MJJ) over the past 3 years indicates, however, that restricting electronic prescriptions to patients with whom a previous off-line relationship has been established would curtail the cherished principle of patient autonomy, prevent establishment of new types of patient-physician relationships, and severely limit the economic and efficiency benefits of Internet prescribing–all without improving patient safety or convenience.

Respect for patient autonomy and the patient-physician relationship are fundamental principles of medical ethics.(n2) Autonomy includes the patient’s right to choose the physicians from whom he receives care. The patient-physician relationship establishes the framework of trust and responsibility under which the care will be rendered. The same House of Delegates meeting that recommended development of guidelines for online prescribing adopted a report on the patient-physician relationship(n3) that, after quoting a medical ethicist on the variety of such relationships “given the complexity of professional styles, patient expectations and values, and contexts in which the relationship is established,”(n4) goes on to say, “Irrespective of the circumstances of the encounter between patient and physician, medical ethicists have characterized it as a moral activity.” More specifically, the part of the report officially adopted as part of the Code of Ethics states, “The relationship between patient and physician is based on trust,” and “A patient-physician relationship is generally created by mutual agreement between physician and patient.” Taken together, these various statements reveal no basis for attempting to prevent patients from seeking online medical care from physicians of their choice, regardless of previous relationship. The essence of the patient-physician relationship is trust and agreement, not a face-to-face encounter, and a reasoned medical decision is based on sufficient information, not on how that information is obtained.

Why Patients Seek On-line Consultation

Sildenafil provides a particularly cogent example of why patients may seek consultation from someone other than their usual physician. Many men have been led to consider the firmness of their erections a sign of their manhood. Others may have been brought up to believe that one does not discuss such matters with someone of the opposite sex–even if that someone is a physician. For still others, it is simply too private and too intimate. For all of these reasons and others, patients may prefer to consult with a physician who does not personally know them.

Yet, face-to-face alternatives are not always easy to find. In rural areas, there may be no physician other than the one they usually see–often a personal friend. Individuals in military service, especially if stationed overseas, may also find it difficult to arrange an appointment with an appropriate nonmilitary physician. Patients may have special reasons for wanting the added psychologic and social distance of Internet-based prescribing. One patient of the NET Doctor group, with which one of us (MJJ) is associated, is a professional-level employee at a large Swiss pharmaceutical company. One may speculate that he feels particularly compelled to ensure that his colleagues never hear he has sought a prescription for another company’s product, and finds it reassuring that the physician he consulted will never encounter his colleagues in person.

Other individuals may prefer an Internet-based physician for the same reason the Roman Catholic Church places a screen in the confessional–the absence of face-to-face contact makes the encounter less personal and encourages openness. One patient said, in so many words, “I can’t bring myself to see a doctor.” However, since he did not have to literally see the doctor, he was able to talk about his problem in considerable detail. Many other patients have also been open and candid about details of their sex life and about how their erectile difficulties are affecting their relationship with their partners. Any physician in a physical office setting who encountered the same degree of candor would be justified in concluding that he had fully won the patient’s trust.

Another category is patients who have consulted other physicians, but with less than satisfactory results. As the editor of Internet Medicine remarked regarding a recently published study of Internet Sildenafil prescribing,(n5) “if a primary caregiver is unwilling to discuss intimate matters of importance to patients, or prescribes treatments that are slow and expensive (like counseling) or simply don’t work, patients turn to the Internet.”(n6)

One such patient noted how, over the previous 2 years, he had less and less frequently had firmness enough for sex. “Doctors say I am fine,” he wrote, “but my wife wants, as I do, more.” Unlike the physicians he had previously consulted, NET Doctor Group took his problem seriously.

There are also the patients, especially younger men, who have no current physician and see no need for one. With a single condition requiring medical attention, they prefer to go to a physician on an as-needed basis when it is convenient. Perhaps that is why the NET Doctor Group has had patients in Rochester, MN, who could choose from among the country’s highest per capita physician population. Conversely, one of the authors (MJJ) has been consulted by a patient who just a month earlier had had a kidney transplant. He obviously trusted his transplant physicians but did not want to discuss his sex life with them. (As it happens, the Internet questionnaire and follow-up telephone interview did not provide sufficient information to justify a Sildenafil prescription so soon after the operation. This may be one instance in which an in-office visit, with opportunity for a thorough physical examination, would have allowed the prescription to be written.)

Often, patients come to NET Doctor Group (as they might visit a physician in a physical office) who have had previous Sildenafil prescriptions. Some patients may have been dissatisfied with their previous physician’s services–that may have been why one such patient said he did not want to “renew locally.” Other patients say they have just moved to a new locale or have had their previous relationship disrupted by a change in insurance coverage and have not yet found a new physician.

There may be other reasons as well. In a particularly interesting case from the literature,(n7) a man’s wife confiscated the supply of Sildenafil that his regular physician had prescribed, intending to dole it out as she saw fit. Desiring a supply under his personal control, and not wishing to explain all this to his regular physician, he sought (and obtained) a telephone prescription from a physician acquaintance he did not see as a patient.

The NET Doctor Group gets patients who say they are seeking “less embarrassing” ways to purchase Sildenafil or are looking for a lower cost. These expressions suggest a visit to their physician’s office was not satisfactory or physician fees for renewal are significantly higher than those found on the Internet. This raises the question of whether such patients have a right to demand that their contacts with one physician not be reported to another. Today, they assume this from the nature of the online consultation. Tomorrow it may be a matter of explicit patient choice.

In an ideal world, every patient would have a physician he trusted to manage all aspects of his medical care, even the most intimate. Unfortunately, we do not live in an ideal world. For reasons that may have nothing to do with an individual physician’s competence or empathy, some patients may choose to go elsewhere for certain aspects of their care. The principle of patient autonomy dictates that their wishes be respected.

Safe and Appropriate prescribing

Since patients demand Internet-based prescribing, guidelines must focus on identifying the information needed to safely and appropriately prescribe a given medication. This will obviously vary with the medication. There are some medications, such as the benzodiazepines and narcotics, that have a high potential for abuse. Such medications can appropriately be prescribed only in a setting where risk of abuse and misuse (which frequently occur even in the office-based setting) is significantly reduced.

Most medications are intended to treat specific diagnostic etiologies. In this case, the initial question becomes: What information is required to make the diagnosis and successfully treat the patient? In most instances, the diagnosis will require physical examination or laboratory tests or both. Clearly, such diagnoses cannot be made or treatment initiated without physical contact with the patient. In some instances, diagnoses are routinely made on the telephone. This usually happens when symptomatic reports point clearly to a common disorder that can be treated on an empirical basis. Or perhaps, as with louse infestations, patient descriptions may be sufficient to establish a definite etiology. Clearly, such disorders can equally well be diagnosed on the Internet, as the AMA recognized in its report.(n1)

In other cases, medications are intended to treat symptoms rather than causes. Antihistamines are one example; Sildenafil is another. In such cases, it is only necessary to establish that the symptom exists and that there are no contraindications.

The key to establishing symptoms and detecting contraindications is a careful medical history. Using the Internet, the history is typically taken through a carefully structured questionnaire that may run to more than 50 detailed items. In an office visit, by contrast, the history-taking is likely to be largely free-form. Research has shown that structured questions elicit far more complete and detailed information. For example, Locke et al(n8) found that substituting a computer-administered questionnaire for a standard American Red Cross interview increased the proportion of donors identified as having risk factors for HIV transmission from 0.13% to 4.4%. Owens and Dalzell(n9) found that in a general pediatric clinic, asking questions about five specific sleep behaviors rather than a single open-ended question more than tripled the proportion of children identified as having bedtime issues and also significantly increased the proportion identified as snoring or exhibiting nighttime awakenings. Structured questionnaires have also been shown to improve identification of psychiatric disorders(n10) and of alcoholism.(n11)

There may be occasions when a patient seeks to have a prescription renewed by a physician other than the one who initially issued it. So long as the patient provides sufficient information to allow the physician to make a reasonable medical decision, the appropriateness of the renewal should be clear.

The question is sometimes raised whether patients cannot lie more readily on the Internet. Physicians typically assume patients are telling the truth to the best of their ability. Only inconsistent responses elicit follow-up questions, just as inconsistent responses to an Internet questionnaire elicit a follow-up telephone interview. In contrast to the typical office setting, the NET Doctor Group specifically warns online patients that any false or incomplete answer may have adverse or even fatal consequences.

In summary, the key to appropriate prescribing is obtaining sufficient information to allow the physician to make a reasoned medical decision, not how that information is obtained.

Office Visits: No Panacea

Gunther Eysenbach,(n12) editor of the Journal of Medical Internet Research, recently wrote the following:

FDA evidence for the alleged risks of online prescribing to date merely consists of a few anecdotal cases. The most frequently cited case is the story of a 52-year-old Illinois man with episodes of chest pain and a family history of heart disease, who died of a heart attack in March 1999 after buying Viagra ( Sildenafil citrate) from an online source that required only a completed questionnaire to qualify for the prescription. Though there is no proof linking the man’s death to the drug, FDA officials say that a traditional doctor-patient relationship, along with a physical examination, may have uncovered any health problems such as heart disease and could have ensured that proper treatments were prescribed. However, it should be noted that there have been several similar cases where patients with a comparable history have died while taking Viagra, despite receiving their prescriptions at the doctor’s office.

What is theoretically possible in a face-to-face visit is often not reflected in the real-life behavior of busy physicians, as is confirmed by a study published in the same issue of the journal just cited.(n5) This study contrasted the information available on the first 2,104 patients seeking Sildenafil prescriptions from the NET Doctor Group with that in the medical records of the 36 patients who received Sildenafil prescriptions during the same period at the clinics of an inner-city teaching hospital. Of these 36 records, only 20 recorded a general physical examination during the previous 6 months (including the prescribing visit) and just 16 included a complete list of medications being taken. Blood lipid profiles and tests for diabetes were uncommon, and descriptions of the patient’s sex life and erectile function tended to be sketchy if present at all. It is thus obvious that few clinic physicians took advantage of the theoretical opportunity to seek out the causes of the erectile dysfunction or to counsel the patient, and many were remiss in determining or documenting whether medications that could constitute a contraindication to Sildenafil use were being taken.

The conclusion that office visits are no panacea is reinforced by data on inappropriate prescription of other medications. For example, in-home interviews of community-dwelling elders found that between 22.5% and 29.0% were taking at least one inappropriate medication.(n13) Tamblyn et al(n14) used a “standard patient” approach to examine prescribing of nonsteroidal anti-inflammatory drugs (NSAIDs), finding that 41.7% of the visits by a patient with symptoms of early osteoarthritis resulted in inappropriate prescriptions. The risk of an inappropriate prescription was significantly increased when contraindications to NSAID therapy were incompletely assessed. Using retrospective chart review, Picketing et al(n15) found that only 25% of the prescriptions for ciprofloxacin in an academically oriented long-term care facility were appropriate. Twenty-three percent of the prescriptions were written in the absence of any indication for this medication, while in 49% of the cases an alternative medication was cheaper or more effective or both.

Recent data suggest that the office visit is not effective in ensuring accurate diagnosis and treatment of allergies; 65% of the patients given antihistamine prescriptions for presumed allergies had no IgE reaction to common allergens.(n16) Batty et al,(n17) applying an indicator algorithm to judge the appropriateness of benzodiazepine prescriptions for elderly patients at 17 English and Welsh hospitals, found that 65% of the prescriptions examined were inappropriate.

Clearly, ways to help physicians prescribe more appropriately must be sought. However, it is equally clear that it is inappropriate to judge Internet-based prescribing by an ideal of in-office prescribing that is rarely approached in practice. Focused Internet prescribing may be one way of achieving a higher standard of practice.

Need for Further Research

Guidelines for online prescribing, like clinical guidelines, should be based on solid evidence. Unfortunately, such evidence is largely lacking. The study by Jones(n5) is the only one to report an extensive patient series. Even this study was limited by the fact that patients, having been promised they would receive no unsolicited email, could not be recontacted for follow-up.

Papers published in the New England Journal of Medicine(n18) and Annals of Internal Medicine(n19) cast a negative light on Internet prescribing but provide no direct evidence of patient harm or adverse outcome. These reports are not based on clinical experience, and they use an unverified clinical standard that could almost be called a dogma. As Eysenbach said in his editorial:

This is the bottom line: Currently, we simply do not have sufficient evidence whether, and under which conditions, online prescribing of relatively safe drugs such as the impotence drug Viagra ( Sildenafil citrate) actually creates more harm than benefit, or vice versa. More research is urgently needed to address questions such as which drugs can be prescribed safely and to which kinds of patients, and which safeguards we can install to monitor adverse events.

Eysenbach concluded his editorial by calling for more research. The only conclusion of this editorial is to echo his call and to encourage investigation into the relationships among prescribing paradigms, practice reality, and the Internet.

Key Points

• A valid patient-physician relationship may be established solely on the basis of electronic contact.

• The value and necessity of physical examination for all patient and all medical conditions is unsubstantiated.

• Internet prescribing is an extremely convenient, cost-effective, ostensibly safe system of medical practice suitable for some medications and patients.

• Non-Internet-based practice does not meet the needs of all patients; conversely, Internet prescribing is satisfactory, even preferable, for a substantial number of patients.

• Significant research on the relationship of the Internet to patient safety and prescribing must be conducted before practice guidelines and regulations for Internet prescribing are developed.

On-line Medicine

Carrns A. Is there a doctor on the desktop? Wall St J 2002 May 2;D4, D6.

Some patients in the United States now have the option of logging onto a web site round-the-clock for an on-line “visit” with a physician, in which they can receive a diagnosis and have a prescription faxed to their pharmacy without ever seeing the doctor in person. Roche Diagnostics, a division of Roche Holding AG, has launched the Mydoc.com web site in Indiana and Illinois, with Missouri and other states to follow. In a typical on-line “visit,” the patient responds to a symptom questionnaire that is developed on the basis of the patient’s own answers while progressing through it. A doctor on call is summoned to a computer, which emits a loud tone to alert him or her. The doctor reviews the patient’s symptoms and the software-generated diagnosis, initiates an instant-messaging on-line “chat” with the patient if needed, and either advises the patient to see a physician in person or faxes a prescription to the patient’s pharmacy.

Although the Illinois State Medical Society is not directly in opposition to the practice, the chair of the society’s board of trustees stated that the board has “serious questions” about this practice. Traditional medical ethics require that doctors have an established relationship with a patient before providing the patient with medical advice over the telephone or on-line. The Federation of State Medical Boards has adopted guidelines stating that “treating or prescribing based solely on an on-line questionnaire or consultation does not constitute an acceptable standard of care.” The North Carolina Medical Board recently disciplined three physicians who prescribed ciprofioxacin (Cipro; Bayer HealthCare, West Haven, CT), the antibiotic used to treat anthrax, for patients whom they had never examined.

Although many illnesses require a visit to the doctor’s office, the on-line medical “visit” is designed to help with minor ailments such as earache, nail fungus, or some other problem that the doctor ordinarily would diagnose on the basis of information supplied by the patient. Employers originally offered access to the Mydoc.com web site as an employee benefit, and Roche offered it to employees this year. Mydoc.com executives and doctors who work for them (for which they earn $45-$65/h) point out that their service is not suited to every medical problem, does not offer incentives to prescribe Roche products, and will not operate in states that prohibit doctors from issuing prescriptions without a medical examination. To date, Mydoc.com reports that it has provided more than 800 on-line “visits,” 65% of which involved the issuance of a prescription. One user stated that 30 minutes was the longest wait that she had encountered for an on-line consultation. Insurance does not cover the cost of the on-line visit, but it does pay for prescriptions issued by any licensed physician. Mydoc.com’s charges are $39.95/visit or $15/mo for an annual subscription of six visits. There are extra charges if the patient initiates instant-messaging chats with the on-line doctor.

From Consultative & Diagnostic Pathology, Inc., Lee’s Summit, MO, and Thomasson Editorial Services, Oak Park, IL.

Reprint requests to Miles J. Jones, MD, Consultative & Diagnostic Pathology, Inc., 1704 S.E. 11th Street, Lee’s Summit, MO 64081.

Accepted January 25, 2002.

Copyright © 2003 by The Southern Medical Association

0038-4348/03/9601-0001

References

(n1.)
Report 4 of the Council on Medical Service. Medical care online. Presented at the annual meeting of the American Medical Association House of Delegates, Chicago, June 17-21, 2001.

(n2.)
American Medical Association, Council on Ethical and Judicial Affairs. Opinion 10.01: Fundamental elements or, the patient-physician relationship. Code of Medical Ethics: Current Opinions with Annotations, 2000-2001. Chicago, AMA Press, 2000.

(n3.)
Report of the Council on Ethical and Judicial Affairs. The patient-physician relationship. Presented at the annual meeting of the American Medical Association House of Delegates, Chicago, June 17-21, 2001.

(n4.)
Thomasma DC. Beyond medical paternalism and patient autonomy: A model of physician conscience for the physician-patient relationship. Ann Intern Med 1983;98:243-248.

(n5.)
Jones MJ. Internet-based prescription of Sildenafil : A 2104-patient series. J Med Internet Res 2001;3(1):E2.

(n6.)
Ward BO. Even without peer review, Viagra research shows doctors why patients become Internet-positive. Internet Med 2000;5(6):1,7.

(n7.)
Finkbeiner A. Random musing about a little blue pill. J Ark Med Soc 1998;95:100-101 (editorial).

(n8.)
Locke SE, Kowaloff HB, Hoff RG, et al Computer-based interview for screening blood donors for risk of HIV transmission. JAMA 1992;268: 1301-1305.

(n9.)
Owens JA, Dalzell VP The “BEARS” screening for pediatric sleep problems in the primary care setting. Sleep 2001;24:A216 (abstr).

(n10.)
Staab JP, Datto CJ, Weinrieb RM, et al. Detection and diagnosis of psychiatric disorders in primary medical care settings. Med Clin North Am 2001;85:579-596.

(n11.)
Perdrix A, Decrey H, Pecoud A, Burnand B, Yersin B. Detection of alcoholism in the medical office: applicability of the CAGE questionnaire by the practicing physician: Group of Medical Practitioners PMU [in French]. Schweiz Med Wochenschr 1995;125:1772-1778.

(n12.)
Eysenbach G. Online prescriptions of pharmaceuticals: Where is the evidence for harm or for benefit? A call for papers–and for reflection. J Med Internet Res 2001;3(l):El (editorial).

(n13.)
Hanlon JT, Fillenbaum GG, Schmader KE, Kuchibhatla M, Homer RD. Inappropriate drug use among community-dwelling elderly. Pharmacotherapy 2000;20:575-582.

(n14.)
Tamblyn R, Berkson L, Dauphinee WD, et al. Unnecessary prescribing of NSAIDs and the management of NSAID-related gastropathy in medical practice. Ann Intern Med 1997;127:429-438.

(n15.)
Pickering TD, Gurwitz JH, Zaleznik D, Noonan JP, Avorn J. The appropriateness of oral fluoroquinolone-prescribing in the long-term care setting. J Am Geriatr Soc 1994;42:28-32.

(n16.)
Szeinbach S, Boye M, Muntendam P, O’Conner R. Diagnostic assessment and resource utilization in patients prescribed non-sedating antihistamines. Presented at the annual meeting of the American College of Osteopathic Family Physicians, Philadelphia, March 28, 2001.

(n17.)
Batty GM, Oborne CA, Swift CG, Jackson SH. Development of an indicator to identify inappropriate use of benzodiazepines in elderly medical in-patients. Int d Geriatr Psychiatry 2000;15:892-896.

(n18.)
Armstrong K, Schwartz JS, Asch DA. Direct sale of Sildenafil (Viagra) to consumers over the Internet. N Engl J Med 1999;341:1389-1392.

(n19.)
Henney JE, Shuren JE, Nightingale SL, McGinnis TJ. Internet purchase of prescription drugs: buyer beware. Ann Intern Med 1999; 131:861- 862 (editorial).

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By Miles J. Jones, MD and William Alvis Thomasson, PHD

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Source: Southern Medical Journal, Jan2003, Vol. 96 Issue 1, p1, 5p

Title: GENE THERAPY WON’T REPLACE viagra -YET ,  By: J.R., Science News, 00368423, 04/14/2001, Vol. 159, Issue 15

Section: Biology

From Orlando, Fla., at the Experimental Biology 2001 meeting

Older men who want to revive flagging sexual function have turned in large numbers to viagra . For a few hours, the pills restore the vascular system’s sensitivity to nitric oxide, a compound that facilitates erections. However, viagra doesn’t work in all men, and it also can aggravate heart conditions in some people. That’s why several university teams have been investigating gene therapy as a different way to cure impotence.

With age comes a natural waning in the activity of the genes for making nitric oxide and many other chemicals critical to vascular health. By inserting healthy copies of these genes directly into the penises of affected individuals, researchers hope to offer long-lasting but localized vascular improvements that are unlikely to pose side effects in the heart or other tissues. Last week, urology researchers reported promising preliminary data. By injecting a gene into the penises of aging rats, they restored the organs’ vascular responsiveness and erectile function.

Trinity Bivalacqua of Tulane University School of Medicine in New Orleans and his colleagues focused on the gene that produces CGRP, or calcitonin-gene-related peptide. A CGRP shortfall can make the penis’ blood conduits ignore nerve signals that tell them to relax. That relaxation normally enables these conduits to expand, allowing the flow of blood for erections.

Bivalacqua’s team inserted the CGRP gene into a virus, which they injected into the animals. As long as the carrier virus survived in the rats’ penises-about 1 month-the smooth muscle there produced CGRP. After that, CGRP diminished and so did the old rats’ erections.

Because the diminished activity of different genes may underlie impotence, Bivalacqua expects that gene combos delivered via a longer-lasting virus are the way to go. “The best-case scenario,” he says, “would be something you’d need to inject just once or twice a year. But we’re nowhere near that.”

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By J.R. eiss

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Source: Science News, 04/14/2001, Vol. 159 Issue 15, p237, 1p

Title: SILDENAFIL EFFECTIVE EVEN FOR MEN WITH THE MOST SEVERE CASES OF ERECTILE DYSFUNCTION ,  Modern Medicine, 00268070, Jul98, Vol. 66, Issue 7

Section: meeting abstracts: UROLOGY MEETING

Sildenafil citrate (Viagra) produces some degree of firmness in up to 80% of men with erectile dysfunction of broad-spectrum etiology and in up to 50% of those with the most severe form of impotence –that is, those who never or almost never attain an erection, according to a new clinical trial and a meta-analysis:

CLINICAL TRIAL. Harin Padma-Nathan, MD, presented the results of the largest U.S. trial to date. (His study also appears in the May 14 issue of The New England Journal of Medicine [1998;338:1397-404].) This 6-month, multicenter, safety and efficacy study involved 532 men (mean age: 58) with erectile dysfunction who were randomized to one of four cohorts. One group took placebo, and the others took 25, 50, or 100 mg of sildenafil.

The researchers assessed the frequency of penetration and the frequency of maintained erections at 12 and 24 weeks with a log that patients kept called the International Index of Erectile Function and by simply asking the men if treatment improved their erections. Responses were graded on a scale of 1 (never or almost never) to 5 (always or almost always). The results indicated a clear dose-response effect

At 6 months, 56% of the men who took 25 mg of sildenafil had a mean score of 3.19 for frequency of penetration. This indicates that the men obtained erections sufficient for sex on better than half of their attempts.

The mean score for the frequency of maintained erections in the 25-mg group was 4.02, indicating that the drug helped the men achieve and maintain tumescence in well over two-thirds of their attempts.

In the 50-mg group, the respective scores were 3.51 and 3.49.

In the 100-mg group, scores were 4.02 and 3.93.

Placebo scores were 2.24 and 2.11.

META-ANALYSIS. William Steers, MD, and colleagues looked at sildenafil’s effects in men who had the most severe forms of dysfunction.

They culled data from 10 studies involving a total of 3,361 men. Subjects took either placebo or 50 or 100 mg of sildenafil. Once again, efficacy was assessed by the frequency of penetration and frequency of maintained erection.

Some 46% of the men achieved a mean score of at least 4 for frequency of penetration, and 48% had a score of at least 4 for frequency of maintained erection. Only 8% of the controls scored 4 or higher in both of these areas.

“The take-home message,” says Steers, “is that even in the most severe cases, sildenafil works in almost half the cases.”

Dr. Padma-Nathan is director of the Male Clinic in Santa Monica, Calif., and a clinical? professor of urology at the University of Southern California Medical School in Los Angeles.

Dr. Steers is Chairman of the department of urology and a professor of urology at the University of Virginia Medical School in Charlottesville.

Source: Presentations by and correspondence with Harin Padma-Nathan, MD, and William Steers, MD.

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Source: Modern Medicine, Jul98, Vol. 66 Issue 7, p56, 2p

Title: VIAGRA FALLS ,  By: Clinton, Kate, Advocate, 00018996, 06/23/98, Issue 762

Section: Don’t get me started

I’m no Margaret Mead (although one halloween I cut in some blunt bangs, slipped on a sarong and some sensible shoes, and carried a big walking stick), but I would have to say that straight people are in the middle of a bigger end-of-the-century sex panic than gay people could ever dream of having. On a scale of 1 to Jeff Stryker, it’s big.

Who pushed the actual panic button is debatable. Ken Starrgave rise to President Clinton’s Unwilling National Dialogue on Sex. Every press conference is turned into a town meeting on sex, no matter what visiting head of state is standing next to the First Babe Magnet. “Are you an insatiable sex addict?” “Do you consider oral sex, sex?” (I am so glad he’s not into anal sex.) Even the grande dame of press conferences, Helen Thomas, shouts out, “Mr. President! Show me the monty!” One suspects there is someone behind the podium and that’s why he talks so long.

With banks merging with banks merging with insurance companies merging with entertainment conglomerates merging with phone companies merging with networks merging with arms makers and with nations merging into one European Union, we aretold that bigger is better. Better for whom? Certainly not for poor people, who are actually described as the “unbanked.” Not better for me. I dialed a wrong number the other day and bought a small prison by mistake.

Into this straight sex panic comes the panacea, the so-called magic bullet, Pfizer’s Riser, the Mo’ Bigger Blues, Viagra. What was originally tested as angina treatment to help blood flow to the heart proved unsuccessful in opening the coronary arteries but very successful in keeping a penis erect. This side effect was discovered when test subjects were reluctant to turn in their leftover pills. The drug’s name, suggesting vigor and a trip to Niagara Falls, had been kicking around the company for years. So had Sunny Boner, but Viagra seemed a better fit.

Fueled by stories from Rogained newscasters smirking over their noticeably rising anchor desks, an average of 10,000 prescriptions were written per day in the first month of availability. Some enterprising doctors had rubber stamps made to prevent hand cramping, while other unscrupulous doctors sold through www.penispill.com without so much as a hello, how are you, first I’m going to take your blood pressure. Who knew there was so much impotence in this, the last remaining superpower?

And Viagra is not just for diabetic geezer boomers in Florida, which already looks thicker and straighter on my map. I asked my harried-looking local pharmacist if any women were taking it. She was standing in front of a hastily written THE VIAGRA IS HERE! sign. She shook her head and said with a glimmer of disgust on her usually stoic face, “No, only old men with canes.”

What is the trickle-down effect, if you’ll pardon the image, for the gay community? My gay men friends think it will make straight men happier, which is good for gay men who are often the target of straight sexual resentment. Maybe with something to do at home other than spin cats by the tail, Jesse Helms, Strom Thurmond, even Dan Burton will retire.

It promises to be one heck of a summer. Viagra is already a registered drag name in Miami. Tea dances will be sponsored by Absolut Viagra and replaced by hour-long V dances. Don’t Panic! will put out a BUGGER IS BETTER T-shirt. At circuit parties, renamed Eli Lillith Fairs, someone will have to announce, “Don’t eat the brown Viagra.” There will be Viagra testing at the Gay Games in Amsterdam. If you’re not on it, you’re disqualified.

In all the Viagra-rama there is never any mention of Viagra verite: safe sex, condoms, responsibility, or, dare I say it, rape. I for one am nervous. I am going to stay home this summer and watch the WNBA. In that alternating week that I am gay, I’ll watch that missing episode of EllenVirago.

PHOTO (COLOR): Kate Clinton

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By Kate Clinton

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Source: Advocate, 06/23/98 Issue 762, p85, 1p

Title: Gene data slows drug discovery ,  By: Coghlan, Andy, New Scientist, 02624079, 9/21/2002, Vol. 175, Issue 2361

Section: This week

FAR from speeding up the discovery of drugs, the sequencing of the human genome has actually slowed it down, claims a report unveiled last week.

No one doubts that information revealed by the genome will eventually help researchers develop a vast range of novel drugs, but in the short term the reverse seems to be true. “We are drowning in data,” says Martin Wales of UBS Warburg, the Swiss-based financial services company that produced the report.

“In the long run, perhaps a decade from now, we will see benefits of the genome, but at present the industry is still wrestling with how best to use the information,” he said at a conference in London organised by the BioIndustry Association.

The genome project has revealed thousands of hitherto unknown genes, many of which have been linked to specific diseases. The idea is that if you can work out what protein a gene codes for and what role it plays in a disease, you can understand how to intervene to treat the disease. In other words, you can identify a specific target — a a protein, say — and then develop drugs that “hit” that target.

Up to 70 per cent of the targets identified through genome research may be completely novel, according to an earlier study by the Boston Consulting Group, an international company. The trouble is that it takes expensive and lengthy studies to prove that hitting them will have the desired effect.

A drug called Sildenafil , for example, was originally designed to act on a target linked to cardiovascular disease. Only when researchers at Pfizer began giving the drug to people did another effect emerge — and the bestseller Viagra was born.

Most pharmaceuticals companies aren’t so lucky. To avoid costly failures, they will only invest in developing drugs when the target has been “validated” already. So although the genome is throwing up plenty of potential targets, the bottleneck of validation is deterring companies from making use of the information. Instead, they’re trying to develop better drugs that hit known targets.

The UBS report cites estimates from the Boston Consulting Group suggesting that making sense of genome data will add as much as two years to the development of each drug and cost an extra $290 million. “This greater understanding will come at a cost, certainly for the first three to five years from initial discovery,” it says.

The estimates help to explain the woes of genomics companies attempting to sell information derived from the genome. Wales says that their best bet for survival is to try to develop drugs themselves. Celera Genomics, the company that raced to complete the human genome before the publicly funded project, did just that this year.

“People who say the genome is holding things up are talking nonsense because it’s providing new opportunities,” says John Sulston, former head of the Sanger Centre in Cambridge, a key partner in the public project. “If big pharma can’t see that then they should get out of the way and let universities get on with it.” If the industry focuses on tiny improvements on existing “safe” targets, we could miss out on massive, lifesaving breakthroughs, he adds.

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By Andy Coghlan

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Source: New Scientist, 9/21/2002, Vol. 175 Issue 2361, p11, 1p

Title: REBUILDING THE MALE MACHINE ,  By: Cowley, Geoffrey, Rogers, Adam, Newsweek, 00289604, 11/17/97, Vol. 130, Issue 20

Section: Lifestyle

PHYSICIANS HAVE SPENT CENTUries trying to pump life into flagging male sex organs. Until recently, the treatments were crude and the options limited. But impotence research has come of age in the past two decades, and the arsenal is exploding. If several new drugs fulfill their promise, “taking the pill'’ could soon have a whole new meaning.

As recently as the 1970s, no one knew exactly how erections came about, but the workings of the penis are now well understood. The shaft houses a pair of erectile chambers filled with spongelike tissue that expands dramatically when filled with blood (chart). The chambers would be engorged all the time if blood entered them as freely as it does other tissues. So the body walls them off. Smooth-muscle cells constrict the local arteries, keeping blood flow to a trickle. Similar cells surround the blood-filled spaces in the erectile tissue, preventing any buildup. As long as all these smooth-muscle cells are flexed, the penis stays flaccid.

In a healthy male, that arrangement is easily reversed. Sexual stimulation triggers the release of a neurotransmitter called nitric oxide, which sets off production of several other substances. One of them, a chemical called cyclic GMP, has a knack for relaxing smooth-muscle cells. When doused by cyclic GMP, the cells loosen their grip on the erectile chambers, and the spongelike tissue starts to swell. If nearby veins continued to siphon off excess blood, the effects would be pretty modest. But the swelling tissue pinches those veins against the wall of the erectile chamber, temporarily pinching them shut. “It’s like filling a bathtub,'’ says Dr. Harin Padma-Nathan, director of the Male Clinic in Santa Monica, Calif., and an associate clinical professor at the University of Southern California. “You turn on the faucet, and you put a plug in the drain.'’

Until they understood this sophisticated plumbing system, experts usually blamed erectile problems on psychological ones. Today other factors appear more important. It’s well known, for example, that bike injuries and prostate operations can damage the nerves that control the penile smooth-muscle cells. So can diseases like diabetes, alcoholism or multiple sclerosis. And even when the erectile nerves are intact, drugs prescribed for depression, high blood pressure and other conditions can keep them from firing properly. But the most common cause of impotence is arteriosclerosis, the vascular hardening that leads to heart attack and stroke. Virtually anything that raises the risk of coronary heart diseasecan also cause problems below the belt.

Urologists are rarely able to fix damaged nerves or arteries, but they can usually help men compensate. Until recently, implants and vacuum pumps were all they could offer. But everything changed in 1982, when a surgeon named Ronald Virag accidentally injected a smooth-muscle relaxer called papaverine into the pelvic artery of an anesthetized patient. The man on the table spiked a three-hour erection, inspiring Virag and others to try the same trick on men with erectile problems. It worked. Home injections of papaverine and other smooth-muscle relaxers, such as alprostadil, have since become standard treatments for impotence . The trend began with the off-label use of existing drugs, but pharmaceutical companies are now racing to patent unique formulations.

The first to reach the market was Caverject, an injectable form of alprostadil that Pharmacia & Upjohn introduced in 1995. A similar injectable called Edex received FDA approval this year. And a California company called Vivus has introduced the same drug in a soft pellet called MUSE, which is inserted into the urethra with an applicator. By dilating arteries and relaxing the erectile tissue, these drugs quickly trigger involuntary erections that can last an hour or more. They can also cause pain and, in rare cases, priapism–an excruciating, nonstop erection that destroys penile tissue unless the user gets an antidote. And for all their efficiency, these treatments definitely lack subtlety. “If you’re taking an injection therapy or MUSE,'’ boasts Vivus president Leland Wilson, “you can be doing the dishes or washing your car. You’ll have an erection regardless.'’ What fun.

The ideal remedy would be easier to take, and would make erections possible instead of compulsory. That’s where the pills come in. Three are now in the final stages of development. They have different mechanisms of action, but none requires any fancy equipment, and each can improve sexual function without interfering with dish washing. TAP Holdings’ Spontane (apomorphine) is a non-narcotic morphine relative that stimulates the brain centers involved in erection. In premarketing studies, 70 percent of mildly impotent users have found it useful. Zonagen’s Vasomax (phentolamine) gently dilates penile blood vessels by blocking the effects of adrenaline. Urologists have long included phentolamine in injectable cocktails, but this will be its first time out in pill form. Like Spontane, it’s intended for men with mild problems, but studies suggest only 40 percent benefit. The third pill, Pfizer’s Viagra, looks like the star of its class. When it hits the market, says Dr. John Mulcahy of Indiana University, “most physicians will just say, `You have impotence ? Try it’.'’

Viagra’s active ingredient, sildenafil, was originally studied as a treatment for high blood pressure. It didn’t solve that problem, but it had powerful effects on the penis. By blocking the enzyme that breaks down cyclic GMP, it boosts that chemical’s relaxing effect on the penile smooth-muscle cells. Premarketing studies have included men with varying degrees of impotence , and 60 to 80 percent have benefited. The drug’s most common side effects include indigestion and headaches, and some users report visual disturbances, such as a loss of color perception or a halo effect. But those effects are transitory. Experts are hopeful that low-dose combinations of the new pills will boost benefits and reduce side effects. And researchers are now exploring gene-based therapies that may someday prevent impotence altogether. Until then, an occasional headache may be the price of admission.

PHOTO (COLOR): ‘It’s all hydraulics’: Dr. Irwin Goldstein sees erectile dysfunction as an engineering problem.

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By GEOFFREY COWLEYAND and ADAM ROGERS

With ANDREW MURR

IN SICKNESS AND IN HEALTH

As recently as the 1970s, no one knew exactly how erections came about, but the workings of the penis are now well understood. The organ houses two chambers filled with spongelike tissue that expands dramatically in response to stimulation. Unfortunately, the system is prone to disruptions.

How organ works

Relaxed Erectile chambers would be engorged all the time if blood entered them as freely as it does other tissues. So smooth muscle cells keep a tight grip on the incoming arteries and blood-filled spaces.

Erect: Sexual excitement triggers the release of chemicals that relax smooth muscle cells. Arteries widen and spaces in the erectile chambers fill with blood. The expanding tissue shuts veins, trapping blood.

How it fails

Vascular problems: Arteriosclerosis is the leading cause of impotence . Anything that damages the circulatory system–smoking, inactivity, poor diet-can cause problems below the belt.

Nerve problems: Injury, surgery or disease can damage the nerves that trigger erections. Drugs used for other conditions sometimes prevent the nerves from firing properly.

DIAGRAM: Relaxed

DIAGRAM: Erect

DIAGRAM: Vascular problems

DIAGRAM: Nerve problems

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Source: Newsweek, 11/17/97, Vol. 130 Issue 20, p67, 2p

Title: viagra ’s Good for Your…Heart? ,  Joe Weider’s Muscle & Fitness, 07445105, Dec2002, Vol. 63, Issue 12

Section: Hotline

HEALTH

Men with congestive heart failure and erectile dysfunction safely used viagra to improve sexual function, reports a study in Circulation: Journal of the American Heart Association. The popular medication may even make patients more likely to take their heart-failure drugs, say researchers from the Sao Paulo University Medical School in Brazil. “Heart failure patients may become noncompliant with their congestive heart failure treatment if they feel it causes or aggravates their erectile dysfunction,” explains Edimar Alcices Bocchi, MD. “However, our study suggests that treating the ED may make patients more motivated to take their medicines.”

Most of the men (average age 50) had moderate or severe heart failure, and each had been referred for treatment of erectile dysfunction. When they underwent treadmill tests after taking either 50 mg viagra or a placebo, those treated with viagra had significantly lower blood pressure and heart rate, and improvement in measures of oxygen consumption and carbon dioxide production, compared with those on placebo. Total exercise time also increased significantly. A separate evaluation showed that treatment with viagra was associated with higher scores on a questionnaire related to erectile dysfunction.

By the Numbers

• 28 million: The number of Americans who suffer from migraines.
• 157 million: The number of work days lost each year due to migraine pain.

National Institute of Neurological Disorders and Stroke

QUICK TIP: To stay healthy, maintain a normal weight, eat a nutritious diet, exercise and don’t smoke, advise U.S. health officials.

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Source: Joe Weider’s Muscle & Fitness, Dec2002, Vol. 63 Issue 12, p42, 1p

Title: CAN VIAGRA HELP DISABLED MEN–IS IT SAFE? ,  Accent on Living, 00014508, Winter98, Vol. 43, Issue 3

Now that an impotence pill has been approved, the above question is being asked. The best information we have seen appeared in the July issue of Paraplegia News, who has given ACCENT permission to reprint it. The author is PVA’s Associate Director of Research Melinda Kelley, Ph.D. We have seen no data on the benefit of Viagra to those with disabilities other than SCI, such as polio, muscular dystrophy, multiple sclerosis, etc. Physiatrist Julie Silver, M.D., told ACCENT it should be used very cautiously and only under the close supervision of the personal physician. She warned that in addition to a disability, other conditions may be present that could cause severe complications.

On March 27, the Food and Drug Administration (FDA) approved a new pill that can be used by men to treat erectile dysfunction (impotence). Viagra ( Sildenafil citrate) is the first drug for impotence that can be taken orally; it is now available by prescription nationwide.

Although Viagra is approved to treat impotence, the drug Sildenafil has an interesting history. It was originally tested in the early 1990s as a potential treatment for angina (heart pain). Although Sildenafil is not very useful in treating this condition, it did produce a surprising side effect in subjects involved in clinical testing: It improved erections. Further investigation by the company revealed how the chemical action of Sildenafil (or Viagra) might be causing erections in these subjects and suggested that this drug might be an effective treatment for erectile dysfunction.

Unlike many other impotence treatments (see “Impotence Update,” February 1998), Viagra works by enhancing the normal function of the male reproductive system when it receives sexual stimulation. Under normal conditions, stimulation releases a chemical called nitric oxide (NO) inside the penis. NO in turn increases levels of a chemical signal called cGMP that relaxes the penis’s smooth muscles and allows blood to flow into the organ. The flow of blood causes an erection. As long as cGMP is present, the erection continues.

Viagra helps maintain erections by preventing cGMP from being broken down too quickly so that even small amounts of the signaling chemical are sufficient to cause a prolonged effect. It is important to note that Viagra works with sexual stimulation to maintain penile erections, but it will not produce erections directly. In addition, although the drug may lead to greater self-confidence in the user, it does not improve libido directly. Viagra is currently available in several different doses. Users take it once per day, approximately one hour before intercourse.

In clinical trials, Viagra reduced impotence resulting from many different causes. Specifically, men with erectile dysfunction resulting from spinal-cord injuries (SCIs) are believed to be one of the groups that may benefit from taking Viagra. News reports and the manufacturer’s web site suggest that 70-80% of men with SCI who have taken Viagra report improvement in sexual function (as opposed to 12% of the men on placebos, or “dummy pills”). However, many details of this study have not been provided, such as the levels and severity of SCI present in the subject population. It is not clear if all individuals with SCI/D can benefit from using Viagra.

Dr. Stanley Ducharme, a clinical psychologist at Boston University, agrees. He says, “The jury is still out as to Viagra and SCI. Not enough men with SCI have tried the drug to really know what we can expect. Viagra improves blood flow to the pelvic/genital region and, as we know, this is not the primary issue for men with SCI.” Although problems with nerve function are the cause of impotence in many men with SCI, Dr. Ducharme believes Viagra may help some men who have incomplete injuries and reflex erections. Although Viagra is a promising therapy, it has a number of side effects that may affect some of the men who take the drug. These side effects include the following symptoms:

• Headaches
• Flushing
• Upset stomach
• Stuffy nose
• Urinary-tract infection
• Changes in color vision, particularly in blue-green vision
• Diarrhea, and
• Dizziness

Although these side effects may be mild and temporary in able-bodied men, those with SCI/D should be extremely cautious when considering the use of Viagra. For example, the drug can also produce a decrease in blood pressure (particularly in combination with medications that contain nitrates, such as nitroglycerin either skin patches or tablets). This side effect can be especially problematic for individuals with SCI/D who may also experience lowered blood pressure as a complication of their spinal-cord condition.

In addition, two of the milder side effects, headache and flushing, are also similar to symptoms of autonomic dysreflexia, a condition characterized by dangerous increases in blood pressure in response to number of stimuli in the environment. It is possible for a person to mistake the warning signs of autonomic dysreflexia for the milder side effects of Viagra.

Overall, the FDA’s approval of Viagra is a promising development in the treatment of erectile problems in men with SCI/D. However, more research is necessary to determine the drug’s safety and efficiency in men with different levels and types of spinal-cord conditions.

In addition, Viagra has not been tested in combination with other-treatments for impotence, so the use of this drug with other impotence therapies is not recommended. Some medications may also interact with Viagra so all interested individuals should discuss their medical histories with their healthcare providers to determine whether Viagra will help.

Copyright 1998, Paralyzed Veterans of America, by permission of PN/Paraplegia News

TO LEARN MORE

For more general information about Viagra, contact:

Pfizer, Inc. (Viagra’s manufacturer) (800) 879-3477 www.viagra.com/

Food and Drug Administration (800) 532-4440 www.fda.gov/cder/news/viagra.htm For specific information about whether Viagra is right for you, consult your personal healthcare provider.

Copyright 1998, Paralyzed of America, by permission of PN/Paraplegia News

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Source: Accent on Living, Winter98, Vol. 43 Issue 3, p44, 3p

Title: OPHTHALMOLOGY KEEPS AN EYE ON VIAGRA ,  By: Sabbagh, Leslie B., Ophthalmology Times, 0193032X, 09/01/98, Vol. 23, Issue 17

The remarkable attention showered on Sildenafil citrate (Viagra, Pfizer, Inc.) can be attributed to a variety of factors, not the least of which is its efficacy. Viagra, oral therapy for erectile dysfunction, was approved by the FDA in March and launched in the United States in May.

The medical community has been scrutinizing the drug’s performance and side effects, and ophthalmology is no exception.

Concerns have been raised about the drug’s effects on ocular function, including the well-publicized transient blue-tinged vision and increased light sensitivity phenomena and the potential, relatively unknown, risk in a small minority of patients with retinitis pigmentosa (RP).

“I think Viagra has been shown to be relatively safe in terms of the preclinical studies. There are no clear points of evidence to indicate that unexpected retinal toxicity will occur, but that does not mean that there won’t be,” said Michael F. Marmor, MD, who is a spokesperson for the American Academy of Ophthalmology (AAO) on the issue of Viagra.

“The difficulty with Viagra is several-fold: it causes bluish vision and light sensitivity, which are real signs of irritating the retina. We know pharmacologically that the drug cross-reacts with phosphodiesterase (PDE) 6, the specific form of the enzyme within the eye, although it is designed to be a selective PDE 5 inhibitor,” said Dr. Marmor, professor of ophthalmology, Stanford University School of Medicine, Stanford, CA.

PDE 6 is part of the cascade of events that changes light into a neural signal, and when this is blocked there is a rise in cyclic GMP in the photoreceptor cells, which, if persistent, is toxic.

“The fact is that cGMP rises and falls normally in light and dark and it’s possible that Viagra, which periodically will cause a rise in cGMP, is no more harmful than our daily cycle of light and dark,” Dr. Marmor said.

“But we also know that when it is persistently abnormal, it is toxic, so I think there is at least a rationale for being concerned about a drug that plays with this chemical system within the eye,” he said.

“The amount of data we have clearly supports the safety of Viagra in subjects who do not have retinal degenerative eye disease,” said Ian H. Osterloh, MD, global candidate, team leader, Viagra, Pfizer, Inc., Central Research, Sandwich, England.

A transient effect

However, in cases of hereditary retinal conditions, such as RP, it is wise for doctors and patients to discuss the issue, he advised. The drug, which has a short half-life, has transient inhibition of PDE 6.

The package insert states that a “minority of patients with the inherited condition retinitis pigmentosa have genetic disorders of retinal phosphodiesterases. There is no safety information on the administration of Viagra to patients with the retinitis pigmentosa. Therefore, Viagra should be administered with caution to these patients.”

Viagra is a selective inhibitor of PDE 5 but also has a weaker effect on PDE 6 (10 times weaker in vitro), which is present in photoreceptor cells and is involved in the phototransduction pathway in the retina, Dr. Osterloh said.

“The role of the active PDE 6 is to remove cyclic guanosine monophosphate (cGMP) from the sodium channels in the eye, thereby allowing those channels to close and the light signal to be transduced into an electrical signal in the optic nerve,” explained Peter Ellis, PhD, senior clinical project manager, Pfizer, Inc. Central Research, Sandwich, England.

“The type 6 phosphodiesterase is clearly an important component of the phototransduction cascade,” he said.

The issue arises whether Viagra is toxic at all or more toxic to certain people, noted Dr. Marmor.

“The studies to date did not look at any objective measures, like the ERG, that actually measure electrical activity and viability of cells,” he said.

“Pfizer did one inadequate short-term study dosing eight patients only with 200 mg. However, the subjects showed blood levels that were only equivalent to 100 mg. The results were essentially uninterpretable because there was so much variability. They did no long-term studies and no ERGs were done on diabetics, according to a Pfizer report given on May 15,” Dr. Marmor said.

Pfizer knew, comparatively early on, of Viagra’s effect on PDE 6.

“Importantly, Viagra is a preferential inhibitor of the PDE 5, which is not located in the retina, but in the corpus cavernosum,” Dr. Ellis continued.

In vitro, Viagra can significantly inhibit PDE 6, but this requires about 10 times higher concentrations.

“That we see visual side effects of Viagra is consistent with its pharmacological effect against PDE 6. At therapeutic concentrations effects on the eye are mostly mild and transient, affecting 2.7% of patients, and are consistent with a transient inhibition of a small proportion of PDE 6 in eye,” Dr. Ellis said.

Caution for RP

“We think that the precautions for retinitis pigmentosa that have been included in the U.S. package insert are appropriate. We haven’t formally tested the effect of the drug in those patients, and only one patient with this condition has been treated for about 3 years in the trials,” said Dr. Osterloh.

“The last report we received indicated that he has noticed no change in his condition since he started treatment with Sildenafil ,” he continued.

“We know that a minority of patients with RP have a phosphodiesterase disorder, so giving them a phosphodiesterase inhibitor may make their visual symptoms different from other patients: it could worsen or lessen them,” he speculated.

In fact, one of the exclusion criteria for the clinical trials was the history of RP. The condition occurs in about 1 in 4,000 people, “so even if we hadn’t excluded them, we would have very few in the study,” said Dr. Osterloh.

Pfizer decided that to do a specific study would be very difficult because these “patients often have very variable test results. So while we did specific studies in diabetics, healthy patients, and patients with macular degeneration, we found this would be far more difficult in RP patients,” Dr. Osterloh said.

Visual function testing

In these studies, using a standard battery of visual function tests conducted in patients taking Viagra for up to 12 months, no long-term effects on any aspect of visual function were observed, said Drs. Ellis and Osterloh.

Investigators determined that, in a small number of subjects, Viagra had a transient effect on ability to distinguish blue and green.

Intensive visual function testing of the acute effects of Viagra (visual acuity, contrast sensitivity, visual fields, ERG, IOP, recovery from photo stress, pupillometry; slit lamp examination, and color vision testing) has been done in 31 patients-seven diabetics with pre-proliferative retinopathy and 24 healthy volunteers aged 40 to 65 years, said Dr. Ellis.

“These 31 patients all received twice maximum recommended doses of Viagra (200 mg) because we wanted to give a dose that was high enough to induce visual side effects in a significant proportion of subjects,” Dr. Ellis said.

“The patients may be reporting blue-tinged vision, increased perception of brightness, or possibly blurred vision, but when challenged in visual function tests during those adverse event reports there is no measurable effect on the visual function other than a small difficulty in distinguishing between blue and green shades of color,” Dr. Osterloh said.

The company data also indicated that Viagra had no effect on visual acuity, visual fields, or contrast sensitivity.

These studies, which made up an important part of the drug’s development program, were part of a planned series of a combination of clinical and preclinical research to investigate its visual effects.

Since then the research team has done another study, at the 100-mg dose, in nine patients with macular degeneration. Preliminary analysis reveals only the expected transient change in color vision testing with no effect on visual acuity or photostress.

Controversial issue

Another issue that caused consternation in organized ophthalmology was a statement released by the AAO on May 1, written by Dr. Marmor. The statement cautioned Viagra users about the drug’s potential visual side effects and was printed in the June 1 Ophthalmology Times.

“This press release had a number of statements we wouldn’t disagree with, namely, that patients should stay at the recommended dose,” Dr. Ellis said.

“However, there was a statement in the original press release erroneously referring to a 30% to 50% decrease in electrical activity on ERG lasting at least 5 hours. That was very surprising to us because our ERG results did not suggest any clinically relevant effect of Viagra,” he continued.

“We subsequently discovered that this information was extracted from a very brief summary on the FDA’s web site of a complex study and was taken out of context,” said Dr. Osterloh. “The Web site has now been modified to clarify the data and the bottom line is that Viagra does not have any clinically relevant effect on electrical activity in the eye of healthy 40- to 65-year-old subjects. Subsequently, on May 28 the AAO corrected their press release to reflect this modification.”

Dr. Marmor agrees that this was an erroneous statement, but notes that it had been based on the available public data at the time, the FDA summary. He also pointed out that the study in question was “inconclusive and does not resolve the issue of acute effects one way or the other.”

He said there is “no reason to doubt the veracity of what Pfizer says. However, Pfizer has not done adequate short-term or any long-term objective ERG studies. My hope is, in fact my expectation is, that the drug will turn out not to be a problem. But I don’t know, and I don’t think anyone can know. Frankly, I think it was wrong of Pfizer not to have done long-term ERG studies. Now it will be a year or two down the road before these data will be available to us.”

Long-term data needed

Dr. Marmor said he is “actually not terribly concerned about the short-term data. We know the drug causes blue vision and light sensitivity, and I would expect that if you look critically you will find some subtle ERG changes.”

“My concern is what happens after 6 months or 1 year. We have to be prepared for the long-term effects we’re actually going to see, not the long-term effects the drug company postulates with conservative dosage. If people take Viagra in higher levels than what is prescribed, then we have to expect occasional overdoses,” he said.

Viagra has a short plasma half-life of about 4 or 5 hours, said Dr. Ellis. “We believe we understand the reason for the visual side effects, which are related to a transient pharmacological effect on the enzyme PDE 6 in the photoreceptors.”

“The timing of the visual side effects is consistent with the time of peak plasma concentration. Typically patients report the onset of symptoms about an hour or so after taking the drug and the symptoms may last a few minutes to a few hours,” he said.

Objective examination with a battery of tests including visual acuity, contrast sensitivity, and others has revealed no abnormal findings except some difficulty in distinguishing blue and green during the peak plasma levels on the Farnsworth-Munsell 100 hue test. This side effect is fully reversible.

In long-term studies when the drug is taken as needed, usually once or twice a week, the incidence, type, and severity of the side effects do not increase over time, the researchers contend.

Dogs and rats were dosed at 30 times higher than the maximum recommended clinical dose on a daily basis. The dogs were dosed for 12 months and the rats were dosed for 2 years. Histologic slides reviewed by an independent toxicologist showed normal findings in the treated animals; no retinal pathology was found, Drs. Ellis and Osterloh said.

Still, ophthalmologists note that now is the time to begin researching long-term effects.

“Because information concerning possible long-term effects is lacking, I think a generic note of caution should be made to patients taking it,” said Gerald A. Fishman, MD, professor, Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago.

“I don’t think it is necessarily prudent to alarm individuals that having those symptoms will result in long-term consequences, but they must understand there is an unknown here. I would advise awareness and monitoring for people with normal retinas, and a cautious vigilance for patients with hereditary diseases,” said Dr. Fishman, a retinal specialist, and an AAO spokesperson on the issue of Viagra’s ophthalmic side effects.

Dr. Osterloh stressed the importance of physicians reviewing patient history before prescribing the drug.

“The bottom line is that the patient being prescribed Viagra should be guided by the package insert: one contraindication is concomitant use of nitrates, another precaution is patients with RP. It is important that the prescriber ask the patient if he has any of the medical conditions relevant to the warnings and precautions, including a history of rare eye conditions,” he said.

Dr. Marmor noted that “patients and physicians should be told that this is a new drug with some uncertainties, that it has a direct pharmacological effect on the retina, which so far does not seem to show chronic or persistent symptoms, but which has not been studied objectively,” he said.

“It does have an abuse potential, and some people may be using it outside the indications. We have to be cognizant of that,” he continued.

“Our field force is distributing information about Viagra’s ophthalmic side effects, and RP is part of that. This information is in addition to the package insert, which we hope that every physician would read prior to prescribing any new drug,” said Richard L. Siegel, MD, medical director, sexual health, U.S. pharmaceutical division, Pfizer, Inc.

AMD and diabetes

Concerns have been raised about patients with macular degeneration. Pfizer’s researchers found nothing different in macular degeneration patients and diabetic retinopathy patients (about 10 to 20 in each group) from those seen in the general patient population.

“We have done a study in a group of patients with macular degeneration at the top recommended dose of 100 mg,” Dr. Ellis said.

Although complete results are not yet available, the investigators report no unusual findings. Patients with macular degeneration who participated in long-term controlled clinical trials (up to 1 year), reported the same visual symptoms as patients without known eye disease, he explained.

“We believe the effects on PDE in the eye are similarly transient (4 to 5 hours) and related to the time the drug is in the system, then return to baseline,” Dr. Ellis said.

“So if the average person takes this once or twice a week, data indicate there should be no permanent or long-term problem caused as a result. We are continuing to monitor adverse events in those patients currently in open extension studies,” he added.

Dr. Marmor commented that “Pfizer has looked at diabetics and has found no higher incidence of symptoms, according to their still-unpublished data. I think these patients and individuals with macular degeneration and RP should be more cautious and aware that they’re taking a drug that may have some unknown effects on their eyes.”

As to the concerns raised, Dr. Osterloh said, “all we can do is to publish the results of the studies already performed, continue to monitor safety as we do with all new drugs, and continue to perform studies to reassure ourselves we understand Sildenafil ’s mechanism of action; that it produces a transient effect; that its actions are reproducible; and that side effects do not worsen over time.”

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By LESLIE B. SABBAGH

Reviewed by Gerald A. Fishman, MD, and Michael F. Marmor, MD

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Source: Ophthalmology Times, 09/01/98, Vol. 23 Issue 17, p1, 4p