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Also in this issue:Anthrax Vaccine . Page 52
Dolasetron . Page 53Corrections . Page 54
SILDENAFIL: AN ORAL DRUG FOR IMPOTENCE
Sildenafil citrate (Viagra − Pfizer) is the first oral drug approved by the FDA for treatment
of erectile dysfunction. Alprostadil is also marketed for this indication but must be injected
into the corpus cavernosum (Caverject) or pushed into the urethra (MUSE).
MECHANISM OF ACTION —
Sildenafil potentiates the physiological response causing
penile erection after sexual arousal. Nitric oxide released from nerve endings and endothelial
cells binds to receptors on the smooth muscle of the corpus cavernosum, causing formation
of cyclic guanosine monophosphate (cGMP); cGMP relaxes smooth muscle, allowing engorge-
ment (TF Lue in PC Walsh et al, eds, Campbell’s Urology, 7th ed, Philadelphia:Saunders, 1998,
page 1157). The process is reversed by conversion of cGMP to GMP, which is catalyzed in the
corpus cavernosum by phosphodiesterase type 5. Sildenafil inhibits this phosphodiesterase,
which is also found in vascular smooth muscle, and, to a lesser extent, inhibits phospho-
diesterase type 6 in the retina. It has little effect on phosphodiesterase type 3, which is in-
Sildenafil has an oral bioavailability of about 40%. Taken fast-
ing, plasma concentrations reach a peak in about 1 hour. A fatty meal delays the peak by
about 1 hour and decreases the peak concentration without affecting total absorption (GJ
Muirhead et al, Br J Clin Pharmacol, 42:268P, 1996). The drug is metabolized in the liver to an
active metabolite, primarily by CYP3A4. It is excreted largely as metabolites, about 80% in
stool, 13% in urine, and less than 0.001% in the semen. Both the parent drug and the active
metabolite have a half-life of about 4 hours. Clearance is slower in men more than 65 years
old and in those with hepatic or severe renal insufficiency.
CLINICAL STUDIES —
Only one published study of sildenafil used objective measure-
ments. In a randomized controlled crossover trial after visual sexual stimulation, plethysmo-
graphic measurements in 12 men with erectile dysfunction of unknown etiology found that
the mean duration of erections was about 1 minute with placebo, 4 minutes with 10 mg of
sildenafil, 7 to 8 minutes with 25 mg and 8 to 11 minutes with 50 mg. These same men then
kept records of erectile activity after taking 25 mg of sildenafil or placebo once daily for 7
days; the number of erections within 2 hours after taking the drug was about 5 times greater
with the drug than with placebo (M Boolell et al, Br J Urol, 78:257, 1996).
The manufacturer reports unpublished studies in which more than 3,000 men with erec-
tile dysfunction took 25, 50 or 100 mg of the drug or placebo at home for up to 6 months in
EDITOR: Mark Abramowicz, M.D.
CONSULTING EDITOR: Martin A. Rizack, M.D., Ph.D.,
Rockefeller University ASSOCIATE EDITORS: Donna Goodstein, Amy Faucard
CONTRIBUTING EDITORS: Philip D. Hansten, Pharm. D.,
University of Washington; Neal H. Steigbigel, M.D.,
Albert Einstein College of Medicine
ADVISORY BOARD: Martin D. Abeloff, M.D.,
Johns Hopkins University; William T. Beaver, M.D.,
Georgetown University School of Medicine; Louis S. Goodman, M.D.,
of Utah College of Medicine; Jules Hirsch, M.D.,
Rockefeller University; James D. Kenney, M.D.,
Yale University School of Medicine; Gerhard Levy, Pharm.D.,
of N.Y. at Buffalo; Gerald L. Mandell, M.D.,
University of Virginia School of Medicine; Hans Meinertz, M.D.,
University Hospital, Copenhagen; Dan M. Roden, M.D.,
School of Medicine; F. Estelle R. Simons, M.D.,
University of Manitoba EDITORIAL FELLOWS: Sandip K. Mukherjee, M.D.,
Yale University School of Medicine; Jordan W. Smoll-
Harvard Medical School; Gianna Zuccotti, M.D.,
Albert Einstein Coll. of Medicine EDITORIAL ADMINISTRATOR: Marianne Aschenbrenner
Founded 1959 by Arthur Kallet and Harold Aaron, M.D. Copyright
The Medical Letter, Inc. (ISSN 0025-732X)
double-blind trials and completed questionnaires on sexual function. The drug did not affect
the frequency of attempted intercourse. In 4 fixed-dose trials, improvement in erections was
reported by 63% of 214 patients taking 25 mg, 74% of 391 taking 50 mg and 82% of 380 taking
100 mg of the drug, and in 24% of 463 taking placebo. The effect was detectable as soon as
30 minutes after taking the drug and for as long as 4 hours. Some patients have reported in-
creased erectile activity the next day. The manufacturer reports statistically significant im-
provement in subgroups with cardiovascular disease, diabetes, transurethral prostatectomy,
spinal cord injury and in those taking antidepressants, antihypertensives or antipsychotic
drugs. After radical prostatectomy, improvement in erections was reported by 43% of pa-
tients taking the drug and 15% taking placebo.
ADVERSE EFFECTS —
In recommended doses, sildenafil lowers blood pressure slightly
in normal patients and substantially in patients taking nitrates for angina pectoris. Headache,
flushing and dyspepsia have been the most common adverse effects reported in clinical trials.
Nasal congestion, diarrhea, dizziness and rash have occurred. Transient abnormal vision—
usually a color tinge or increased sensitivity to light—has been uncommon; it occurred more
frequently with 100 mg than with 50 mg of the drug. Unlike other drugs for impotence,
DRUG INTERACTIONS —
Sildenafil potentiates the hypotensive effect of nitrates; con-
current use with any nitrate, short- or long-acting, could cause a potentially fatal drop in
Cimetidine (Tagamet), erythromycin and ketoconazole (Nizoral) inhibit
CYP3A4, decrease metabolism of sildenafil and may increase plasma concentrations. Itra-
conazole (Sporanox) and mibefradil (Posicor), which also inhibit CYP3A4, might act similarly.
Rifampin increases CYP3A4 activity and might decrease the effect of sildenafil.
DOSAGE AND COST —
Viagra is available in 25-, 50- or 100-mg tablets. The manufactur-
er recommends initial dosage of 50 mg, which can be increased to 100 mg if necessary, 1
hour before intercourse. Patients more than 65 years old, those with hepatic or renal impair-
ment and those taking a CYP3A4 inhibitor should probably start with 25 mg. The drug should
not be used more than once a day. Viagra costs the pharmacist $262.50 for a bottle of 30 ta-
blets of any size, according to First DataBank PriceAlert, April 15, 1998.
Sildenafil appears to be an effective oral drug for treating erectile dys-
function, but some patients do not respond and its safety remains to be established. The hy-
potensive effect of the drug may be troublesome in some patients. Men who take nitrates or
use nitrate patches for angina pectoris should not take sildenafil.
Now that the US Secretary of Defense has decided to vaccinate more than 2 million
members of the US armed forces against anthrax, US physicians may be asked to answer
some questions about the vaccine and the disease.
THE DISEASE —
Anthrax is caused by the gram-positive, spore-forming bacterium Ba-
cillus anthracis. The spore may persist in nature for many years and infect grazing animals
such as sheep, goats and cattle. Cutaneous anthrax is the most common form of the disease,
but inhalation anthrax is most important to the military. Within 1 to 6 days, or possibly
longer, inhaled anthrax spores can cause fever, cough and weakness, which can progress in 2
The Medical Letter • Vol. 40 (Issue 1026) May 8, 1998
or 3 days to respiratory failure, followed by septic shock and multi-organ failure. Untreated,
the mortality rate of inhalation anthrax is about 95% (DR Franz et al, JAMA, 278:399, 1997).
THE VACCINE —
Anthrax vaccine, produced by the Michigan Biologic Products Institute
in Lansing, is a sterile filtrate of cultures of an avirulent strain that elaborates protective an-
tigen. It has been licensed by the FDA since 1970. No controlled trials are available, but ex-
perience with the current vaccine in high-risk industries with exposure to imported animal
products has been that anthrax generally has not occurred in workers who received 2 or more
doses of the vaccine, and has occurred in some unvaccinated workers. A protective antibody
response usually does not develop until 7 days after the second dose. In rhesus monkeys,
vaccination has been highly effective against a lethal aerosol challenge. The vaccine is well
tolerated. Erythema and tenderness, usually mild, occur uncommonly at the site of injection.
Anthrax vaccine is given in a volume of 0.5 ml subcutaneously at 0, 2 and 4
weeks and at 6, 12 and 18 months. An annual booster is recommended to maintain immunity.
For emergency use after exposure to an anthrax aerosol, the vaccine should be given prompt-
ly and again 2 weeks later, accompanied by an appropriate antibiotic.
The anthrax bacillus is highly susceptible in vitro to penicillin, amoxicil-
lin, chloramphenicol, doxycycline, erythromycin, streptomycin and ciprofloxacin, among oth-
ers, but resistant to third-generation cephalosporins. In animal studies, an appropriate antibi-
otic started after respiratory exposure to anthrax spores and continued for 5 to 10 days pro-
tected against the disease during therapy, but animals died when the antibiotics were discon-
tinued. Thirty days’ treatment with an antibiotic alone is generally effective in animals, even
after discontinuation, but vaccination alone is not (AM Friedlander et al, J Infect Dis,
167:1239, 1993). The current recommendation for prophylaxis after exposure is vaccination
plus oral doxycycline 100 mg b.i.d. or ciprofloxacin 500 mg b.i.d. for at least 30 days. For
treatment of a symptomatic patient with inhalation anthrax, the drug of choice, until suscepti-
bility tests are available, is ciprofloxacin 400 mg IV q 8-12h.
It is possible to produce B. anthracis strains that are resistant to antibiot-
ics. Whether it would be possible to produce strains resistant to the current vaccine remains
Anthrax vaccine is safe and effective for pre-exposure prevention of an-
thrax. After exposure, both vaccination and a prolonged course of antimicrobial prophylaxis
are recommended for the previously unvaccinated.
DOLASETRON FOR PREVENTION OF NAUSEA AND VOMITING
DUE TO CANCER CHEMOTHERAPY
Dolasetron (Anzemet − Hoechst Marion Roussel), a selective serotonin (5-HT ) receptor
antagonist similar to ondansetron (Zofran) and granisetron (Kytril − Medical Letter, 36:61,1994), is now available for both oral and intravenous use in prevention of nausea and vomit-
antagonist plus dexamethasone (Decadron, and
others) is the most effective regimen for prevention of acute vomiting caused by cancer
chemotherapy. Dolasetron has also been approved by the FDA for prevention and treatment
of postoperative nausea and vomiting.
The Medical Letter • Vol. 40 (Issue 1026) May 8, 1998
Dolasetron is rapidly metabolized in plasma and in the liver to
hydrodolasetron, an active metabolite that is further metabolized in the liver by CYP2D6 and
CYP3A, and eliminated mainly in urine and partly in feces, with a half-life of about 8 hours.
CLINICAL TRIALS —
The effectiveness of dolasetron as an antiemetic appears compar-
able to other 5-HT antagonists (F Roila et al, Eur J Cancer, 33:1364, 1997). A randomized trial
in 609 patients receiving cisplatin (Platinol) found that a single dose of 1.8 mg/kg of do-
lasetron IV was completely effective in preventing acute vomiting in 49% of patients, com-
pared to 46% with 2.4 mg/kg of dolasetron IV, and 50% with ondansetron 32 mg IV (P Hesketh
et al, J Clin Oncol, 14:2242, 1996). Dolasetron IV has also been found equivalent to gran-
isetron (B Audhuy et al, Eur J Cancer, 32A:807, 1996). Oral dolasetron in a dose of 100 mg
completely prevented emesis in about 60% of patients treated with moderately emetogenic
regimens (EB Rubenstein et al, Cancer, 79:1216, 1997).
ADVERSE EFFECTS —
The adverse effects of dolasetron are similar to those of ondan-
Mild headache and dizziness may occur. Transient ECG interval
changes (PR, QTC, JT prolongation and QRS widening) are dose-related, usually clinically
insignificant and resolve spontaneously. Dolasetron given for 24 months increased the in-
cidence of hepatocellular adenomas and carcinomas in mice.
DOSAGE AND COST
Dolasetron − Anzemet (Hoechst Marion Roussel)
Granisetron − Kytril (SmithKline Beecham)
1. Cost to the pharmacist based on wholesale price (AWP) listings in Drugs Topic Red Book Update, April 1998.
2. Based on the cost of a 5-ml single-dose vial containing 100 mg.
3. Based on 80% of the cost of one 20-ml multidose vial containing 40 mg.
4. Many clinicians have found 8-mg doses of ondansetron as effective as the FDA-approved 32-mg doses.
5. Based on the cost of a 1-ml single-dose vial containing 1 mg.
Dolasetron is effective for prevention of acute nausea and vomiting due
to cancer chemotherapy, but offers no clinical advantage over ondansetron or granisetron.
The article on raloxifene (vol. 40, page 29, March 13, 1998) stated that
raloxifene and cholestyramine should be taken at least 2 hours apart. Data are lacking, how-
ever, and the manufacturer recommends that the drugs not be used concurrently.
Antibacterial Drugs Corrections:
In The Choice of Antibacterial Drugs (vol. 40, page 42, March
27, 1998) under "Spirochetes," the name Leptospira was omitted between Borrelia andTreponema. Also, the wholesale cost of cefaclor should be $24.08 for the generic and $67.26
for Ceclor, and the cost of generic cefadroxil should be $55.34. The cost of azithromycin
tablets is correct for 10 days’ use, but azithromycin is usually recommended for 5 days, 500
mg on day 1 and 250 mg qd on days 2 through 5, which costs $38.33.
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The Medical Letter • Vol. 40 (Issue 1026) May 8, 1998
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Abstract of study submitted for presentation at the 18th Annual Meeting of the North American Skull Base Society, Chicago, USA, May 24-27, 2007 A safety study of the use of Vivostat® patient-derived fibrin sealant containing tranexamic acid in neurosurgery. Poulsgaard L*, Mørck A# and Holm NE#: *The Neuroscience Center, Department of Neurosurgery, Rigshospitalet, Copenhagen, Denmark. #V