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Biotech / Medical : PFE (Pfizer) How high will it go? -- Ignore unavailable to you. Want to Upgrade?

To: BigKNY3 who wrote (6937)	2/7/1999 11:33:00 AM
From: BigKNY3	Respond to of 9523

No cause for alarm over retinal side-effects of sildenafil Eberhart Zrenner 01/30/99 The Lancet Page 340 Are the visual symptoms of which some patients taking sildenafil complain an alarming side-effect of the drug? In this issue of The Lancet, Michael Vobig and colleagues report a decrease in the a-wave and b-wave amplitude in the electroretinogram (ERG) of five healthy men 1 h after they took 100 mg sildenafil citrate (Viagra) orally. The changes had completely disappeared 5 h later. Results of all other electrophysiological and clinical tests (visual acuity, visual field, colour vision, intraocular pressure) were normal. Phosphodiesterase type 6 is required for the transformation of light into electrical signals; therefore, retinal effects of phosphodiesterase inhibitors are not unexpected and are well known from studies in cats 1 2 and in human beings.2 4 Since sildenafil, which is mainly an inhibitor of phosphodiesterase type 5, also weakly inhibits phosphodiesterase type 6, high plasma concentrations of sildenafil can be expected to inhibit the phototransduction process in retinal photoreceptors, if the drug passes the blood-retina barrier. Tests by Pfizer in anaesthetised dogs5 have shown that sildenafil transiently increases the implicit times of the a-waves and b-waves and reduces the amplitude of the a-wave at threshold plasma concen-trations that were four times higher than those achieved after the recommended maximum therapeutic dose in human beings. These effects were reversible and declined in a manner consistent with the plasma half-life (4 h) of sildenafil. McNemar's test of the results of a pilot randomised double-blind placebo-- controlled crossover study (protocol 148-232, report of Nov 25, 1997, Pfizer) in eight volunteers who took 200 mg sildenafil did not reveal statistically significant effects of sildenafil on cone-mediated or rod-mediated ERG responses. Can there be an explanation for the discrepancy between these findings and those that Vobig and colleagues found with only 100 mg of the drug? First, there are methodological questions. Vobig and colleagues' report does not make clear whether the protocol satisfied every important specification made by the International Standard for Clinical Electrophysiology (ISCEV)6 for ERGs-eg, fixed duration of dark adaptation (at least 25 min), full dilatation of the pupil by mydriatic agents, and stimulation by standardised light flashes-because although their test light produced a fully developed ("saturated") a-wave, the amplitudes of the a-wave show less than half the amplitude of scotopic a-waves recorded according to the ISCEV standard.7 Second, mydriatic agents generally used for ERG have a short duration of action. If the investigators had assumed that the drops applied before the recording of the control ERG were still active and did not reapply them before the recording 1 h after ingestion of sildenafil, the ERG amplitude would be reduced, as observed. However, the reduction would be due to a narrowing of the pupil,8 not to sildenafil. The drops would certainly have been reapplied for the final test 6 h after ingestion of sildenafil, so the response then would be the same as that obtained before sildenafil. Nevertheless, even if the ERG changes were confirmed to be due to sildenafil, they are not alarming. The drop in b-wave amplitude correlates with only a very weak loss in light sensitivity of less than 0.2 log units, which is similar to the light-absorbing effect of a car windshield. No sensitivity decrease was observed in the visual field data and all effects were fully reversible. Such an effect would not be deemed toxic (as long as the individual has a normal healthy retina) but would be taken to be the expected reversible effect of retinal phosphodiesterase, probably in principle not different from the effect in sexual organs. Studies in dogs that received 65 times the maximum recommended dose for human beings daily for 12 months indicate that repeated exposure of human beings to therapeutic doses of sildenafil are unlikely to impair retinal function or alter retinal morphology. Thus, Vobig and colleagues' findings do not imply that sildenafil taken in therapeutic doses and not repeated excessively increases the risk of visual impairment for healthy individuals with normal retinas. Nor do they imply that patients taking sildenafil should have their retinal function monitored. People with genetic phosphodiesterase defects, which are very rare, will know from an early age of their retinal impairment, and they should be advised not to take sildenafil.9 More extensive and carefully controlled studies are necessary to clarify the mode of action of sildenafil on retinal function and to study the long-term effects of the drug in patients with retinal diseases. Eberhart Zrenner University Eye Hospital Tubingen, Department of Pathophysiology of Vision and Neuro-Ophthalmology, D-72076 Tubingen, Germany

To: BigKNY3 who wrote (6937)	2/7/1999 11:36:00 AM
From: BigKNY3	Read Replies (2) \| Respond to of 9523

The Math of Stock Splits: 1 + 1 = 2, or Maybe More By SANA SIWOLOP 02/07/99 The New York Times Page 10, Column 5 ACCORDING to one version of a story, Yogi Berra was once asked whether he'd like to have his pizza cut into six or eight slices. He figured he was pretty hungry; he asked for eight. When it comes to stock splits, many investors seem to have similar ideas. In anticipation of stock splits, they are bidding up stocks by extraordinary amounts. Yet by definition, when companies split their stocks, they create nothing in the way of new wealth, because investors simply receive a greater number of shares at reduced prices. The total value stays unchanged. Consider Pfizer, which announced on Jan. 28 that its board would vote on a 3-for-1 stock split in April. Its stock jumped $5.625 that day, to $127.5625. Yet when Pfizer handed in stronger-than-expected fourth-quarter earnings on Jan. 19, its stock actually fell a little over 6 cents. Splits may be adding to market volatility, analysts say. Shares of I.B.M. slipped more than $17 on Jan. 22, when it posted better-than-expected earnings, yet did not announce a long-speculated stock split. Four days later, when I.B.M. did announce a split, its shares rose $3.625, to $185.625; the next day, they fell more than $7 a share on profit-taking. ''Stock splits have garnered their own momentum players,'' said Paul Cherney, an analyst at the Standard & Poor's Corporation. ''At one time a split might have meant something more intrinsically fundamental about a company's future prospects, but now splits are adding to the market volatility.'' AMONG companies on the New York Stock Exchange, there were 224 splits of at least 3 for 2 last year. In January of this year, splits set a blistering pace -- a total of 35, versus 22 in January 1998. Splits used to be of some importance because brokers charged penalties for so-called odd-lot purchases -- less than 100 shares of a given stock. That meant that a small investor had reason to delay buying until he could buy a round lot of 100 shares; splits thus increased the pool of available buyers. But the odd-lot penalties were eliminated years ago. A share split can be read as a vote of confidence by management, who wouldn't authorize it if they thought the share price would soon fall. But the issue of when to buy a splitting stock is the subject of much research. Studies conducted last year by both Merrill Lynch and S.& P. found big gains in companies' stock shortly before a split, though they did not specifically address performance at the time a split is announced. The S.& P. study looked at 359 New York Stock Exchange issues that had splits of at least 2 for 1 between January 1995 and December 1997. It found that the stocks gained an average of 3.97 percent between the 20th trading day that preceded the official split and the day of the split. The S.& P. 500 stock-index averaged a 2.03 percent gain during that time. The S.& P. study found that the companies that split their stocks saw them grow an average of 16.2 percent in the year after the split, while the S.& P. gained 28.2 percent. The Merrill Lynch study, which looked at stocks in the S.& P. index that split between 1986 and 1998, found that companies outperformed the S.& P. 500 by an average of 27.44 percentage points during the year before a split, but by just 3.91 percentage points in the year after. Graph: ''Splitsville, Baby'' shows splits of stocks listed on the New York Stock Exchange with 3-for-2 exchange ratios or more, from 1991 through Jan. 31., 1999 (Source: Standard & Poors Corp.)