Silicon Investor (SI) -- The First Internet Community

STOCKTALK

We've detected that you're using an ad content blocking browser plug-in or feature. Ads provide a critical source of revenue to the continued operation of Silicon Investor. We ask that you disable ad blocking while on Silicon Investor in the best interests of our community. If you are not using an ad blocker but are still receiving this message, make sure your browser's tracking protection is set to the 'standard' level.

Biotech / Medical : Ligand (LGND) Breakout! -- Ignore unavailable to you. Want to Upgrade?

To: David L. Hachey who wrote (15886)	2/26/1998 8:07:00 AM
From: Henry Niman	Read Replies (1) \| Respond to of 32384

Dave, Here's an interesting update on isotretinoin: W A S H I N G T O N, Feb. 25 - Makers of a popular prescription acne medication said today they would add a warning to the label telling doctors to look out for depression and suicidal tendencies in their patients. Hoffmann-La Roche said it had received reports of depression and suicide in teen-agers taking Accutane, its prescription product for severe acne. The Nutley, New Jersey-based company would not say how many reports it had received but said it was worried enough to strengthen label warnings that already describe the risk. "The people that treat people with acne should be more attentive to symptoms of depression, psychosis ... and suicide," Roche spokeswoman Kellie McLaughlin said. She said there was no evidence the drug actually caused these symptoms. "It's based on some of the MedWatch reports that FDA and Hoffman have received," she said. MedWatch is a system set up by the FDA with drug companies to track reactions to drugs that are on the market. May Just Be Depression "We looked at it and we thought this was a population at risk," she added. "Teen-agers have a higher incidence of depression than most. It's very hard to tease out exactly what is causing the depression." McLaughlin said Roche had invited experts to examine the reports, but they were unable to find evidence of anything the drug might be doing to cause depression. The label, written up with the approval of the U.S. Food and Drug Adminstration (FDA), says no mechanism of action has been established. This means the drug might not be the cause, and taking a depressed teenager off Accutane might not solve the problem. "Discontinuation of Accutane therapy my be insufficient; further evaluation may be necessary," it will say. McLaughlin said some of the reportedly depressed patients had stopped Accutane before their symptoms were reported. "In many cases they had no taken Accutane for a year and we know that Accutane leaves your system after seven days," she said. Lower Rate for Accutane Users McLaughlin said the average background rate of suicide is about 0.05 percent of the population among teenagers. The suicide rate among those taking Accutane is "far, far, far below that" but she would not say what the rate was. Eight million people have taken Accutane, known generically as isotretinoin. Approved by the FDA in 1982, it is also sold as Roaccutane. Accutane is prescribed for "severe, reclacitrant acne." "It's for the very worst form of acne and recalcitrant means that nothing else has worked," McLaughlin said. "I like to describe the accutane patient as the kid we all remember as having the worst acne in the school-the face that breaks your heart." Teenagers, already at a higher risk of depression, might understandably be upset by such a problem, she said. Accutane can cause severe birth defects and must not be used by women who might become pregnant. It is a vitamin A derivative that decreases the production of oil. Overproduction of oil, which converts to a waxy substance in the glands, is one cause of acne. This waxy build-up irritates the skin, which can become infected.

To: David L. Hachey who wrote (15886)	2/26/1998 8:51:00 AM
From: Henry Niman	Read Replies (1) \| Respond to of 32384

Here's an interest abstract on Type II diabetes: Disruption of IRS-2 causes type 2 diabetes in mice Human type 2 diabetes is characterized by defects in both insulin action and insulin secretion. It has been difficult to identify a single molecular abnormality underlying these features. Insulin-receptor substrates (IRS proteins) may be involved in type 2 diabetes: they mediate pleiotropic signals initiated by receptors for insulin and other cytokines. Disruption of IRS-1 in mice retards growth, but diabetes does not develop because insulin secretion increases to compensate for the mild resistance to insulin. Here the authors show that disruption of IRS-2 impairs both peripheral insulin signalling and pancreatic beta-cell function. IRS-2-deficient mice show progressive deterioration of glucose homeostasis because of insulin resistance in the liver and skeletal muscle and a lack of beta-cell compensation for this insulin resistance. Their results indicate that dysfunction of IRS-2 may contribute to the pathophysiology of human type 2 diabetes. D J Withers, J S Gutierrez, H Towery, D J Burks, J-M Ren, S Previs, Y Zhang, D Bernal, S Pons, G I Shulman, S Bonner-Weir & M F White Disruption of IRS-2 causes type 2 diabetes in mice (Letters to Nature) Nature 391, 900 (1998)

To: David L. Hachey who wrote (15886)	2/26/1998 8:52:00 AM
From: Henry Niman	Read Replies (1) \| Respond to of 32384

Here's what Reuters had to say: Wednesday February 25 6:15 PM EST Gene Linked To Type 2 Diabetes NEW YORK (Reuters) -- Researchers reporting in the current issue of the journal Nature say they may have discovered a gene that plays a role in the development of adult-onset, type 2 diabetes. "Functional abnormalities in (the) IRS-2 (gene) could be involved in the pathogenesis of this human disease," according to researchers at the Howard Hughes Medical Institute at Harvard Medical School, in Boston, Massachusetts. Problems with both the secretion and action of insulin are markers of type 2 diabetes mellitus, the form of the disease which occurs in adults and accounts for 95% of all cases of diabetes. But scientists have so far been unable to pinpoint an underlying mechanism responsible for both of these types of insulin-related malfunction. Research into the IRS-2 gene may help solve that puzzle. The Boston scientists say the gene is linked to the function of insulin receptor substrates (IRS), specific proteins which help regulate the cell's ability to produce and respond to insulin and other diabetes-related compounds. The researchers bred a strain of mice lacking the IRS-2 gene, and compared the medical history of those mice with that of normal mice. None of the mice exhibited diabetic symptoms in the first few weeks after birth. However, the study authors say the gene-deficient mice developed high blood sugar levels by 3 to 6 weeks of age, "and at 6 to 8 weeks of age these mice exhibited marked glucose (blood sugar) intolerance...." By 10 weeks, they say the gene-deficient mice were "overtly diabetic," displaying marked abnormalities in both insulin secretion and insulin action. The investigators note that "this combination of features is a hallmark of human type 2 diabetes." They say the exact mechanisms involved in this gene-related breakdown of insulin function remains unknown, and requires further study. SOURCE: Nature (1998;391:900-904)

To: David L. Hachey who wrote (15886)	2/26/1998 9:02:00 AM
From: Henry Niman	Respond to of 32384

Dave, I suspect that some structural info will be in this report: Drug Metab Dispos 1997 Oct;25(10):1144-1149 Oxidative metabolism of a rexinoid and rapid phase II metabolite identification by mass spectrometry. Shirley MA, Wheelan P, Howell SR, Murphy RC Department of Drug Safety and Disposition, Ligand Pharmaceuticals, Inc., San Diego, CA 92121, USA. LGD1069 (Targretin), a retinoid "X" receptor-selective ligand, or rexinoid, is in clinical trials for treating cancer. Biologically-active oxidized LGD1069 metabolites have been observed in patient plasma samples, making corresponding structural characterizations necessary. Formation of multiple metabolite isomers in vivo has created technical challenges in metabolite structural analysis; however, mass spectrometry (MS) was able to pinpoint two sites of Phase I metabolism. A carbon-13 trideuterated analog was used as an isotopic marker to probe Phase II metabolism of LGD1069. Rats were orally gavaged with an equimolar mixture of LGD1069 and [13C2H3]LGD1069, then anesthetized prior to bile-duct cannulation. Bile was collected for 7 hr, extracted, and concentrated. Recovered metabolites were analyzed by narrow-bore, gradient liquid chromatography (LC) with negative ion, electrospray ionization MS detection. When resultant total ion chromatograms were interrogated for mass spectra exhibiting isotope clusters separated by 4 daltons, 13 such clusters corresponding to Phase II LGD1069 metabolites of nine different molecular weights were detected. Acyl-glucuronide and taurine conjugates of both parent compound and hydroxy-LGD1069 were observed. The sulfate and taurine conjugates of oxo-LGD1069 were also identified, as were 6,7-dihydroxy-LGD1069 taurine, LGD1069 ether glucuronide, and a secondary conjugate (taurine) of the latter. Identities of selected conjugates were confirmed by MS/MS. The results of this study demonstrate that when combined with traditional GC/MS and MS/MS data, the isotope cluster technique can provide powerful selectivity in identifying numerous Phase II drug metabolites during a single LC/MS analysis. PMID: 9321517, UI: 97464548

To: David L. Hachey who wrote (15886)	2/26/1998 9:10:00 AM
From: Henry Niman	Read Replies (1) \| Respond to of 32384

This paper describes Targretin (LGD1069) as well as more potent analogs (LGD1268): J Med Chem 1995 Aug 4;38(16):3146-3155 Design and synthesis of potent retinoid X receptor selective ligands that induce apoptosis in leukemia cells. Boehm MF, Zhang L, Zhi L, McClurg MR, Berger E, Wagoner M, Mais DE, Suto CM, Davies JA, Heyman RA, et al Department of Retinoid Chemistry Research, Ligand Pharmaceuticals, Inc., San Diego, California 92121, USA. Structural modifications of the retinoid X receptor (RXR) selective compound 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2- naphthyl)ethenyl]benzoic acid (LGD1069), which is currently in phase I/IIA clinical trials for cancer and dermatological indications, have resulted in the identification of increasingly potent retinoids with > 1000-fold selectivity for the RXRs. This paper describes the design and preparation of a series of RXR selective retinoids as well as the biological data obtained from cotransfection and competitive binding assays which were used to evaluate their potency and selectivity. The most potent and selective of the analogs is 6-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2- yl)cyclopropyl]nicotinic acid (12d; LG100268). This compound has proven useful for investigating RXR dependent biological pathways including the induction of programmed cell death (PCD) and transglutaminase (TGase) activity. Our studies indicate that the induction of PCD and TGase in human leukemic myeloid cells is dependent upon activation of RXR-mediated pathways. PMID: 7636877, UI: 95363839