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: Andrew H who wrote (12029)	12/3/1997 9:03:00 PM
From: Henry Niman	Respond to of 32384

Andy, While looking for the leptin story, I ran across this one which may relate to the survival of the species (which I guess could be avoided by either concentrating on the source of environmental estrogens or really focusing on nuclear translantation: A role for oestrogens in the male reproductive system Oestrogen is considered to be the 'female' hormone, whereas testosterone is considered the 'male' hormone. However, both hormones are present in both sexes. Thus sexual distinctions are not qualitative differences, but rather result from quantitative divergence in hormone concentrations and differential expressions of steroid hormone receptors. In males, oestrogen is present in low concentrations in blood, but can be extraordinarily high in semen, and as high as 250pgml-1 in rete testis fluids, which is higher than serum oestradiol in the female. It is well known that male reproductive tissues express oestrogen receptors, but the role of oestrogen in male reproduction has remained unclear. Here the authors provide evidence of a physiological role for oestrogen in male reproductive organs. They show that oestrogen regulates the reabsorption of luminal fluid in the head of the epididymis. Disruption of this essential function causes sperm to enter the epididymis diluted, rather than concentrated, resulting in infertility. This finding raises further concern over the potential direct effects of environmental oestrogens on male reproduction and reported declines in human sperm counts. R A Hess, D Bunick, K-H Lee, J Bahr, J A Taylor, K S Korach & D B Lubahn A role for oestrogens in the male reproductive system (Letter to Nature) Nature 390, 509 (1997)

To: Andrew H who wrote (12029)	12/3/1997 9:07:00 PM
From: Henry Niman	Respond to of 32384

Andy, Here's the Nature summary: Leptin inhibits hypothalamic neurons by activation of ATP-sensitive potassium channels Leptin, the protein encoded by the obese (ob) gene, is secreted from adipose tissue and is thought to act in the central nervous system to regulate food intake and body weight. It has been proposed that leptin acts in the hypothalamus, the main control centre for satiety and energy expenditure. Mutations in leptin or the receptor isoform (Ob-RL) present in hypothalamic neurons result in profound obesity and symptoms of non-insulin-dependent diabetes. Here the authors show that leptin hyperpolarizes glucose-receptive hypothalamic neurons of lean Sprague--Dawley and Zucker rats, but is ineffective on neurons of obese Zucker (fa/fa) rats. This hyperpolarization is due to the activation of a potassium current, and is not easily recovered on removal of leptin, but is reversed by applying the sulphonylurea, tolbutamide. Single-channel recordings demonstrate that leptin activates an ATP-sensitive potassium (KATP) channel. Their data indicate that the KATP channel may function as the molecular end- point of the pathway following leptin activation of the Ob-RL receptor in hypothalamic neurons. D Spanswick, M A Smith, V E Groppi, S D Logan & M L J Ashford Leptin inhibits hypothalamic neurons by activation of ATP-sensitive potassium channels (Letter to Nature) Nature 390, 521 (1997)

To: Andrew H who wrote (12029)	12/3/1997 9:22:00 PM
From: Henry Niman	Read Replies (1) \| Respond to of 32384

Andy, The paper indicates that leptin binds to its recetor in the brain which then activates this ATP channel. They suggest that drugs could target this channel, but I don't think that the channel is specific to the brain, so I'm not sure how the proposed drug would acheive specificity. The article does reinforce the concept that the "full feeling" is activated when leptin binds to its receptor in the brain. This could be acheived in two ways (LGND's two programs). One would increase leptin levels in the blood which would then lead to increases in the brain. The other approach would just send out a drug to mimic the signal. Since obese people already have elevated leptin levels in their blood, it seems likely that an even larger amount is needed to be effective. AMGN found some positive results from injecting leptin, but only saw significant effects at the highest dose which caused irritation. Thye are trying to reformulate the drug to allow higher levels to be acheived. LGND's program with LLY seeks to do this with small oral molecules that will bind to proteins affecting the leptin promotor which will then make the cells make more leptin. The small molecules could cause leptin levels to rise sufficiently high in the blood to ultimately increase the concentration in the brain. However, in many cases, obesity mat be due to a faulty transport system. Since the leptin molecule is large, it must be actively transported across the blood/brain barrier. There is some evdidence for such a defect in obese humans (their leptin levels are lower than expected in spinal fluid which also involves transport). LGND's second leptin program (the one delayed for almost a year now) would use small molecules that would represent the leptin/receptor binding signal. Thus, when they passively cross the blood/brain barrier (without having to be transported by the defective transport system), they would generate this same signal in the brain that activates the ATP channel. However, they would use the leptin/receptor specificity.