anticomplementary activity and inhibition of T-cell targets for the treatment of obesity and diabetes. New proliferation of clionasterol and 5α,8α-epidioxy-24α- compounds included the LIFR antagonist, hLIF05 and ethylcholest-6-en-3-ol isolated from methanolic LG-100641, a selective antagonist of PPARγ but with extracts of the marine spnge, Xestospongia exigua.
insulin sensitizing actions in adipocytes. The smallinsulin sensitizers discussed were CLX-0901, isolated Industrial applications
from plant extracts and currently in phase I clinicaltrials, TLK-17411, a small synthetic compound and S- A synthetic route to two ambergris ketals from 15261, which increases insulin sensitivity. anticopalic acid, the main resin acid extracted fromPinus pinaster Ait needles, was presented by Dr MMarcelo-Curto (INETI, Lisbon, Portugal). Both Introduction
ambraketal and isoambraketal were obtained by This symposium was chaired by Dr Patrick Doyle (F selecting the appropriate catalysts for the 5,6- Hoffmann-La Roche Ltd, Basel, Switzerland) and epoxycarbonyl rearrangement of the α-epoxyketone directly followed on from two consecutive one-day precursor obtained by controlled oxidation of anticopalic acid. Leaves of Salvia scalarea have also respectively. The meeting was attended by been used as the source of the ketone precursor.
Syntheses of other potential odoriferous ketals using pharmaceutical companies and biomedical research. As abietic acid or dehydroabietane as starting materials, with previous IBC conferences, this year's meeting have also been developed by Dr Marcelo-Curto's aimed to review the status of current molecular research group. Dr C Erdelmeier (Dr Willmar Schwabe GmbH and potential future developments in preclinical and & Co, Karlsruhe, Germany) gave a current overview of clinical drug development. It addressed the current some industrially important medicinal plants. Updates knowledge in the fields of adipogenesis and insulin on the phytochemical and pharmacological properties resistance with particular emphasis on new insulin of the medicinally relevant plants Gingko biloba, sensitizer drugs that lack adipogenic actions.
Hypericum perforatum and Crataegus oxyacanthawere discussed. Dr A Stafford (Phytera Ltd, Sheffield, Regulation of adipogenesis and anti-obesity
UK) presented the scope for plant cell cultures to providers of new pharmaceutical leads. Aspects of Dr Gérard Ailhaud (University of Nice, France) opened manipulation, extraction and screening strategy were the day's proceedings with a comprehensive introduction to the molecular mechanisms of adipocyte differentiation.
He focused on the regulation of the early signaling events that occur in confluent pre-adipocytes and lead to their The PSE 2000 meeting attempted to demonstrate the commitment to terminal differentiation. He discussed the importance of plant natural products as sources of roles of two pre-adipocyte factors, prostacyclin (PGI2) pharmaceuticals, as well as cheap and renewable and leukemia inhibitory factor (LIF-1), which are starting materials in the perfume industry. It is clear secreted by these cells and act in an autocrine manner to that plant secondary metabolites and marine natural promote adipocyte differentiation. Binding to the products continue to be areas of major interest. The prostacyclin receptor (IP-R) and LIF receptor (LIF-R), isolation and structure elucidation of plant constituents triggers the PKA and MAPK pathways, respectively, dominated the meeting, with data on the biological which in turn activate the critical expression of C/EBPβ activities of plant natural products given less focus [Ref and C/EBPδ genes. This then ignites the transcriptional events leading to adipocyte differentiation via PPARγexpression. Interestingly, PGI2 antibodies and the LIF-R antagonist, hLIF05, can substantially blunt both Obesity, NIDDM, Adipogenesis and
hormone-induced and thiazolidinedione-induced Insulin Resistance - IBC’s Ninth
differentiation. Although the expression of LIF and IP- International Conference
R is not seen in differentiated adipocytes, theproduction of angiotensin (Ang II) by adipocytes is Adipogenesis and Insulin Resistance
thought to act in a paracrine fashion (via PGI2) to 3-5 April 2000, London, UK
further promote pre-adipocyte differentiation. These Reported by Jaswinder K Sethi, Harvard School of
early upstream signals not only shed light on the Public Health, Boston, MA, USA
adipogenic nature of long chain fatty acids but may alsoprovide potential targets for anti-obesity drugs.
This meeting focused on the recent developments in thefields of adipogensis and insulin resistance. In Remaining with the control of adipogenesis, Dr James particular the molecular mechanisms presented were Paterniti (Ligand Pharmaceuticals Inc, San Diego, CA, those that are likely to be relevant as drug discovery USA) revealed a novel selective antagonist of PPARγ, ID weekly highlights Copyright  Current Drugs Ltd, May 2000. ISSN 1365-5884 Middlesex House, 34-42 Cleveland Street, London W1P 6LB, UK • LG-100641 (Ki = 435 nM; structure not disclosed), that associated TNFα) is not only biologically active in also retains some insulin sensitizing properties similar adipocytes but is disproportionally elevated in adipose to the thiazolidinedione, rosiglitazone (BRL-49653; tissue of obese rodents and human subjects. This SmithKline Beecham plc). Dr Paterniti presented clearly adds a local autocrine mode of action to this Ligand's characterization studies, which suggest that cytokine's complex repertoire. Downstream of ligand LG-100641 inhibits PPARγ-agonist induced activation binding, TNFα acts on multiple loci to inhibit insulin of the PPARγ/RXR heterodimer. It does this by receptor signaling, regulate adipose secretagogue preventing recruitment of co-activators to the receptor production (FFA, leptin PAI-1 and TGFβ) and obesity- complex. This is reflected in the ability of LG-100641 related apoptosis of brown adipose tissue. An to inhibit fat cell differentiation induced by understanding of its mechanisms of action would rosiglitazone. However, like rosiglitazone, LG-100641 provide obvious potential for novel targets for (in a similar micromolar range) also acts to stimulate therapeutic intervention. The use of in vivo models basal fat cell glucose uptake in cultured 3T3-L1 deficient in functional receptors has indicated that adipocytes, as well as to potentiate insulin-stimulated TNFR1 (p55) is the dominant mediator of TNFα glucose uptake. Although the mechanism of this function in obesity. However, the role of TNFR2 (p75) agonist-like action of LG-100641 remains unclear, this remains unclear. The recent development of pre- in vitro profile is consistent with an agent that promotes adipocyte cell lines deficient in either or both of the insulin sensitivity but not adipogenesis. LG-100641 TNF receptors promises to facilitate a better may therefore have important potential for the understanding of the complexities of TNFα biology and treatment of obesity-linked Type II diabetes.
Unfortunately, the fact that LG-100641 was unable toinhibit differentiation induced by a standard adipogenic Currently, it is not clear whether preventing TNFα cocktail (cf LIF-R antagonists), brings its potential for signals in humans has any impact on Type II diabetes.
use as an anti-adipogenic agent into question. Future in However, the use of pentoxyfilline (an inhibitor of TNF vivo tests should reveal whether it is active in a production) in treating vascular complications that occur in diabetes has already indicated improvementsinsulin sensitivity of Type II patients. Numerous Dr Patrick Doyle (F Hoffman La Roche Ltd, Basel, therapies that block TNFα are also already available Switzerland) discussed the importance of lipid lowering and are currently being tested as potential therapies for in future treatments of Type II diabetes. He rheumatoid arthritis (RA). Most seem to be well recapitulated the public health burden of both obesity tolerated and issues regarding their efficacy are being and its consequences and suggested that, by targeting addressed. It will be interesting to see how insulin dietary fats with drugs such as Xenical (orlistat; F sensitivity is altered (if at all) in these trials. In all, as Hoffman La Roche Ltd), which is a lipase inhibitor, wecan combat diet-induced obesity. He stated that with other anti-diabetic strategies, targeting TNFα although Xenical blocks up to 30% fat absorption in the production and/or signaling has great potential to gut, which translates into a 5 to 10% weight loss improve insulin sensitivity in obesity. If successful, maintained over a period of 1 year, this small such a strategy carries with it the added bonus of percentage is clinically meaningful, since it correlates decreasing production of other modulators of insulin well with improved glycemic control. This observation action (ie, FFA and leptin) that are also elevated in has also been made in the orlistat studies. In addition, obesity. Furthermore, the associated action on reducing the recent preliminary findings of the 2-year XENDOS circulating PAI-1 and TGFβ has obvious benefits in (Xenical for the prevention of non-insulin dependent reducing the CVD risk that is also associated with diabetes in obese Swedes) study demonstrate that obesity. In addition, unlike thiazolidindiones such as subjects treated with this lipase inhibitor show a roziglitazone, anti-TNF therapy is unlikely to increase markedly reduced rate of development of Type II fat mass. Alternatively, the efficacy of several diabetes when compared to their placebo controls.
therapeutic approaches such as leptin and β3andrenoreceptor agonists may be enhanced if combined TNFα signaling as a target for the
with anti-TNF therapy, as the latter should lead to treatment of Type II diabetes?
healthier target tissues with improved β3andrenoreceptor numbers. Future clinical studies In obesity, elevated levels of adipose-derived TNFα have been linked to insulin resistance, as well as to anumber of other obesity-related pathological states, New insulin sensitizer molecules for the
such as dislipidemias, hypertension, and increased riskto cardiovascular diseases. Dr Jaswinder Sethi (Harvard treatment of diabetes
School of Public Health, Boston, MA, USA) reported Perhaps the most excting aspects of this year's meeting that amongst the most recent work carried out at were the developments in small molecule insulin Harvard School of Public Health, it was demonstrated sensitizers. Dr Prasad Manchem (Telik Inc, San that the precursor of soluble TNFα (membrane- Francisco, CA, USA) informed us that Telik has ID weekly highlights Copyright  Current Drugs Ltd, May 2000. ISSN 1365-5884 Middlesex House, 34-42 Cleveland Street, London W1P 6LB, UK• utilized target receptor affinity profiling (TRAP) methoxy-2-[3-trifluoromethyl)-phenyl]-ethylamino)ethyl- technology to screen and identify a number of 4-(2-(9H-9-fluorenyl)acetyl]aminoethyl)benzoate]; chemically synthesized drugs that activate insulin Servier) and its active metabolite, S-15511 [(-)-5- receptor tyrosine kinase (IRTK). One of these is TLK- methoxy-5-[3-(trifluoromethyl)phenyl]-3-azapentanol].
17411 (TER-16998; structure not disclosed) a potent The orally active agent was developed for the treatment (micromolar range) and highly selective agonist for of the 'insulin resistance syndrome'. Although the IRTK (ie, it does not activate similar RTKs, such IGF-1 mechanism of action of this compound is not fully or EGF). It may inhibit IGF-1-induced mitogenicity and understood, the current pharmacological data suggests EGF-stimulated EGFR phosphorylation. However, that S-15261 acts at both the liver and skeletal muscle, when used at sub-threshold concentrations, TLK-17411 at least in part to enhance insulin sensitivity. In addition can also enhance insulin-stimulated tyrosine recent studies using the JCR:LA-cp/cp rat model (a phosphorylation of IR and IRS-1 leading to increased non-diabetic, insulin resistant model that also develops insulin-stimulated glucose uptake. It is orally active and atherosclerotic lesions and cardiovascular dysfunction), can reduce blood glucose in hyperglycemic rodents.
indicate that S-15261 improves insulin sensitivity, Furthermore, it can potentiate insulin-stimulated decreases food intake body weight and circulating glucose uptake in at least three rodent models of Type insulin concentrations and improves vascular function.
II diabetes. In all, the profile appears to be remarkably In comparison, 100 mg/kg troglitazone (Sankyo Co similar to that previously reported for the fungal Ltd) may reduce insulin but it increases both food compound, L-783281 (Merck Research Laboratories), intake and body weight and does not reduce the extent which is presently undergoing preclinical investigation.
of vasculopathy in the same model. Metformin (Merck- Despite this promising data, a number of issues such as Lipha SA) was not effective at 100 mg/kg in this study.
action on fat tissue development, weight gain and S-15261 does not appear to have significant adverse effects, even at doses higher than the pharmacologicallyeffective range. In conclusion, all these activities make Calyx Therapeutics Inc, a company that has taken a S-15261 a potentially useful drug for simultaneously very different drug discovery approach, reported a third treating obesity related insulin resistance and its small insulin sensitizer. Calyx has screened water- associated pathophysiological complications.
soluble plant extracts already shown to havepharmacological properties and now have a number of Exercise as an alternative method of
compounds in their repertoire that include agonists and increasing insulin sensitivity
antagonists of PPARγ/RXR, and anti-inflammatories The molecular basis of the ability of exercise to reverse that act to inhibit TNFα action, as well as compounds insulin resistance was discussed by Dr Jorgen that improve β-cell function. However, Dr Bishwajit Wojtaszewski (Copenhagen Muscle Research Center, Nag (Calyx Therapeutics Inc, Hayward, CA, USA) Denmark). He presented the investigations using muscle- focused his presentation on the characterization of specific IR or Glut4 knockout rodents. These indicate CLX-0901 (Calyx Therapeutics Inc; structure not that GLUT4 is absolutely required for both insulin- and disclosed) which, like L-783281 and TLK-17411, acts contraction-stimulated glucose uptake and that exercise- by selectively activating IRTK and subsequently stimulated glucose transport is independent of functional stimulating glucose uptake. Unlike these compounds, insulin receptors. Dr Wojtaszewski also suggested that however, the mechanism of interaction may be quite exercise might have the added bonus of enhancing the different since CLX-0901 inhibits insulin binding. This action of insulin for up to 48 h after exercise regimes.
raises the intriguing possibility that it may compete with The mechanism of this sensitization is apparently insulin for the same binding sites; could this be a true independent of IRTK, AKT and GSK activities and insulin mimetic? The extensive in vivo studies that were remains to be identified. However, exercised muscle reported demonstrate that CLX-0901 is orally active in at glycogen is depleted compared to rested muscle and this least four different models of rodent diabetes, it can may be involved in the regulation of glucose transport.
significantly lower glucose, insulin, triglycerides, free Nonetheless, the benefits of exercise training remain fatty acids and cholesterol. High doses (up to 1g/kg) do intact in both NIDDM patients and healthy people. From not show any hypoglycemic effects and, unlike the a drug discovery perspective, this presentation clearly thiazolidinediones, it does not increase body weight and highlighted the possibility that other IR-independent can increase leptin concentrations by up to 40%.
mechanism(s) leading to enhanced glucose transport may Toxicological studies have been completed and the Phase also be available for therapeutic targeting.
1 trials (using single doses of up to 2 g) indicate that it isremarkably safe and very well tolerated.
Dr David N Brindley (University of Alberta, In the light of the recent withdrawal of troglitazone, Edmonton, Canada) presented the investigations on the news of a number of potentially 'safe' insulin mimetics insulin-sensitizing actions of S-15261 ([2-(2-(2- and/or sensitizers lacking adipogenic activity was ID weekly highlights Copyright  Current Drugs Ltd, May 2000. ISSN 1365-5884 Middlesex House, 34-42 Cleveland Street, London W1P 6LB, UK • received with enthusiasm. Indeed, it is clear that current particularly the direct costs (including the cost of drug approaches are not simply being limited to complications), together with a quality of life treating insulin sensitivity or obesity alone, but also targeting other associated complications. However,these are early days since only one of the drugs Data were collected according to a common study discussed (CLX-0901) has reached clinical trials and its design using a practitioner questionnaire (used in all long-term use in human subjects remains to be tested.
eight countries) and a patient questionnaire (used in Despite this, the initial profile together with news of five countries). More than 500 general practitioners other similar drugs in the pipeline does seem very supplied data on more than 7000 patients with an age diagnosis of more than 30 years and with diagnoseddiabetes for more than 6 months. In the practitioner Meanwhile, major strides are also being made in surveys, items assessed included clinical evaluation, understanding the molecular mechanisms involved in such as glucose concentration, lipids and blood obesity-related insulin resistance. These have clearly pressure, and economic considerations, including the been aided by the development of powerful new costs of patient visits, hospitalization and drug approaches such as a variety of knockout models (both treatment. Both surveys gave rise to demographic data, in vivo and in vitro) that promise to facilitate the rapid which included the indirect costs, such as travel time dissection of the molecular events leading to for treatment, loss of earnings and early death. Patient adipogenesis and insulin resistance. These will no data contributed to the assessment of quality of life.
doubt provide multiple novel targets for future drugdiscovery approaches [Ref IDdb].
The study concluded that prevalence rates across thecountries ranged from 2% in the UK up to 7.7% inItaly. Across the 7000 population in the study the mean Obesity, NIDDM, Adipogenesis and
age of the patients was 66 years, 50% being female Insulin Resistance - IBC's Ninth
with a mean body mass index (BMI) of 29 with a mean9 years since diagnosis. Insulin therapy was being used International Conference (Part II)
by 24% of the patients and 17% were on dietary and Non-Insulin Dependent Diabetes Mellitus
exercise regimes, with the remaining patients being 3-5 April 2000, London, UK
treated with oral hypoglycemic drugs. Expenditure as apercentage of overall healthcare costs varied across theeight countries: 3.4% in the UK; 6.7% in Belgium; Introduction
3.2% in France; 4.4% in Spain; 7.4% in Italy; 6.3% in This three-day meeting focused on obesity on the first Germany; 1.6% in Netherlands; and, 4.5% in Sweden.
day, non-insulin dependent diabetes mellitus (NIDDM) The overall mean of total healthcare costs was 5.0%.
on the second day, and insulin resistance andadipogenesis on the final day. The well-organized The healthcare costs of the diabetic population were at meeting attracted an audience of around 70 people from least 65% more than the average healthcare costs.
academia and the pharmaceutical industry, most of Analysis of the direct costs shows that the proportion of whom attended for all three days. The NIDDM day had those costs spent on diabetic drugs was only 7%, a broad focus that included the costs and the origins of whereas the cost of other drugs used in the diabetic diabetes, and new strategies and data on potential population was three-fold higher at 21% of direct costs.
targets, including clinical data. The sessions were The major cost, however, was hospitalization (55% of chaired by Professor Mike Cawthorne (University of Buckingham, UK) and Professor Nick Hales(Cambridge University, UK).
The cost of other drugs arose mainly through the use ofcardiovascular and lipid-lowering drugs in the diabetic Cost of diabetes in Europe
population. With respect to complications, the patient Dr Jeff Kirsch (SmithKline Beecham Pharmaceuticals, population was divided up into those with no Harlow, UK) presented the CODE-2 study (cost of complications, those with microvascular complications, diabetes in Europe - Type II), the first European effort those with macrovascular complications, and those with to measure the cost of Type II diabetes using similar both micro- and macrovascular complications. Patients methodology across eight countries: Belgium; France; with microvascular complications have 1.7-fold higher Germany; Italy; The Netherlands; Spain; Sweden; and, healthcare costs than patients with no complications; the UK. The study was set up to address the similarly, patients with macrovascular complications misconceptions about the severity of diabetes and to have 2.2-fold higher costs. However, it appears that provide up-to-date economic data needed for policy micro- and macrovascular complications have an decisions. The primary objective of the study was to additive effect as the additional costs in patients with measure the total healthcare cost, with secondary both complications was 3.4-fold higher than in those objectives of measuring the components of those costs, ID weekly highlights Copyright  Current Drugs Ltd, May 2000. ISSN 1365-5884 Middlesex House, 34-42 Cleveland Street, London W1P 6LB, UK• In utero origins of NIDDM
Buckingham, the University of Geneva and ProteomeSciences plc. Professor Mike Cawthorne (University of Professor Nick Hales (Cambridge University, UK) Buckingham, UK) presented on behalf of Jean-Charles discussed the growing hypothesis that much of the Sanchez (University of Geneva, Switzerland). It was etiology of NIDDM arises from in utero programming in noted that whilst the genomic approach has identified, response to protein deprivation. In studies conducted by at least in animal studies, a number of genes potentially Dr Hales and David Barker (Southampton University, associated with the development of obesity and UK) on a Hertfordshire population, they found a high diabetes, so far none of these have materialized into correlation between low birth weight and the successful drug targets. One possible reason is that the development of NIDDM and hypertension in later life. A messenger RNA level in a tissue does not correlate well critical factor in the development of NIDDM in low birth-weight subjects is the development of obesity. Alow birth-weight infant who remains slim does not carry Proteomics has the additional advantage of being able the risk of having diabetes. However, if the low birth- to detect post-translational modifications that cannot be weight infant becomes obese in adult life there is then a predicted from gene sequences. Professor Cawthorne significant risk of developing diabetes. The ratio in terms argued that the chances of successful use of the of developing insulin resistance syndrome is much higher proteomics approach could be enhanced by the use of than in developing diabetes in later life and is 14-fold phenotypically well-defined experimental paradigms.
higher than that of a normal birth weight subject, He illustrated this by demonstrating a paradigm for irrespective of obesity. The relationship between low detecting downstream insulin sensitizer targets in birth-weight and development of diabetes is not genetic.
various tissues using genetically obese and lean mice Studies on monozygotic and dizygotic twins have shown treated with the insulin sensitizer drug rosiglitazone that the lower birth-weight twin is very much more likely (SmithKline Beecham plc). The obese but not the lean to become diabetic than the higher birth weight twin. Dr mice showed improved insulin sensitivity with Hales discussed a wide range of studies throughout the rosiglitazone. The selective modulation of differentially world where the general correlation had been shown, expressed proteins in various tissues of lean and obese including studies in the Polynesian Islands and in Mysore mice by rosiglitazone treatment provides potential in India. In the Mysore study, 29% of 506 babies had a molecular targets. Such differentially expressed birth weight of less than 2.5 kg. The rate of diabetes in proteins could be targets for therapy or could have this population was 15%, compared to a UK survey in diagnostic value, or could indeed represent pathway Ely that gave a figure of 6%. In individuals over 50 years proteins for use as tags to identify further secondary of age, abnormal glucose tolerance was found in 46% of targets using Biocore or yeast two-hybrid systems. This experimental paradigm was able to yield differentiallyexpressed proteins in insulin-responsive tissues such as Professor Hales then went on to demonstrate how the muscle, liver and adipose tissue and also in pancreatic human syndrome could be largely replicated in rats by islets. Since insulin sensitizers have been shown to be providing a reduced protein diet to pregnant rats with post- islet-protective in animal models, and there are weaning transference to a high fat diet. Such a strategy indications that they are also islet-protective in humans, produced permanent changes in carbohydrate metabolism these findings of differentially expressed proteins in in the liver, which included increased gluconeogenesis and islets represent potential new therapeutic targets that resistance to both insulin and glucagon in skeletal muscle, might be associated with the remodeling of islet cell where there was an increase in basal glucose uptake. There was also an increased sensitivity to sub-maximal insulinconcentrations in adipose tissue, where there was a reduced Islet cell metabolism was also discussed by Dr Dennis insulin response with respect to the antilipolytic action of McGarry (University of Texas Southwestern Medical insulin, and a change in expression of P110β. There was Center, Dallas, TX, USA). In his talk on fatty acids and also a reduction in the β-cell mass of pancreatic islets.
insulin secretion, Dr McGarry noted that the Professor Hales concluded by examining longevity and stimulatory effect of circulating free fatty acids on demonstrated that pups that were malnourished during the insulin secretion has been known since the early 1960s, fetal period but undertook catch-up growth during lactation but it has only been in the last five years that the had a lower longevity. This seemed to be associated with a molecular basis of this response has begun to be loss of telomeres in kidney. Kidney damage was also understood. Dr McGarry demonstrated that in fasted manifest as an early increase in albuminuria.
subjects the presence of fatty acids in the circulation isessential in establishing a normal insulin secretory New drug target strategies
response to a carbohydrate or meal challenge. In The potential of proteomic studies in obesity and in contrast to this physiological role of fatty acids in the NIDDM to identify new molecular targets was the regulation of insulin secretion, it now appears that subject of a joint presentation by the University of chronic exposure of the β-cell to higher levels of free ID weekly highlights Copyright  Current Drugs Ltd, May 2000. ISSN 1365-5884 Middlesex House, 34-42 Cleveland Street, London W1P 6LB, UK • fatty acids or to very low density lipoproteins can bring the post-meal glucose surge and also allow the β-cell to about both basal hyperinsulinemia and an inadequate rest and recover between meals. Dr McCormack insulin response to a glucose challenge, ie, the claimed that repaglinide was more β-cell-specific than phenotype that characterizes Type II diabetes. McGarry suggested that the accumulation of triglycerides inmuscle could lead to insulin resistance whilst the R&D programs within Novo Nordisk are directed at all accumulation of triglycerides in pancreatic β-cells major areas of phenotypic expression of NIDDM. The could induce a β-cell lipotoxicity with the subsequent inhibition of phosphotyrosine phosphatase-1B as a means of enhancing and prolonging insulin signalingevents is of particular interest. This arises from studies The use of animal models for evaluating potential in knockout mice, which showed increased insulin therapies for diabetes and obesity was discussed by sensitivity and obesity resistance. Phosphotyrosine Professor Cawthorne, who noted that obesity and phosphatase-1β inhibitors can normalize plasma NIDDM were diseases in which there was a defect in glucose and insulin levels in the ob/ob and db/db the multi-organ interaction that regulates fuel balance.
diabetic mouse models. Novo Nordisk is also looking Both diseases involve the brain, the pancreas, the liver, at the inhibition of glucagon action and of glycogen skeletal muscle and adipose tissue, and there is no cell phosporylase inhibition. It was suggested that chronic line that can mimic the diabetic phenotype. With inhibition of glycogen phosphorylase was a means of respect to animal model systems, no models, with the achieving glucose lowering without the danger of possible exception of the Rhesus monkey colony in hypoglycemia. In the context of increased insulin Baltimore, truly represent the human condition. Most secretion, glucagon-like peptide (GLP)-1 is a unique researchers have used monogenic rodent models or hormone with five separate actions. It stimulates insulin rodents fed on a high fat diet to look at individual secretion and decreases glucagon secretion in a aspects of the syndromes, such as insulin sensitivity glucose-dependent manner, and also inhibits gastric measurements. Models need to be carefully selected emptying, decreases appetite and promotes β-cell based on the nature of the molecular target and the rescue. However, GLP-1 is rapidly deactivated by dipeptidyl peptidase IV such that the half-life is about 2min after iv administration. Novo Nordisk is seeking Dr Jim McCormack (Novo Nordisk A/S, Bagsvaerd, long-acting GLP-1 analogs as a means to overcome this Denmark) presented part of Novo Nordisk's developing portfolio of new therapeutic approaches. He noted thatthe landmark UK prospective diabetes study (UKPDS) Enhancement of endogenous GLP-1 by inhibition of of NIDDM led to the conclusion that intensive blood dipeptidyl peptidase IV was the subject of the final talk glucose control by whatever means leads to of the day, presented by Dr Hans-Ulrich Demuth significantly fewer late complications. This study also (Probiodrug Gesellschaft für Arzneimittelforschung led to the recommendation that treatment should be mbH, Halle, Germany). Dr Demuth noted that not only more aggressive and should aim to achieve HbAIC was GLP-1 very unstable, but the cleavage product, values that are as low as possible and that treatment GLP-19-36, was a potent antagonist. Dr Demuth outlined should include more combination therapies, together the strategy for identifying useful inhibitors of GLP-1 with earlier and more frequent use of insulin. The hydrolysis which led to the compound P32/98 UKPDS study also pointed to the inadequacies of (Probiodrug Gesellschaft für Arzneimittelforschung current therapies and the requirement for new mbH), a reversible inhibitor with fast offset and onset approaches to treating diabetes. Dr McCormack kinetics. Chronic daily application of P32/98 to obese suggested that earlier and more frequent use of insulin Zucker rats led to improved glycemic control relative to (as recommended by UKPDS) could be achieved by the both controls and to rats given glibenclamide. P32/98 development of a device and formulation whereby was given at 5.00 pm with the glucose measurements insulin is delivered by the pulmonary route. Novo being made at 9.00 am the following morning, Nordisk is currently evaluating this approach in clinical demonstrating a long duration of response. This was trials. Issues such as bioavailability and precision of further exemplified by measurements of HbA1C. Safety dose and breath control need to be addressed but the and tolerability have been established in phase I clinical expected greater patient compliance and the removal of studies, which also demonstrated that the peptidase IV the need for injections are obvious advantages.
activity of P32/98 is dose-dependent in plasma.
A second modification of an established therapy is the concept of prandial glucose regulation using the non-sulphonylurea secretagogues such as repaglinide It is clear that NIDDM (which should now be called (Boehringer Ingelheim Corp). Data were provided Type II diabetes) is a major disease with considerable showing that these short-acting prandial glucose unmet clinical need. The data on the cost of Type II regulators could induce a more efficient clearance of diabetes in Europe together with earlier data from the ID weekly highlights Copyright  Current Drugs Ltd, May 2000. ISSN 1365-5884 Middlesex House, 34-42 Cleveland Street, London W1P 6LB, UK• US indicate that patients have much greater healthcare countries attended the meeting and approximately 500 costs than non-diabetics. The finding that the majority oral and poster presentations were displayed. The of these costs relate to the morbidity of drug treatment and the cost of severe diabetic complications, with primary antidiabetes treatment only being responsible nanoparticles, liposomes, emulsions, dermal and for 7% of total costs indicates the potential economic transdermal delivery, analytics and quality assurance, benefit of effective therapies. It has long been the belief pulmonary delivery, ophthalmics, mucosal and that a genetic predisposition was a key element in the epithelial carriers, and controlled release.
development of Type II diabetes. This may have beenover-stated and there is growing data that in utero Opening session
nutritional programming is a significant factor in the The introductory talks and the APV and APGI award etiology of type II diabetes. The meeting demonstrated ceremonies were followed by the APV lecture by that there was significant scope for developing new Professor Charles Weissman (Imperial College of therapies to improve metabolic control, with Science, Technology & Medicine, London, UK) on the combination therapy is likely to be the norm in the molecular biology of prion diseases. Professor future. The potential of proteomics used in carefully Weissman presented data on human prion diseases and defined model systems to identify proteins discussed the resistance to heat sterilization and to differentially expressed in diseased and normal tissue radiation of scrapie agent (prion). He explained that was highlighted as a tool to identify new molecular prions do not contain nucleic acid and asked 'How can a protein replicate without a nucleic acid?' ProfessorWeissman concluded that these diseases are bothinherited and transmissible, with transmission occurring Pharmaceutics, Biopharmaceutics and
mostly by feeding bone/meat meal, but the details are Pharmaceutical Technology - Third
World Meeting (Part II)
Pharmaceutical biotechnology
Pharmaceutical Biotechnology,
Microparticles, Emulsions and

Professor HE Junginger (Rijksuniversiteit Te Leiden,Leiden, The Netherlands), recently awarded the Pharmaceutical Packaging
Maurice-Marie Janot Award on the basis of the quality 3-6 April 2000, Berlin, Germany
and originality of his work in pharmaceutical Reported by H Suheyla Kas, Hacettepe University,
technology, gave a talk on 'multifunctional polymers' Ankara, Turkey
and discussed the oral delivery of peptides usingabsorption enhancers. He discussed the advantages, This meeting consisted of invited lectures by capabilities and mechanisms of iontophoresis and listed distinguished scientists and oral and poster the drug candidates for iontophoretic study. Professor communications based on refereed abstracts. Recent Junginger also presented information and data on developments in the field of pharmaceutics, iontophoretic delivery of apomorphine using in vitro biopharmaceutics and pharmaceutical technology were Biomimetic biodegradable polymers for drug delivery Introduction
and tissue engineering applications were discussed by Joerg Tessmar (University of Regensburg, Germany), who stated that his group's polymer model was able to Verfahrenstechnik eV (APV; Mainz, Germany) and the suppress unspecific material/cell interactions and Association de Pharmacie Galénique Industrielle allowed the covalent attachment of model compounds.
(APGI; Châtenay-Malabry, France) under the auspices Elias Fattal (Université Paris Sud XI, France) described of the European Federation of Pharmaceutical Sciences his team's work on polyisobutylcyanoacrylate (EUFEPS) and the International Pharmaceutical nanocapsules containing an aqueous core as a novel Federation (FIP). The chair of the conference was colloidal carrier for the delivery of antisense Professor RH Müller (Berlin Free University, oligonucleotides. They showed, for the first time, a Germany) and the co-chairs were Professor D Duchêne successful methodology for oligonucleotide (Université Paris Sud XI, Paris, France), Professor P encapsulation. This methodology may be useful for Couvreur (Université Paris Sud XI, France), Professor DNA and peptide delivery. Professor Claus-Michael R Gurny (University of Geneva, Switzerland) and Dr Lehr (Universität des Saarlandes, Saarbrücken, W Mehnert (Berlin Free University, Germany). The Germany) discussed the use of human epithelial cell meeting venue was the Hotel Continental in Berlin, cultures for the evaluation of novel concepts in Germany. Over 800 participants from different macromolecular drug delivery. Professor Lehr ID weekly highlights Copyright  Current Drugs Ltd, May 2000. ISSN 1365-5884 Middlesex House, 34-42 Cleveland Street, London W1P 6LB, UK •


Microsoft word - research support for the developmental-final031204.doc

RESEARCH SUPPORT FOR A COMPREHENSIVE DEVELOPMENTAL APPROACH TO AUTISTIC SPECTRUM DISORDERS AND OTHER DEVELOPMENTAL AND LEARNING DISORDERS: The Developmental, Individual Difference, Relationship-Based (DIR™) Model Autistic Spectrum Disorders (ASD) and other disorders of relating and communicating often involve a number of different challenges or problems. Each child, even though

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