摘要:

Understanding the mechanisms by which growth hormone (GH) interacts with its receptor has led to the design of compounds that function as GH receptor antagonists. One such compound has been conjugated to polyethylene glycol (PEG) to produce a drug, pegvisomant, which has been extensively investigated as a treatment for acromegaly. It was recently approved for clinical use in the US and will shortly be available on prescription in Europe. Studies have shown that the drug is able to normalize circulating levels of insulin-like growth factor-1 (IGF-1), the principal mediator of GH action, in 97% of patients with active acromegaly, as well as improve the symptoms and signs associated with GH excess. Serum IGF-1 levels have been used as the chief marker of efficacy of treatment with pegvisomant. The drug is able to achieve biochemical control in patients wholly or partially resistant to somatostatin analogs. Preliminary data suggests that pegvisomant may be a particularly suitable choice of medical therapy for patients with acromegaly and coexistent diabetes mellitus.

ISSN:1175-6349    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

Childhood overweight is a significant and growing health problem in the US and other parts of the world. Secular trend data in the US suggest that children have become substantially heavier over the last several decades and that their risk for a number of health problems is increasing as a result. Defining obesity in children has been difficult as assessing body fat is expensive and impractical. Body mass index (BMI), derived from weight and height, is used as a surrogate indicator in adults. In children, the consensus is to use BMI percentiles statistically derived from a reference population. There is evidence that the prenatal, early childhood, and adolescent periods are critical in the development of obesity but the mechanisms involved are yet to be elucidated. The recent rapid increase in childhood overweight and obesity is attributed to the modern obesogenic environment. Changes in dietary constituents including higher derivation of energy from nutritionally poor and energy dense foods, increased sweetened drink consumption, larger portion sizes, and more frequent intake of food outside the home have been associated with poorer diets and higher weights. Further, physical activity has reduced with decreases in school physical education classes and organized sports, fewer opportunities to expend energy for daily living activity due to more mechanization, lower frequency of walking and biking, and greater use of sedentary activities for leisure. Television watching remains the most common activity for children.There are significant health outcomes associated with childhood obesity, including the presence of cardiovascular risk factors, and greater prevalence of various medical problems including insulin resistance, type 2 diabetes mellitus, the metabolic syndrome, orthopedic problems, and pseudotumor cerebri. Of further concern is the increased risk for obesity in adulthood with its attendant co-morbidities.Interventions are imperative but not widely studied. The most effective interventions include comprehensive behavioral management, dietary modification, and exercise. Family-based interventions have been most successful at maintaining long-term weight loss. School-based interventions have the potential to significantly impact childhood overweight as large numbers of children can be reached. However, such programs require long-term follow-up and are expensive. Very low calorie diets, pharmacotherapy, and surgery remain experimental options for children. More recently, metformin has shown promise in promoting weight loss and improving insulin sensitivity among adolescents.Combining multiple approaches for treatment, addressing obesity-promoting sociocultural practices and policies, and focusing on prevention strategies will be necessary to address this epidemic.

ISSN:1175-6349    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

Diabetic neuropathy is common, related to increased morbidity and mortality, and has no effective treatment at present. Interventions based on putative pathways thought to contribute to damage and repair of nerve fibres have yielded little success to date. Pain is a potentially debilitating manifestation of diabetic neuropathy and has many potential sites of origin and, hence, modulation. Its cause is unclear and it does not respond well to traditional pain therapies, proposed to mediate their benefits via multiple peripheral and central mechanisms. A better understanding of the mechanisms leading to nerve fibre degeneration and regeneration as well as pain has recently resulted in the development of a more targeted approach to the treatment of diabetic neuropathy. Thus, specific NMDA receptor antagonists and more specific neuronal serotonin and norepinephrine (noradrenaline) uptake inhibitors offer promise in the treatment of painful diabetic neuropathy. A number of treatments which include the aldose reductase inhibitors and neurotrophins have failed to reach the clinical arena. However, the antioxidant alpha-lipoic acid, as well as compounds which correct vascular dysfunction and hence neuropathy, such as ACE inhibitors and protein kinase C-β inhibitors, have demonstrated more success.

ISSN:1175-6349    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

The expression meglitinide analogs was introduced in 1995 to cover new molecules proposed as non-sulfonylurea insulinotropic agents and displaying structural analogy with meglitinide, such as repaglinide, nateglinide, and mitiglinide. Meglitinide analogs display, as judged by conformation analysis, a U-shaped configuration similar to that of antihyperglycemic sulfonylureas such as glibenclamide (glyburide) and glimepiride.In rat pancreatic islets incubated in the presence of 7.0 mmol/L D-glucose, repaglinide and mitiglinide demonstrate comparable concentration-response relationships for stimulation of insulin release, with a threshold value <10² nmol/L and a maximal secretory response at about 10³ nmol/L. Several findings indicate that meglitinide analogs provoke the closing of adenosine triphosphate-sensitive potassium channels, with subsequent gating of voltage-sensitive calcium channels. The effects of meglitinide analogs upon the binding of [3H]glibenclamide to islet cells membranes reinforces this concept. At variance, however, with other meglitinide analogs, the ionic and secretory response to repaglinide (10 μmol/L) is not rapidly reversible in perifused rat islets.In experiments conductedin vivoin control and diabetic rats, repaglinide provokes a greater and more rapid increase in plasma insulin concentration and an earlier fall in glycemia than glibenclamide or glimepiride. Onset of effect is also more rapid and duration of effect shorter with nateglinide versus glibenclamide.In clinical studies, single or repeated daily administration of repaglinide increased plasma insulin concentration in a dose-dependent manner, with an incremental peak reached about 2 hours after repaglinide intake. Plasma concentrations of repaglinide are about 5.0 μg/L 2–2.5 hours after oral intake of the drug. Despite the slow reversibility of repaglinide actionin vitro, this drug offers advantages over glibenclamide in terms of the possible occurrence of hypoglycemia if a meal is missed.In volunteers receiving a single oral dose of nateglinide (120mg) 10 minutes before a standardized 800 Kcal breakfast, the plasma insulin concentration was higher 5, 10, and 20 minutes after meal intake than when they received a single dose of repaglinide (0.5 or 2.0mg) or placebo 10 minutes before breakfast. Peak plasma concentrations of nateglinide were reached within 2 hours in most volunteers.Peak plasma concentrations of mitiglinide were reached 30 minutes after a single oral dose in a representative volunteer. Mitiglinide significantly suppressed meal-induced elevations in blood glucose concentrations in a study of patients with type 2 diabetes.In conclusion, two obvious differences among these meglitinide analogs should be underlined. First, on a molar basis, nateglinide is somewhat less potent than repaglinide or mitiglinide, as an insulinotropic agent. The maximal secretory responses evoked by these three meglitinide analogs are, however, identical to one another. Secondly, and as already mentioned, the functional effects of nateglinide and mitiglinide are more rapidly reversible than those of repaglinide, for instance in perifused rat islets. The meglitinide analogs offer the advantage over the long-acting antihyperglycemic sulfonylurea glibenclamide of minimizing the risk of undesirable hypoglycemia.

ISSN:1175-6349    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

▴ Risedronate (risedronic acid), an orally administered pyridinyl bisphosphonate, inhibits osteoclast-mediated resorption of bone and modulates bone metabolism in women with postmenopausal osteoporosis. The long terminal exponential half-life of risedronate (480 hours) has led to the development of a 35mg tablet for once-a-week administration.▴ The beneficial effects of risedronate 35mg once a week on total hip, femoral neck and trochanter bone mineral density (BMD) at 12 months were similar to those of risedronate 5mg once daily.▴ Risedronate 35mg once a week was as effective as risedronate 5mg once daily in improving lumbar spine BMD in a randomized, double-blind, multicenter trial of 1456 women with postmenopausal osteoporosis. Mean percentage increases in BMD from baseline at 12 months were 3.94% and 4.25% in the 35mg and 50mg once-a-week dose groups, compared with 4% in the 5mg once-daily dose group. The differences between the once-a-week doses and the once-daily dose met the predetermined criterion for non-inferiority.▴ An historical analysis suggested that risedronate 35mg once a week reduced the incidence of vertebral fracture significantly more than placebo.▴ The tolerability profile (including the incidence of upper gastrointestinal adverse events) of risedronate 35mg once a week in women with postmenopausal osteoporosis, was similar to that of risedronate 5mg once daily.Table.  Features and properties of risedronate  (risedronic acid, Actonel®)  once a week

ISSN:1175-6349    

出版商:ADIS    

年代:2003

数据来源: ADIS

ISSN:1175-6349    

出版商:ADIS    

年代:2003

数据来源: ADIS