Treatments in Endocrinology最新文献

Diabetic nephropathy occurs in 20-40% of diabetic patients, making it one of the most important causes of end-stage renal disease (ESRD). It has a large impact in terms of associated morbidity and mortality for the individual patient and in terms of costs for healthcare. Several studies have demonstrated that micro- and macroalbuminuria predict cardiovascular morbidity and mortality in patients with diabetes mellitus.Current nephroprotective therapies for diabetic nephropathy include the pursuit of normoglycemia and normotension, and a consensus is emerging that there is a necessity to also achieve as low a level of albuminuria as possible. However, the search for innovative and ancillary approaches to the prevention and treatment of this diabetic complication is warranted since strict metabolic control can be difficult, and sometimes dangerous, to achieve and even diabetic patients responding to ACE inhibitors (ACEIs) or angiotensin II receptor antagonists (angiotensin receptor blockers; ARBs) and metabolic control show progressive renal damage and eventually ESRD. A number of drugs are currently being investigated; glycosaminoglycans are particularly interesting since, in theory, they target the generalized endothelial dysfunction and metabolic defect in matrix and basement membrane synthesis which, according to the Steno hypothesis, are responsible for diabetic nephropathy and macroangiopathy.Treatment with glycosaminoglycans, and with sulodexide in particular, significantly improves albuminuria in type 1 and type 2 diabetic patients with micro- or macroalbuminuria. The albuminuria-lowering effect of sulodexide enhances the effect of ACEI/ARB therapy. Most studies have shown that the effect of sulodexide on albuminuria is sustained, strongly suggesting that favorable chemical and anatomic remodeling is induced by exogenous glycosaminoglycans in renal tisues, as observed in the experimental model.

Metabolic bone disease in children includes many hereditary and acquired conditions of diverse etiology that lead to disturbed metabolism of the bone tissue. Some of these processes primarily affect bone; others are secondary to nutritional deficiencies, a variety of chronic disorders, and/or treatment with some drugs. Some of these disorders are rare, but some present public health concerns (for instance, rickets) that have been well known for many years but still persist. The most important clinical consequences of bone metabolic diseases in the pediatric population include reduced linear growth, bone deformations, and non-traumatic fractures leading to bone pain, deterioration of motor development and disability. In this article, we analyze primary and secondary osteoporosis, rickets, osteomalacia (nutritional and hereditary vitamin D-dependent, hypophosphatemic and that due to renal tubular abnormalities), renal osteodystrophy, sclerosing bony disorders, and some genetic bone diseases (hypophosphatasia, fibrous dysplasia, skeletal dysplasia, juvenile Paget disease, familial expansile osteolysis, and osteoporosis pseudoglioma syndrome). Early identification and treatment of potential risk factors is essential for skeletal health in adulthood. In most conditions it is necessary to ensure an appropriate diet, with calcium and vitamin D, and an adequate amount of physical activity as a means of prevention. In secondary bone diseases, treatment of the primary disorder is crucial. Most genetic disorders await prospective gene therapies, while bone marrow transplantation has been attempted in other disorders. At present, affected patients are treated symptomatically, frequently by interdisciplinary teams. The role of exercise and pharmacologic therapy with calcium, vitamin D, phosphate, bisphosphonates, calcitonin, sex hormones, growth hormone, and thiazides is discussed. The perspectives on future therapy with insulin-like growth factor-1, new analogs of vitamin D, strontium, osteoprotegerin, and calcimimetics are presented.

Recent clinical trials have demonstrated an increase in the risk of cardiovascular disease (CVD) in women using oral hormone replacement therapy (HRT). Bio-identical HRT (BHRT) is widely used by alternative healthcare practitioners for the treatment of symptoms of menopause, with the prevailing assumption that BHRT provides the benefits of HRT while attenuating the risks. However, considering the serious risks of HRT, the use of any form of HRT, including BHRT, without sufficient scientific evaluation may create considerable risk.The main hormone found in BHRT is estriol. Estriol is used alone or in combination with estradiol and estrone. The total daily oral dose of BHRT used is, on average, ten times higher than that used in HRT, and both oral and topical forms are used for bio-identical hormone administration. The clinical trials that have examined cardiovascular outcomes associated with estriol therapy are limited, and there is evidence to demonstrate variable effects on markers associated with cardiovascular risk.Based on the current evidence, the same cardiovascular risks that have recently been found to be associated with oral HRT may also be associated with the administration of oral estriol in BHRT. The use of oral bio-identical hormones cannot be promoted until further evidence is available to demonstrate its safety.

In healthy humans, growth hormone (GH) is secreted in distinct pulses with an underlying nyctohemeral pattern. Current forms of somatropin replacement are unable to closely mimic such a release pattern, but are still able to exert the beneficial action of GH. A limited number of short-term studies in rodents and humans suggest that longitudinal growth may be superior when somatropin is given with a pulsatile mode of administration, whereas hepatic insulin-like growth factor-I generation and beneficial changes in body composition appear to be equal or even enhanced with continuous somatropin administration.Recent developments in drug delivery technology have allowed the use of slow-release preparations of somatropin in humans. The most successful technology so far has been the encapsulation of somatropin molecules in poly(D,L-lactic-co-glycolic acid) biodegradable microspheres. Pharmacokinetic and pharmacodynamic data have been published on two such preparations; Nutropin Depot((R)) and hGH-Biosphere((R)). The latter has a superior release profile, but outcomes data from multicenter trials in both children and adults have been presented for the former: catch-up growth was observed in children, although to a lesser degree than historic comparative data obtained with the use of daily somatropin injections and the effects on metabolic derangements in GH-deficient patients appeared similar to those observed with daily injections. Improved sustained-release somatropin preparations will need further study of their long-term efficacy, but, if successful, will be highly attractive in terms of patient compliance and convenience.

Type 2 diabetes mellitus in children and adolescents is becoming an increasingly important public health concern throughout the world. This epidemic is closely associated with the increased prevalence of obesity among youth of all ethnic backgrounds, as increased visceral adipose tissue produces adipokines that increase insulin resistance. Type 2 diabetes represents one arm of the metabolic syndrome, which includes abdominal obesity, disturbed glucose regulation and insulin resistance, dyslipidemia, and hypertension. The treatment of type 2 diabetes and the metabolic syndrome poses a challenge for pediatric endocrinologists. This review provides information regarding diagnosis of type 2 diabetes in children, as well as prevention strategies, such as lifestyle modification and pharmacologic options for weight loss, including metformin, orlistat, and sibutramine. Pharmacologic treatment options, their modes of action, and clinical indications for use are also reviewed. Treatment regimens for youth-onset type 2 diabetes that are discussed include metformin, sulfonylureas, glucosidase inhibitors, thiazolidinediones, glucagon-like peptide-1, and insulin.

Prader-Willi syndrome is a neurogenetic disorder that occurs due to the lack of a paternally expressed gene or genes on chromosome 15q11-q13. Many of the symptoms present in Prader-Willi syndrome are due to a hypothalamic-pituitary dysfunction. The main characteristics are muscular hypotonia, delayed psychomotor development, insatiable appetite resulting in overweight if a diet is not maintained, compromised growth and puberty resulting in a short final height and incomplete sexual development, respiratory disturbances, and dysmorphic features. Individuals with Prader-Willi syndrome have compromised growth and abnormal body composition with increased fat mass, decreased lean body mass, and low bone density, resembling a growth hormone-deficient status. Somatropin treatment has a beneficial effect on growth with increased final height and an improvement in and maintenance of body composition, as well as a beneficial effect on respiratory functions. Before initiating somatropin therapy, weight should be kept at an appropriate level, and polysomnography, as well as an otorhinolaryngologic examination should be performed. During somatropin therapy, carbohydrate metabolism and the development of scoliosis should be monitored, as well as bodyweight.A comprehensive team to manage the various components of medical, psychologic, and sociologic care is required for individuals with Prader-Willi syndrome.

Osteogenesis imperfecta is a heritable condition characterized by abnormally brittle bones, with an approximate prevalence of 1/20 000 births. Fractures are the main cause of suffering and disability, but owing to the abundance and wide distribution of the defective type I collagen in the body, a variety of symptoms occur. Several types of osteogenesis imperfecta (I-VII) have been described that vary in severity. For many years, therapy consisted of rehabilitation and orthopedic surgery. Presently, pharmacologic therapies aimed at strengthening bone are available, which decrease the pain and fracture rate associated with this condition, and allow more appropriate rehabilitation programs that will hopefully result in a less marked failure to thrive in affected children. In particular, the bisphosphonates, especially pamidronate, have been used for several years. They have been successful in increasing bone mineral density (BMD) and improving bone resistance, leading to a decrease in the fracture rate. Various regimens have been proposed, but it is the therapeutic regimen first used by Glorieux and co-workers in Montreal that has been the most frequently applied.However, as yet there is no definite consensus regarding the indications for therapy, the osteogenesis imperfecta types that are of the greatest concern, the appropriate age at the outset of therapy, and the treatment duration, without yet speaking about the best bisphosphonate regimen for use. The authors have proposed some personal recommendations for the clinical use of bisphosphonates, based on their own experience with the management of patients with this condition; these include the indications for therapy, based on the clinical status, and the treatment duration. These recommendations will certainly not be unanimously endorsed, but they should help to stimulate discussion. Ameliorating BMD is an important step, but will not prevent all fractures because bisphosphonate therapy does not correct the underlying genetic defect. More recently, stem cell replacement therapy in the child or fetus has been proposed as a therapeutic option.All in all, it is possible that, in order to dramatically decrease the fracture rate, combined therapies aimed at both circumventing the consequences of the gene defect using stem cells and reinforcing bone strength with bisphosphonates will have to be considered. Much work is still necessary before recommending these techniques in clinical practice.

The prevalence of hypertension and cardiovascular disease increases dramatically after menopause in women, implicating estrogen as having a protective role in the cardiovascular system. However, recent large clinical trials have failed to show cardiovascular benefit, and have even demonstrated possible harmful effects, of opposed and unopposed estrogen in postmenopausal women. While these findings have led to a revision of guidelines such that they discourage the use of estrogen for primary or secondary prevention of heart disease in postmenopausal women, many investigators have attributed the negative results in clinical trials to several flaws in study design, including the older age of study participants and the initiation of estrogen late after menopause.Because almost all clinical trials use oral estrogen as the primary form of hormone supplementation, another question that has arisen is the importance of the route of estrogen administration with regards to the cardiovascular outcomes. During oral estrogen administration, the concentration of estradiol in the liver sinusoids is four to five times higher than that in the systemic circulation. This supraphysiologic concentration of estrogen in the liver can modulate the expression of many hepatic-derived proteins, which are not observed in premenopausal women. In contrast, transdermal estrogen delivers the hormone directly into the systemic circulation and, thus, avoids the first-pass hepatic effect.Although oral estrogen exerts a more favorable influence than transdermal estrogen on traditional cardiovascular risk factors such as high- and low-density lipoprotein-cholesterol levels, recent studies have indicated that oral estrogen adversely influences many emerging risk factors in ways that are not seen with transdermal estrogen. Oral estrogen significantly increases levels of acute-phase proteins such as C-reactive protein and serum amyloid A; procoagulant factors such as prothrombin fragments 1+2; and several key enzymes involved in plaque disruption, while transdermal estrogen does not have these adverse effects.Whether the advantages of transdermal estrogen with regards to these risk factors will translate into improved clinical outcomes remains to be determined. Two ongoing clinical trials, KEEPS (Kronos Early Estrogen Prevention Study) and ELITE (Early versus Late Intervention Trial with Estradiol) are likely to provide invaluable information regarding the role of oral versus transdermal estrogen in younger postmenopausal women.

black triangle An oral formulation of paricalcitol has been developed for the prevention and treatment of secondary hyperparathyroidism in patients with stage 3 or 4 chronic kidney disease.black triangle Paricalcitol is a synthetic vitamin D analog that binds to the vitamin D receptor inducing suppression of parathyroid hormone (PTH) secretion.black triangle Oral paricalcitol was significantly more effective than placebo in treating secondary hyperparathyroidism in patients with stage 3 or 4 chronic kidney disease. In a pooled analysis of three well designed, 24-week trials, two consecutive reductions from baseline in intact PTH levels of >/=30% were achieved by significantly more paricalcitol than placebo recipients (91% vs 13%).black triangle In addition, mean levels of the biochemical bone markers serum bone-specific alkaline phosphatase, serum osteocalcin, and urinary pyridinoline were reduced from baseline to a significantly greater extent with paricalcitol than with placebo, indicating a reduction in bone turnover.black triangle Oral paricalcitol was well tolerated; there was no significant difference between paricalcitol and placebo recipients in the incidence of hypercalcemia, hyperphosphatemia, or elevated calcium-phosphorus product.

Objectives: To determine current and potential patterns of prescription of human insulins and insulin analogs in patients with diabetes mellitus in hospitals and general/specialist practice in France.

Methods: This was a survey of diabetologists and endocrinologists working in hospital and/or private practice in France. The clinicians answered a six-part questionnaire during a face-to-face interview at the clinician's practice regarding current and potential patterns of use of human insulin and insulin analogs.

Results: A total of 80 French clinicians were interviewed. The majority of clinicians prescribed insulin analogs to their diabetic patients, with human insulin being prescribed in a minority of patients. When asked their opinions on switching from a regimen involving human insulin to one involving insulin analogs, clinicians generally recommended a treatment regimen that involved very little change. Most clinicians recommended that basal insulin analogs replace NPH human insulin, rapid-acting insulin analogs replace rapid-acting (regular) human insulin, and premix insulin analogs replace human premix insulins, with little change in the recommended number of injections or the dose of the insulin. Precaution was recommended in the elderly, pregnant patients, those of certain ethnicities, and those at risk of hypoglycemia.

Conclusion: Insulin analogs are currently prescribed by the majority of diabetologists and endocrinologists in this survey in France. When switching from a regimen involving human insulin to one involving insulin analogs, clinicians generally recommend a treatment program that involves very little change.