Treatments in Endocrinology最新文献

Orlistat is an inhibitor of gastrointestinal lipases and, therefore, prevents the absorption of dietary fat. This agent reduced weight in obese adults and adolescents with or without co-morbidities (including type 2 diabetes mellitus, hypercholesterolemia, hypertension, metabolic syndrome) who received up to 4 years of therapy in conjunction with a hypocaloric diet. In obese patients, orlistat in combination with a hypocaloric diet improved metabolic risk factors and reduced the risk of developing type 2 diabetes. Furthermore, this agent was cost effective in patients with obesity, particularly those with type 2 diabetes. Orlistat is generally well tolerated, with gastrointestinal adverse events being most commonly reported. Orlistat, in addition to lifestyle and dietary intervention, is thus an attractive option for the treatment of patients with obesity, especially those with associated co-morbidities or at risk of developing type 2 diabetes.

Extended use of oral contraceptive (OC) pills can successfully suppress endometrial activity and prevent menstruation for several months. Given that missed menses in women not using hormonal contraception may be of medical concern, understanding how hormonal contraceptives eliminate these concerns is important for both patient and healthcare provider acceptance. OC withdrawal bleeding is an artificial, iatrogenic event, which results from the deliberate, periodic interruption of hormonal support of the endometrium. Historically, it was important to provide periodic bleeding to reassure OC efficacy, but today it is recognized that these bleeding episodes are medically unnecessary and cause patient discomfort and out-of-pocket expenses. Decades of experience with prolonged use of OCs have been accumulated for women with specific menstrual-related problems such as endometriosis, dysmenorrhea, and menstrual migraine headaches. Today there is a US FDA-approved product to routinely reduce the number of withdrawal periods. Clinical trials show that there is an initial increase in unscheduled bleeding and spotting days with extended-cycle OC use, but an absolute decrease in total days of bleeding and spotting from the first cycle of use. Over time, unscheduled bleeding and spotting decreases to rates found with the use of conventional-cycle regimens. Every woman who is interested in using OC pills should be offered the opportunity to choose how to use them, to determine if and when she will have withdrawal bleeding.

Paricalcitol (Zemplar) is a synthetic vitamin D2 analog that inhibits the secretion of parathyroid hormone (PTH) through binding to the vitamin D receptor. It is approved in the US and in most European nations for intravenous use in the prevention and treatment of secondary hyperparathyroidism associated with chronic renal failure in adult, and in the US pediatric, patients. Paricalcitol effectively reduced elevated serum PTH levels and was generally well tolerated in children and adults with secondary hyperparathyroidism associated with chronic renal failure. In well designed clinical trials, paricalcitol was as effective as calcitriol and as well tolerated in terms of the incidence of prolonged hypercalcemia and/or elevated calcium-phosphorus product (Ca x P). Thus, paricalcitol is a useful option for the management of secondary hyperparathyroidism in adults and children with chronic renal failure.

Maturity-onset diabetes of the young (MODY) is a dominantly inherited form of non-ketotic diabetes mellitus. It results from a primary defect of insulin secretion, and usually develops at childhood, adolescence, or young adulthood. MODY is a heterogeneous disease with regard to genetic, metabolic, and clinical features. All MODY genes have not been identified, but heterozygous mutations in six genes cause the majority of the MODY cases. By far MODY2 (due to mutations of the glucokinase gene) and MODY3 (due to mutations in hepatocyte nuclear factor-1alpha) are the most frequent. As with MODY3, all the other MODY subtypes are associated with mutations in transcription factors. The clinical presentations of the different MODY subtypes differ, particularly in the severity and the course of the insulin secretion defect, the risk of microvascular complications of diabetes, and the defects associated with diabetes. Patients with MODY2 have mild, asymptomatic, and stable hyperglycemia that is present from birth. They rarely develop microvascular disease, and seldom require pharmacologic treatment of hyperglycemia. In patients with MODY3, severe hyperglycemia usually occurs after puberty, and may lead to the diagnosis of type 1 diabetes. Despite the progression of insulin defects, sensitivity to sulfonylureas may be retained in MODY3 patients. Diabetic retinopathy and nephropathy frequently occur in patients with MODY3, making frequent follow-up mandatory. By contrast, other risk factors are not present in patients with MODY and the frequency of cardiovascular disease is not increased. The clinical spectrum of MODY is wider than initially described, and might include multi-organ involvement in addition to diabetes. In patients with MODY5, due to mutations in hepatocyte nuclear factor-1beta, diabetes is associated with pancreatic atrophy, renal morphologic and functional abnormalities, and genital tract and liver test abnormalities. Although MODY is dominantly inherited, penetrance or expression of the disease may vary and a family history of diabetes is not always present. Thus, the diagnosis of MODY should be raised in various clinical circumstances. Molecular diagnosis has important consequences in terms of prognosis, family screening, and therapy.

The risk of cardiovascular disease (CVD) in patients with diabetes mellitus is increased more than 3-fold and is the major cause of mortality and morbidity in diabetic patients. Historically, diabetes has been considered an inadequate insulin response leading to elevated plasma glucose levels with morbidities attributable to hyperglycemia. However, diabetes represents a complex pathology that often includes hypertension, dyslipidemia, endothelial dysfunction, microalbuminuria, platelet disaggregation, abnormal fibrinolysis, and chronic inflammation. Furthermore, oxidative stress has been shown to contribute to the pathology of diabetic CVD, having implications in the development of hypertension, renal disease, and stroke. Hypertension is a common feature of diabetes and is the primary contributor to CVD, which highlights the importance of blood pressure control (<130/80 mm Hg). Recent investigations have also implicated the renin-angiotensin-aldosterone system in promoting oxidative stress-induced endothelial dysfunction, inflammation, and insulin resistance. These pathophysiologic considerations will be important in developing prevention strategies for CVD in diabetes. Further research is needed to identify antioxidant and insulin-sensitizing agents that will improve CVD outcomes in patients with diabetes.

Obesity continues to plague our society in epidemic proportions. Surgery for morbid obesity is considered by many as the most effective therapy for this complex disorder. Today, multiple surgical procedures for the treatment of obesity are available. As with most procedures, there are benefits and risks associated with open and laparoscopic gastric bypass surgery, as well as with laparoscopic adjustable gastric banding and partial biliopancreatic bypass with a duodenal switch. The risks and complications associated with bariatric surgery may be serious and in some cases life threatening. However, surgery for obesity has shown remarkable results in helping patients to achieve significant long-term weight control. In addition, it is associated with improvement and often resolution of co-morbid conditions, including type 2 diabetes mellitus, systemic hypertension, obesity hypoventilation, sleep apnea, venous stasis disease, pseudotumor cerebri, polycystic ovary syndrome, complications of pregnancy and delivery, gastroesophageal reflux disease, stress urinary incontinence, degenerative joint disease, and non-alcoholic steatohepatitis.

Pregnancy has an effect on thyroid economy with significant changes in iodine metabolism, serum thyroid binding proteins, and the development of maternal goiter especially in iodine-deficient areas. Pregnancy is also accompanied by immunologic changes, mainly characterized by a shift from a T helper-1 (Th1) lymphocyte to a Th2 lymphocyte state. Thyroid peroxidase antibodies are present in 10% of women at 14 weeks' gestation, and are associated with (i) an increased pregnancy failure (i.e. abortion), (ii) an increased incidence of gestational thyroid dysfunction, and (iii) a predisposition to postpartum thyroiditis. Thyroid function should be measured in women with severe hyperemesis gravidarum but not in every patient with nausea and vomiting during pregnancy. Graves hyperthyroidism during pregnancy is best managed with propylthiouracil administered throughout gestation. Thyroid-stimulating hormone-receptor antibody measurements at 36 weeks' gestation are predictive of transient neonatal hyperthyroidism, and should be checked even in previously treated patients receiving thyroxine. Postpartum exacerbation of hyperthyroidism is common, and should be evaluated in women with Graves disease not on treatment. Radioiodine therapy in pregnancy is absolutely contraindicated. Hypothyroidism (including subclinical hypothyroidism) occurs in about 2.5% of pregnancies, and may lead to obstetric and neonatal complications as well as being a cause of infertility. During the last few decades, evidence has been presented to underpin the critical importance of adequate fetal thyroid hormone levels in order to ensure normal central and peripheral nervous system maturation. In iodine-deficient and iodine-sufficient areas, low maternal circulating thyroxine levels have been associated with a significant decrement in child IQ and development. These data suggest the advisability of further evaluation for a screening program early in pregnancy to identify women with hypothyroxinemia, and the initiation of prompt treatment for its correction. Hypothyroidism in pregnancy is treated with a larger dose of thyroxine than in the nonpregnant state. Postpartum thyroid dysfunction (PPTD) occurs in 50% of women found to have thyroid peroxidase antibodies in early pregnancy. The hypothyroid phase of PPTD is symptomatic and requires thyroxine therapy. A high incidence (25-30%) of permanent hypothyroidism has been noted in these women. Women having transient PPTD with hypothyroidism should be monitored frequently, as there is a 50% chance of these patients developing hypothyroidism during the next 7 years.

Alendronate/colecalciferol 70 mg/2800 IU, a once-weekly tablet containing the bisphosphonate alendronate and colecalciferol (the precursor of the biologically active form of vitamin D), has been approved for the treatment of osteoporosis in women and for increasing bone mass in men with osteoporosis. The mean oral bioavailability of alendronate or colecalciferol is similar when administered alone or as one once-weekly tablet containing alendronate/colecalciferol 70 mg/2800 IU. In a 15-week, randomized, double-blind, multicenter study in patients with osteoporosis, the proportion of patients with serum 25-hydroxyvitamin D3 levels <15 ng/mL was significantly lower with alendronate/colecalciferol than with alendronate alone. Markers of bone turnover were not significantly different in recipients of alendronate/colecalciferol or alendronate alone. Alendronate is generally well tolerated in men and women with osteoporosis, with adverse events being mainly transient and associated with the upper gastrointestinal tract. The treatment-related adverse event profile of once-weekly alendronate/colecalciferol 70 mg/2800 IU was similar to that of once-weekly alendronate in the 15-week, double-blind study in patients with osteoporosis.

Compliance with treatment is crucial to the optimal management of any chronic disease. Non-compliance with antihyperglycemic treatment is clearly a significant issue for patients with type 2 diabetes mellitus as it decreases the efficacy of the treatment and increases the risk of developing microvascular and macrovascular complications, therefore increasing the human and economic costs of this disease. The effect of low compliance on metabolic control has been shown to represent an increase of up to 1.4% in glycosylated hemoglobin. Achieving optimal compliance is therefore a therapeutic objective of prime importance. Many factors have been cited as contributing to poor compliance. Some of these, such as age, severe complications and disabilities, and social, educational, and financial difficulties, affect compliance with treatment in quite a significant manner, but are not modifiable by the healthcare provider. Other factors, such as the number of tablets per dose and polymedication, are modifiable but do not appear to be of major importance, whereas the frequency of administration is both an important and a modifiable factor affecting compliance with treatment. One strategy for optimization of compliance involves treatment of type 2 diabetes using oral antihyperglycemic agents with once-daily formulations. Recent data indicate that reducing the daily administration frequency of oral antihyperglycemic agents improves compliance with treatment and consequently metabolic control. Therefore, optimization of treatment through a reduction in the frequency of antihyperglycemic administration could be a valuable weapon in the battle to improve health outcomes and reduce the burden of type 2 diabetes.

The inhalation of insulin was conceptualized by the mid-1920s, but the first successful testing of inhaled insulin occurred in the mid-1990s. The lung has proven to be an organ well capable of absorbing insulin in a reproducible and dose-dependent manner. At present, two concepts of pulmonary insulin delivery at relatively advanced stages of development have been investigated in several published studies. The first involves the Exubera device, a system consisting of a formulation of insulin in a dry and amorphous powder, which is then packaged into blisters. A special delivery system generates a pulse of compressed air, which causes the insulin to form a white fog in a transparent reservoir that can be inhaled by deep breathing. The second approach is the AERx insulin Diabetes Management System, which uses an aqueous formulation of insulin, delivered as an aerosol generated by a special, microprocessor-controlled, inhalation device. This device is capable of monitoring the patient's inspiratory flow and guiding the inhalation by a microelectronic feedback system. The therapeutic efficacy and safety of these inhaled insulins seem comparable to those of subcutaneous insulin regimens; however, inhaled insulins do not appear to achieve significantly better glycemic control. Several other concepts for the pulmonary delivery of insulin are also being developed. With the incidence of diabetes mellitus, especially type 2 diabetes, dramatically increasing worldwide, patients with type 2 diabetes appear to be an important target group for new modalities of insulin delivery. In this group, the onset of insulin treatment is frequently delayed due to the fear of self-injection, preventing effective glycemic control. Patient acceptance of inhaled insulins is excellent and no serious adverse effects have been observed to date. Further advantages of inhaled insulins are the more rapid onset of insulin action and a mitigation of postprandial glucose excursions. However, there are some open questions. The most important concerns the possible long-term effects of insulin inhalation on the lung, as insulin is known to have growth-promoting properties. Thus far, there are no observations of the effects of inhaled insulin on lung structure and function that extend beyond 10 years. In patients with pulmonary disease, the smaller cumulative alveolar surface may cause problems in absorption, and in smokers the action of inhaled insulin has been shown to be stronger and with a faster onset. Furthermore, treatment with inhaled insulin requires larger doses of insulin compared with the subcutaneous route of insulin administration to achieve the same systemic effect, and the costs of this therapy could therefore be significantly higher than the costs of present insulin therapies.