Transdermal selegiline for the treatment of major depressive disorder

Non-selective inhibition of monoamine oxidase (MAO) enzymes (ie, isoforms A and B) in the brain are associated with clinically significant antidepressant effects. In the US, the selegiline transdermal system (STS; EMSAM) is the first antidepressant transdermal delivery system to receive Food and Drug Administration (FDA) approved labeling for the treatment of major depressive disorder (MDD). Currently, the use of orally administered MAO inhibitor antidepressants (eg, phenelzine, tranylcypromine) is limited by the risk of tyramine-provoked events (eg, acute hypertension and headache, also known as the “cheese reaction”) when combined with dietary tyramine. The selegiline transdermal system is the only MAOI available in the US for the treatment of MDD that does not require dietary restriction at the clinically effective dose of 6 mg/24 hours. Delivery of selegiline transdermally (EMSAM^®) bypasses hepatic first pass metabolism, thereby avoiding significant inhibition of gastrointestinal and hepatic MAO-A activity (ie, reduced risk of tyramine-provoked events) while still providing sufficient levels of selegiline in the brain to produce an antidepressant effect. At dosages of 6–12 mg/24 hours, EMSAM has been shown to improve symptoms of depression, have good tolerability, and have high rates of medication adherence. However, at higher doses of EMSAM (ie, 9 mg/24 hours or more), dietary restriction of tyramine intake is recommended. The introduction of EMSAM overcomes many of the safety concerns affiliated with the conventional oral MAO inhibitors and EMSAM may be considered another strategy for the treatment of MDD, especially in patients who cannot tolerate oral antidepressants, are poorly adherent, who present with atypical depressive symptoms, or have failed other antidepressants.     

Metabolic Characterization of Nondiabetic Severely Obese Patients Undergoing Roux-en-Y Gastric Bypass: Preoperative Classification Predicts the Effects of Gastric Bypass on Insulin–Glucose Homeostasis

Introduction Obese individuals may have normal insulin–glucose homeostasis, insulin resistance, or diabetes mellitus. Whereas gastric bypass cures insulin resistance and diabetes mellitus, its effects on normal physiology have not been described. We studied insulin resistance and β-cell function for patients undergoing gastric bypass. Methods One hundred thirty-eight patients undergoing gastric bypass had fasting insulin and glucose levels drawn on days 0, 12, 40, 180, and 365. Thirty-one (22%) patients with diabetes mellitus were excluded from this analysis. Homeostatic model of assessment was used to estimate insulin resistance, insulin sensitivity, and β-cell function. Based on this model, patients were categorized as high insulin resistance if their insulin resistance was >2.3. Results Body mass index did not correlate with insulin resistance. Forty-seven (34%) patients were categorized as high insulin resistance. Correction of insulin resistance for this group occurred by 12 days postoperatively. Sixty (43%) patients were categorized as low insulin resistance. They demonstrated an increase of β-cell function by 12 days postoperatively, which returned to baseline by 6 months. At 1 year postoperatively, the low insulin resistance group had significantly higher β-cell function per degree of insulin sensitivity. Conclusions Adipose mass alone cannot explain insulin resistance. Severely obese individuals can be categorized by degree of insulin resistance, and the effect of gastric bypass depends upon this preoperative physiology.     

Regional Variation and Use of Exception Letters for Cadaveric Liver Allocation in Children with Chronic Liver Disease

The Pediatric End-Stage Liver Disease (PELD) score was designed to reduce subjectivity in liver allocation and to advantage patients with a higher probability of waiting list mortality. The aims of this study were to determine the impact of PELD implementation for children with chronic liver disease and to assess whether PELD met its goal of standardization of liver allocation for children. This study used data reported to the United Network for Organ Sharing (UNOS) registry for children with chronic liver disease receiving primary cadaveric liver transplant between January 2000 and December 2001 (pre-PELD) and March 2002 and July 2003 (PELD). PELD reduced the percentage of children transplanted while in an intensive care unit and as status 1. A calculated PELD score was used for allocation in only 52% of recipients. Thirty percent were status 1 at transplant and PELD scores granted by exception were used for allocation in 18% of patients. There was regional variation in PELD score at allocation and use of exception scores with a significant relationship between PELD score and percentage of exception cases. Regional variation suggests that PELD has not resulted in standardization of listing practices in pediatric liver transplantation.     

A randomized trial comparing double-drug and triple-drug therapy in primary cadaveric renal transplants

A controlled trial was carried out in 209 primary cadaveric renal transplants to compare the effects of cyclosporine and steroids (double therapy) with those of cyclosporine in lower initial dose, azathioprine, and steroids (triple therapy). Patients have been followed 1-36 months since transplantation. Actuarial two-year graft survival (double 74%, triple 76%) and two-year patient survival (double 90%, triple 93%) were similar for both groups. Further analysis of particular risk factors including age, diabetes, HLA matching, acute renal failure, and use of sequential Minnesota antilymphocyte globulin in patients with delayed graft function also showed similar outcomes with both immunosuppressive regimens. Initial hospitalization time, rate of rejection, incidence of serious infection, and rate of rehospitalization were not different. Mean CsA doses and mean trough whole-blood levels were higher in double-therapy patients at hospital discharge but not by three months posttransplant. There were no differences between the two groups in iothalamate clearance at any time. Hypertension was more frequent six months posttransplant in the triple-therapy group (p less than 0.05). Thus, similar results were obtained with both regimens, and except for hypertension no regimen appeared to have increased side effects up to three years posttransplant.     

National survey of ethical issues presented to drug information centers

Whether and how drug information centers respond to calls from the public that involve ethical issues was studied. A survey describing six ethical dilemmas typical of those presented by calls from the public was mailed to pharmacists in 154 drug information centers to see how the questions would be handled. Centers that had written policies governing responses to questions with ethical implications were asked to submit those policies. One hundred twenty-six centers (82%) responded to the survey; of these, 81 (64.3%) answered questions from the public. There were no significant differences in characteristics between centers that did and did not respond to public calls. The case analyses, completed only by pharmacists in centers that responded to public calls, covered such issues as invasion of privacy, social responsibility, personal liability, and interference with the patient-physician relationship. Respondents exercised a wide degree of discretion in determining if they would answer a question; for example, while only 4% would not answer a question concerning the efficacy of a weight-loss diet patch, 77% reported they would not respond to a caller asking for information on drugs that could interfere with the results of a polygraph test. Although respondents often cited institutional policy as the reason for failing to respond to a question, none submitted a copy of such a policy. The pharmacists' responses indicated a high degree of moral and social sensitivity; nonetheless, written policies should be developed to assist drug information center staff members in handling questions that have ethical implications.     

Transduodenal Sphincteroplasty and Transampullary Septectomy for Papillary Stenosis

Twenty patients received transduodenal sphincteroplasty and transampullary septectomy between 1987 and 1993. Seven patients had post-cholecystectomy pain which was much improved or abolished in 5 of 7 patients at a mean follow-up of 4 years and 5 months. Four of five patients with chronic pancreatitis were improved at 3 years and 2 months. Three of five patients with recurrent acute pancreatitis were improved at 4 years and 5 months. One of three patients with chronic abdominal pain of hepatobiliary origin was improved at 3 years. Transduodenal sphincteroplasty and transampullary septectomy can relieve pain in patients with post-cholecystectomy pain, recurrent acute pancreatitis, chronic pancreatitis, and chronic abdominal pain of hepatobiliary origin, presumably by improving drainage of the obstructed ducts.     

Antibody to intercellular adhesion molecule 1 protects the kidney against ischemic injury.

The pathophysiology of ischemic acute renal failure is complex, and the role of leukocyte adhesion in this process is not well defined. A monoclonal antibody (mAb) against intracellular adhesion molecule 1 (anti-ICAM-1), administered at the time of bilateral renal ischemia in the rat, prevented both functional impairment and histologic changes of acute renal failure. Plasma creatinine measured (mg/dl) 24 hr after 30 min of ischemia was 0.61 +/- 0.05 in the anti-ICAM-1-treated animals compared with 2.4 +/- 0.14 (P < 0.0001) in the vehicle-treated ischemic group. Forty-eight hours after ischemia, creatinine values were 0.46 +/- 0.05 and 2.03 +/- 0.22 (P < 0.0001) in anti-ICAM-1 and vehicle-treated groups, respectively. A low dose of anti-ICAM-1 that was itself nonprotective, when given with partially protective doses of a mAb against lymphocyte function-associated antigen-1 (anti-LFA-1), acted synergistically to prevent renal failure. Anti-ICAM-1 mAb also protected the kidney when administered 0.5 or 2 hr but not 8 hr after restoration of blood flow and when the ischemic period was extended to 40 min. Ischemia-induced increases in tissue myeloperoxidase, a marker of neutrophil infiltration, were mitigated with anti-ICAM-1 treatment. Thus, anti-ICAM-1 mAb protected the kidney against ischemic renal failure, even when the antibody was administered after the ischemic period. These results suggest a critical role for leukocytes and adhesion molecules in the pathophysiology of ischemic injury and may have important therapeutic implications.     

The human homologous pairing protein HPP-1 is specifically stimulated by the cognate single-stranded binding protein hRP-A.

Homologous pairing and strand exchange of DNA are catalyzed by the human homologous pairing protein HPP-1 in a magnesium-dependent, ATP-independent reaction that requires homologous DNA substrates and stoichiometric quantities of HPP-1. Here we show that the addition of the purified human single-strand binding (SSB) protein hRP-A to the reaction mixture stimulates the rate of homologous pairing 70-fold and reduces the amount of HPP-1 required for the reaction at least 10-fold. The identification of hRP-A as a stimulatory factor of HPP-1-catalyzed reaction was facilitated by its recognition as a member of a high molecular weight complex of recombination components. Neither the Escherichia coli SSB protein, bacteriophage T4 gene 32 protein, nor the highly conserved Saccharomyces cerevisiae yRP-A SSB protein could substitute for hRP-A in this stimulation. Because only the cognate SSB was capable of stimulating HPP-1, these results suggest that eukaryotes depend on unique and specific interactions between DNA recombination components.