A clinical trial of 7 alpha-methyl-19-nortestosterone implants for possible use as a long-acting contraceptive for men

Several preparations of testosterone and its esters are being investigated alone or in combination with other gonadotropin-suppressing agents as possible antifertility agents for men. We studied the effectiveness of 7 alpha-methyl-19-nortestosterone (MENT) as an antispermatogenic agent in men. MENT has been shown to be more potent than testosterone and to be resistant to 5 alpha-reduction. For sustained delivery of MENT, we used a system consisting of ethylene vinyl acetate implants containing MENT acetate (Ac), administered subdermally. Thirty-five normal volunteers were recruited in 3 clinics and were randomly assigned to 1 of 3 doses: 1 (12 men), 2 (11 men), or 4 (12 men) MENT Ac implants. The initial average in vitro release rate of MENT Ac from each implant was approximately 400 micro g/day. Implants were inserted subdermally in the medial aspect of the upper arm under local anesthesia. The duration of treatment was initially designed to be 6 months. However, in 2 clinics the duration of treatment was extended to 9 months for the 2-implant group and to 12 months for the 4-implant group. Dose-related increases in serum MENT levels and decreases in testosterone, LH, and FSH levels were observed. Effects on sperm counts were also dose related. None of the subjects in the 1-implant group exhibited oligozoospermia (sperm count, <3 million/ml). Four subjects in the 2-implant group became oligozoospermic, 2 of whom reached azoospermia. Eight subjects in the 4-implant group reached azoospermia, with 1 exhibiting oligozoospermia, whereas 2 were nonresponders. Side effects generally seen with androgen administration, such as increases in erythrocyte count, hematocrit, and hemoglobin and a decrease in SHBG, were also seen in this study and were reversible. Changes in lipid parameters were moderate and transient. Liver enzymes showed small changes. This study demonstrates that MENT Ac, when administered in a sustained release fashion via subdermal implants, can inhibit spermatogenesis over a prolonged period after a single administration and has the potential to be used as a male contraceptive.     

Interleukin-10 haplotype associated with increased mortality in critically ill patients with sepsis from pneumonia but not in patients with extrapulmonary sepsis

STUDY OBJECTIVE: To test the hypothesis that haplotypes of the interleukin (IL)-10 gene are associated with clinical outcomes, comparing critically ill patients with sepsis from pneumonia vs those with extrapulmonary sepsis. DESIGN: Genetic association study. SETTING: Medical/surgical ICUs in a tertiary-care, university-affiliated teaching hospital. PATIENTS: Of 550 white patients with sepsis, 158 had pneumonia as the principle cause of their sepsis and 392 had an extrapulmonary source of sepsis. MEASUREMENTS: Haplotypes of the IL-10 gene were defined by measurement of haplotype tag single-nucleotide polymorphisms (SNPs). Primary outcome was 28-day survival. Secondary outcomes were days alive and free of organ dysfunction. RESULTS: Three SNPs in the IL-10 gene (-592 C/A, +734 G/T, and +3367 G/A) identified four major haplotypes: CGG, AGG, CTA, and CTG. Patients with pneumonia who carried one or two copies of the CGG haplotype had greater 28-day mortality (51.4%) than patients who did not carry this haplotype (29.1%, p = 0.007). Carriers of CGG had significantly more cardiovascular dysfunction (and use of vasopressors), renal dysfunction (and requirement of dialysis), hepatic dysfunction, and hematologic dysfunction (p < 0.05 in each case). In contrast, in patients with an extrapulmonary source of infection there was no significant association of the CGG haplotype (or any measured IL-10 genotype) with 28-day mortality or organ dysfunction. CONCLUSIONS: The IL-10 haplotype - 592C/734G/3367G is associated with increased mortality and organ dysfunction in critically ill patients with pulmonary sepsis but not in similarly ill patients with extrapulmonary sepsis. Therefore, polymorphisms within the IL-10 gene may be predictors of outcome in patients with sepsis from pneumonia.     

Safety and efficacy of ampreloxetine in symptomatic neurogenic orthostatic hypotension: a phase 2 trial

Clinical Autonomic Research - In neurogenic orthostatic hypotension, blood pressure falls when upright owing to impaired release of norepinephrine, leading to dizziness. Ampreloxetine, a selective...     

Human immunodeficiency virus type 1 and other viral co-infections among young heterosexual men and women in Argentina

Infections with hepatitis C virus, (HCV), hepatitis B virus (HBV), and human T lymphotropic type I/II (HTLV-I/II) virus are commonly found in patients infected with human immunodeficiency virus type 1 (HIV-1). We conducted a seroepidemiologic study among 174 HIV-positive heterosexuals in Buenos Aires, Argentina in 1999. Evidence of exposure to HCV, HBV, and HTLV-I/II was found in 32%, 17%, and 5%, respectively. A higher prevalence of HBV infection was observed among males (33%) compared with females (12%; P < 0.05). Among women, a prior history of a sexually transmitted infection, injecting drug use (IDU), having had more than five lifetime sex partners, and having exchanged sex-for-goods were significantly associated with HCV infection, whereas an IDU history, syringe sharing, and having exchanged sex-for-goods were found to be associated with HBV infection. Among men, an IDU history and syringe/needle sharing were significantly associated with HCV infection. The IDU-related and sexual transmission of hepatitis viruses constitute a significant problem among young, HIV-infected, heterosexuals in Argentina.     

Evaluación prospectiva del desarrollo de nefropatía inducida por contraste en pacientes con síndrome coronario agudo tratados con angiografía coronaria rotacional vs. angiografía coronaria convencional: Estudio CINERAMA

Introduction and objectives

Rotational coronary angiography (RCA) requires less contrast to be administered and can prevent the onset of contrast-induced nephropathy (CIN) during invasive coronary procedures. The aim of the study is to evaluate the impact of RCA on CIN (increase in serum creatinine ≥0.5 mg/dl or ≥25%) after an acute coronary syndrome.

Tacrolimus (FK 506), a Treatment for Primary Sclerosing Cholangitis: Results of an Open-Label Preliminary Trial

Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease of the liver that is characterized by progressive cholestasis and the development of secondary biliary cirrhosis. There is no widely recognized therapy for this disease, although anti-inflammatory agents (steroids), immunosuppressive agents (methotrexate), anti-fihrotics (colchicine), and choleretic agents (ursodeoxycholic acid) have been used in various small series. In the present study, Tacrolimus (FK 506), a new and powerful immunosuppressive macrolide antibiotic, has been used to treat 10 patients with PSC. Each subject had a liver biopsy, ERCP with visualization of the intra-and extrahepatic biliary tree, and a panel of hcmatological, serological, and biochemical laboratory tests before the initiation of the FK 506 therapy. The FK 506 was administered orally at 12-h intervals and was monitored by serial plasma FK 506 trough levels. After 360 days of treatment, the median serum bilirubin level was reduced by 75%, and the serum alkaline phosphatase was reduced by 70%. Moreover, the serum ALT and AST levels were reduced by 80 and 86%, respectively. No change in the serum level of BUN and creatinine levels occurred as a consequence of the FK 506 treatment. These data demonstrate that: 1) FK 506 can be used to treat PSC; 2) the response to FK 506 by patients with PSC is rapid; and, 3) no adverse effect on the serum BUN and creatinine levels was observed. It is anticipated that FK 506 will become an important agent for the treatment of patients with PSC because of its powerful immunosuppressive activity.     

The dorsomedial suprachiasmatic nucleus times circadian expression of Kiss1 and the luteinizing hormone surge

Ovulation in mammals is gated by a master circadian clock in the suprachiasmatic nucleus (SCN). GnRH neurons represent the converging pathway through which the brain triggers ovulation, but precisely how the SCN times GnRH neurons is unknown. We tested the hypothesis that neurons expressing kisspeptin, a neuropeptide coded by the Kiss1 gene and necessary for the activation of GnRH cells during ovulation, represent a relay station for circadian information that times ovulation. We first show that the circadian increase of Kiss1 expression, as well as the activation of GnRH cells, relies on intact ipsilateral neural input from the SCN. Second, by desynchronizing the dorsomedial (dm) and ventrolateral (vl) subregions of the SCN, we show that a clock residing in the dmSCN acts independently of the light-dark cycle, and the vlSCN, to time Kiss1 expression in the anteroventral periventricular nucleus of the hypothalamus and that this rhythm is always in phase with the LH surge. In addition, we show that although the timing of the LH surge is governed by the dmSCN, its amplitude likely depends on the phase coherence between the vlSCN and dmSCN. Our results suggest that whereas dmSCN neuronal oscillators are sufficient to time the LH surge through input to kisspeptin cells in the anteroventral periventricular nucleus of the hypothalamus, the phase coherence among dmSCN, vlSCN, and extra-SCN oscillators is critical for shaping it. They also suggest that female reproductive disorders associated with nocturnal shift work could emerge from the desynchronization between subregional oscillators within the master circadian clock.