Pharmacokinetics of orally administered norethisterone enanthate in rabbit, monkey, and women

Norethisterone enanthate (NET-En), an established intramuscular long-acting contraceptive agent, has previously been shown to be effective in inhibiting fertility in two rodent species even 4 days after oral ingestion. Pharmacokinetics of NET and NET-En were studied after oral and intramuscular doses in two animal species and a few women. The results suggest that the NET-En was absorbed within a day in all the species after oral dose. The estimates of relative bioavailability ranged from 13 to 51% in rabbits, monkeys, and women. The elimination half-life was 5–10 days. The presence of the active component, NET, in the circulation over the experimental period of 15 days suggests that NET-En could be useful as a long-acting oral pill. The suppression of progesterone levels during the luteal phase of menstrual cycle in women also supports this finding.     

Heroin-Induces Differential Protein Expression by Normal Human Astrocytes (NHA)

Heroin use is postulated to act as a cofactor in the neuropathogenesis of human immunodeficiency virus (HIV-1) infection. Astrocytes, integral components of the CNS, are reported to be susceptible to HIV-1 infection. Upon activation, astrocytes release a number of immunoregulatory products or modulate the expression of a number of proteins that foster the immunopathogenesis of HIV-1 infection. However, the role of heroin on HIV-1 infectivity and the expression of the proteome of normal human astrocytes (NHA) have not been elucidated. We hypothesize that heroin modulates the expression of a number of proteins by NHA that foster the neuoropathogenesis of HIV-1 infection. We utilized LTR amplification and the p24 antigen assay to quantitate the effect of heroin on HIV-1 infectivity while difference gel electrophoresis (DIGE) combined with protein identification through high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) to analyze the effects of heroin on the proteomic profile of NHA. Results demonstrate that heroin potentiates HIV-1 replication in NHA. Furthermore, heroin significantly increased protein expression levels for protein kinase C (PKC), reticulocalbin 1 precursor, reticulocalbin 1, tyrosine 3-monooxgenase/tryptophan 5-monooxgenase activation protein, chloride intracellular channel 1, cathepsin D preproprotein, galectin 1 and myosin light chain alkali. Heroin also significantly decreased protein expression for proliferating cell nuclear antigen, proteasome beta 6 subunit, tropomyosin 3, laminin receptor 1, tubulin alpha 6, vimentin, EF hand domain family member D2, Tumor protein D54 (hD54), ATP synthase, H+ transporting, mitochondrial F1 complex and ribosomal protein S14. Identification of unique, heroin-induced proteins may help to develop novel markers for diagnostic, preventative and therapeutic targeting in heroin using subjects.     

Association of the renin-sodium profile with the risk of myocardial infarction in patients with hypertension.

BACKGROUND. To test the prognostic value of plasma renin activity prospectively, we determined the pretreatment renin-sodium profile of 1717 subjects with mild-to-moderate hypertension (mean age, 53 years; 36 percent white; 67 percent men) in a systematic work-site treatment program. METHODS. Renin profiles, obtained by plotting plasma renin activity against the urinary excretion of sodium, were classified as high (12 percent of the subjects), normal (56 percent), and low (32 percent), and there were expected variations according to age, sex, and race. Modified stepped-care treatment for hypertension, prescribed without reference to the renin profile, was similar in the three renin groups. RESULTS. Mean (+/- SD) blood pressure at entry was 151 +/- 19/100 +/- 10 mm Hg in the subjects with a high renin profile, 151 +/- 19/97 +/- 10 mm Hg in those with a normal profile, and 151 +/- 20/96 +/- 11 mm Hg in those with a low profile. During 8.3 years of follow-up, there were 27 myocardial infarctions. As adjusted for age, sex, and race, the incidence of myocardial infarction per 1000 person-years was 14.7 among the subjects with a high renin profile, 5.6 among those with a normal profile, and 2.8 among those with a low profile (rate ratio for high vs. low, 5.3; 95 percent confidence interval, 3.4 to 8.3). The rate of mortality from all causes was 9.3 in the high-profile group, 5.3 in the normal-profile group, and 3.9 in the low-profile group. The independent association of a high renin profile with myocardial infarction (but not with stroke or noncardiovascular events) was affirmed by Cox analyses (rate ratio for high vs. normal plus low, 3.2; 95 percent confidence interval, 1.2 to 8.4) after adjustment for race, sex, age at entry, serum cholesterol level, smoking status, electrocardiographic evidence of left ventricular hypertrophy, blood glucose level, body-mass index, history of cardiovascular disease or treatment, blood pressure, and use of beta-blockers. CONCLUSIONS. In the study population, whose blood pressure before and during treatment was in a narrow range, and after other cardiovascular risk factors had been considered, the renin profile before treatment remained independently associated with the subsequent risk of myocardial infarction.     

The respiratory microbiome after lung transplantation: Reflection or driver of respiratory disease?

With the introduction of high-throughput sequencing methods, our understanding of the human lower respiratory tract's inhabitants has expanded significantly in recent years. What is now termed the “lung microbiome” has been described for healthy patients, as well as people with chronic lung diseases and lung transplants. The lung microbiome of lung transplant recipients (LTRs) has proven to be unique compared with nontransplant patients, with characteristic findings associated with disease states, such as pneumonia, acute rejection, and graft failure. In this review, we summarize the current understanding of the lung microbiome in LTRs, not only focusing on bacteria but also highlighting key findings of the viral and the fungal community. Based on our knowledge of the lung microbiome in LTRs, we propose multiple opportunities for clinical use of the microbiome to improve outcomes in this population.     

Antioxidant supplementation effects on low-density lipoprotein oxidation for individuals with type 2 diabetes mellitus.

OBJECTIVE: This study compared susceptibility to oxidation of low-density lipoproteins (LDL) of non-diabetic and diabetic (Type 2) men and examined the response of diabetic men to antioxidant supplementation (alpha-tocopherol, beta-carotene and ascorbate). RESEARCH DESIGN AND METHODS: Twenty adult non-diabetic and 20 diabetic men were recruited. Oxidation of LDL was assessed by four different assay systems, and the extent of oxidation was assessed by four different measurements. Diabetic men received eight weeks of placebo ("baseline"), twelve weeks of antioxidant supplements ("treated") and eight weeks of placebo ("post-treatment"). Supplements provided 24 mg of beta-carotene, 1000 mg of ascorbate and 800 IU of alpha-tocopherol daily. RESULTS: With Cu oxidation at 37 degrees C, thiobarbituric reactive substances (TBARS) formation was significantly higher (p=0.032) and loss of free amine groups was significantly greater (p=0.013) in the LDL from diabetic subjects than controls. Antioxidant supplementation of diabetic subjects significantly decreased all parameters of LDL oxidation with Cu at 30 degrees C and 37 degrees C. At 30 degrees C the lag phase increased from 55 to 129 minutes (p<0.0001); conjugated diene formation decreased from 1.23 to 0.62 OD units (p<0.0001); TBARS formation decreased from 78 to 33 nmoles MDA/mg LDL protein (p<0.0001); and free amine loss decreased from 41 to 12% (p<0.0001). With Cu oxidation at 37 degrees C, similar changes occurred. CONCLUSIONS: These studies indicate that the LDL from diabetic subjects are more susceptible to oxidation than LDL from non-diabetic subjects. Supplementation of diabetic subjects with antioxidant vitamins significantly decreases susceptibility of LDL to oxidation by Cu. These studies are consistent with epidemiological and intervention studies suggesting that antioxidant vitamin use significantly decreases risk for coronary heart disease.