Efficacy and long-term safety of alipogene tiparvovec (AAV1-LPLS447X) gene therapy for lipoprotein lipase deficiency: an open-label trial.

We describe the 2-year follow-up of an open-label trial (CT-AMT-011-01) of AAV1-LPL(S447X) gene therapy for lipoprotein lipase (LPL) deficiency (LPLD), an orphan disease associated with chylomicronemia, severe hypertriglyceridemia, metabolic complications and potentially life-threatening pancreatitis. The LPL(S447X) gene variant, in an adeno-associated viral vector of serotype 1 (alipogene tiparvovec), was administered to 14 adult LPLD patients with a prior history of pancreatitis. Primary objectives were to assess the long-term safety of alipogene tiparvovec and achieve a ≥40% reduction in fasting median plasma triglyceride (TG) at 3-12 weeks compared with baseline. Cohorts 1 (n=2) and 2 (n=4) received 3 × 10(11) gc kg(-1), and cohort 3 (n=8) received 1 × 10(12) gc kg(-1). Cohorts 2 and 3 also received immunosuppressants from the time of alipogene tiparvovec administration and continued for 12 weeks. Alipogene tiparvovec was well tolerated, without emerging safety concerns for 2 years. Half of the patients demonstrated a ≥40% reduction in fasting TG between 3 and 12 weeks. TG subsequently returned to baseline, although sustained LPL(S447X) expression and long-term changes in TG-rich lipoprotein characteristics were noted independently of the effect on fasting plasma TG.

The beta-1 adrenergic antagonist, atenolol, decreases acylation stimulating protein, exercise capacity and plasma free fatty acids in men with type 2 diabetes.

BACKGROUND AND AIMS: Atenolol is a beta-1 adrenergic antagonist commonly prescribed for the treatment of systemic hypertension or coronary artery disease yet its use in individuals with type 2 diabetes mellitus (T2DM) is controversial due to potentially negative side effects on insulin resistance. Non-esterified fatty acid (NEFA) metabolism is altered in T2DM especially under conditions of metabolic stress such as exercise or the postprandial state. We evaluated atenolol effects on circulating NEFA and related hormones in men with T2DM during acute cardiorespiratory exercise in both the fasting and postprandial state, including the adipokine acylation stimulating protein (ASP) which stimulates adipose tissue NEFA uptake. METHODS AND RESULTS: Ten men with T2DM underwent four 1-h exercise sessions at 60% of their maximal oxygen uptake (VO(2max)) under the following conditions: 1) fasting (F), and 2) 2 h postprandial (PP) without medication; and 3) fasting (F-Atenolol), and 4) 2 h postprandial (PP-Atenolol) after a one-week treatment with atenolol. Results were tested for the effects of atenolol via two-way ANOVA for the F vs F-Atenolol and PP vs PP-Atenolol states separately. Atenolol treatment decreased fasting and postprandial glycerol (p < 0.0001) and NEFA (p < 0.0001), postprandial epinephrine (p = 0.048), postprandial cortisol (p = 0.02), postprandial ASP (p = 0.04) and postprandial dopamine (p < 0.004). CONCLUSION: Atenolol alters fatty acid metabolism and associated metabolic hormones including ASP during exercise in men with T2DM and its effects are more apparent during conditions of stress such as the postprandial state, acute exercise and obesity.

Synthetic studies toward diazonamide A. A novel approach for polyoxazole synthesis.

[Reaction in text]The indole-bisoxazole fragment of diazonamide A was prepared by a Chan-type rearrangement of a tertiary amide. This approach represents a remarkably direct strategy for polyoxazole synthesis.

Significant interaction between the nonprescription antihistamine diphenhydramine and the CYP2D6 substrate metoprolol in healthy men with high or low CYP2D6 activity.

The prototype "classic" over-the-counter antihistamine diphenhydramine was shown to interact with the polymorphic P450 enzyme CYP2D6. This project was undertaken to investigate (1) whether diphenhydramine inhibits the biotransformation of the clinically relevant CYP2D6 substrate metoprolol in vitro and (2) whether this in vitro interaction results in a clinically significant pharmacokinetic and pharmacodynamic drug interaction in vivo. In vitro incubations were carried out with microsomes obtained from lymphoblastic cells transfected with CYP2D6 complementary deoxyribonucleic acid to determine the type and extent of inhibition. We then randomized 16 subjects with genetically determined high (extensive metabolizers) or low (poor metabolizers) CYP2D6 activity to receive metoprolol (100 mg) in the presence of steady-state concentrations of diphenhydramine or placebo. In vitro, diphenhydramine was a potent competitive inhibitor of metoprolol alpha-hydroxylation, exhibiting an inhibitory constant of 2 micromol/L and increasing the Michaelis-Menten constant of metoprolol sixfold. In vivo, diphenhydramine decreased metoprolol oral and nonrenal clearances twofold and metoprolol-->alpha-hydroxymetoprolol partial metabolic clearance 2.5-fold in extensive metabolizers (all P < .05) but not in poor metabolizers (P > .2). Although the hemodynamic response to metoprolol was unaltered by diphenhydramine in poor metabolizers (P > .05), metoprolol-related effects on heart rate, systolic blood pressure, and Doppler-derived aortic blood flow peak velocity were more pronounced and lasted significantly longer in extensive metabolizers receiving diphenhydramine compared with poor metabolizers and extensive metabolizers receiving placebo. We conclude that diphenhydramine inhibits the metabolism of metoprolol in extensive metabolizers, thereby prolonging the negative chronotropic and inotropic effects of the drug. Clinically relevant drug interactions may occur between diphenhydramine and many CYP2D6 substrates, particularly those with a narrow therapeutic index.

Total synthesis and stereochemical revision of (+)-aeruginosin 298-A.

[structure:see text] Novel routes toward both enantiomers of the bicyclic proline surrogate 2-carboxy-6-hydroxyoctahydroindole, i.e., Choi, were developed on the basis of the oxidative cyclization of L-tyrosine. Synthesis of the proposed sequence of (+)-aeruginosin 298-A did not provide the natural product. Incorporation of a D-leucine residue, in contrast, led to the total synthesis of this thrombin inhibitor.