The role of organic anion‐transporting polypeptides and formulation in the clearance and distribution of a novel Nav1.7 channel blocker

PF‐06456384 is an extremely potent and selective blocker of the Na_v1.7 sodium channel designed as a potential intravenous (i.v.) analgesic targeting high potency and rapid clearance to minimize the potential for residual effects following the end of infusion. In our previous experience targeting oral molecules, the requirement to obtain potent, Na_v1.7 selective molecules led to a focus on acidic, amphipilic compounds cleared primarily by organic anion‐transporting polypeptide mediated hepatic uptake and subsequent biliary excretion. However, the physicochemical properties of the i.v. lead matter were substantially different, moving from acidic, amphiphilic chemical space to zwitterions as well as substantially increasing molecular weight. This report describes the continued relevance of organic anion‐transporting polypeptide driven hepatic uptake in this physicochemical space and highlights an apparent impact of the formulation excipient Solutol on the clearance and distribution of PF‐06456384.     

A Medical Outreach Elective Course

Objective. To design and implement a Medical Outreach Experience elective course and assess its impact on students’ level of confidence in organizing future medical outreach trips, providing population-specific pharmaceutical care, and achieving learning outcomes.Design. A 2-credit hour elective course was designed for second- and third-year pharmacy students. The course was structured to include 3 sections over 1 semester, a 10-week training and preparation phase, followed by a weeklong international outreach experience and post-outreach reflection.Assessment. Student achievement of curricular outcomes was measured using in-class activities, readings, reflections, and longitudinal projects, as well as performance during the outreach trip. Results from pre- and post-course surveys demonstrated significant improvement in student-rated confidence in several components of outreach trip organization and provision of pharmaceutical care.Conclusions. Students completing the course exhibited increased confidence in their abilities to organize and practice on a medical outreach trip. All students met the learning outcomes of the course, which included providing comprehensive patient-specific pharmaceutical care, communicating effectively, promoting health improvement and self-care, thinking critically, and appropriately managing and using resources of the healthcare system. Students agreed that the elective course was a valuable addition to the curriculum.     

Identification of Tetrahydropyrido[4,3-d]pyrimidine Amides as a New Class of Orally Bioavailable TGR5 Agonists

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Refocusing HIV / AIDS interventions in Thailand: the case for male sex workers and other homosexually active men

Although studies have shown that male sex workers in Thailand are at increased risk of HIV infection, no sustained strategy have so far been directed towards homosexually active men in the country. This paper brings together data from qualitative research carried out in Pattaya and Bangkok, with data generated during a bar-based intervention in Bangkok, to develop a taxonomy of sites in which the recruitment of male commercial sex can occur. The researchers also examined the sexual networks of Thai male sex workers and their clients in order to show the overlap of commercial and non-commercial male-male sex sites, and the intersection of male commercial sex with heterosexual sex. Previous efforts directed towards Thai male sex workers have been non-continuous; largely restricted to high-profile tourist areas; have not acknowledged the importance of recreational sex; and have not built up a capacity for ongoing intervention. With a change of focus, interventions targeted at sex workers could reduce the risks of HIV infection among organized and freelance sex workers as well as their commercial and male and female casual sex partners. Foremost, however, is the need to commit to well planned and long range interventions directed by and at male sex workers.     

Design,Synthesis, and Evaluation of Tetrasubstituted Pyridines as Potent 5-HT2C Receptor Agonists

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Histologic evidence of distal coronary thromboembolism. A complication of acute proximal coronary artery thrombolysis therapy

Distal migration of occluding coronary thrombus during thrombolysis therapy for acute myocardial infarction rarely has been observed angiographically. Necropsy documentation of the final location of embolic fragments in this circumstance has not been reported previously. This report documents multiple occluded intramyocardial vessels with thrombus observed to have showered distally during thrombolysis therapy. Depending on size and number, fragments of dislodging proximal coronary embolus may produce additional myocardial necrosis.     

Herpes simplex virus infection complicating amniotic band syndrome in the newborn

Amniotic band syndrome, which is frequently seen in association with prolonged rupture of membranes, is due to the amnion forming fibrous strands that encircle fetal parts. This causes compression and necrosis of the underlying skin. We report a case of herpes simplex virus infection localized to these lesions.     

Influence of selective endoperoxide/thromboxane A2 receptor antagonism with sulotroban on lysis time and reocclusion rate after tissue plasminogen activator-induced coronary thrombolysis in the dog

The purpose of this investigation was to examine the potential beneficial effect of the selective endoperoxide/thromboxane A2 (TxA2) receptor antagonist, sulotroban (BM 13.177), on tissue type plasminogen activator (tPA)-induced coronary thrombolysis in the dog. A stenosis that eliminated reactive hyperemic capacity was placed on the circumflex coronary artery and an occlusive thrombus was produced by electrical injury to the intimal surface of the artery. Upon occlusion, sodium heparin was administered (300 U/kg i.v.) followed by 100 U/kg i.v. every hour thereafter. All dogs received i.v. tPA 60 min after the formation of the occlusive thrombus at a dose of 10 micrograms/kg/min for up to 90 min, if necessary, to elicit reperfusion. Thrombolysis was demonstrated in all dogs by restoration of coronary blood flow. Dogs were randomized to one of three groups. Group I consisted of 24 animals that received vehicle infusion along with tPA. Group II consisted of 10 animals that received sulotroban at a bolus dose of 1 mg/kg i.v. followed by 1 mg/kg/hr i.v. administered simultaneously with tPA. Group III consisted of 11 animals that received sulotroban at a bolus of 10 mg/kg i.v. followed by 10 mg/kg/hr i.v. administered simultaneously with tPA. Infusions of either vehicle or sulotroban were continued for 2 hr, post-thrombolysis. tPA was infused for at least 30 min, after which infusion of tPA was terminated upon achieving a reperfusion level of coronary blood flow equivalent to 50% or greater than control blood flow. All animals occluded spontaneously to electrolytic stimulation between 32 and 62 min. tPA-induced thrombolysis occurred in Group I vehicle-infused animals at 32 +/- 5 min.(ABSTRACT TRUNCATED AT 250 WORDS)     

A simple binding assay for the direct determination of biotin in urine

BACKGROUND: We have devised a simple assay to detect adequate biotin intake, which uses an alternative configuration from most existing assays. METHODS: The assay depends on the competition of streptavidin peroxidase for immobilized biotin or soluble biotin in standards or samples. Immobilized streptavidin peroxidase is detected using tetramethylbenzidine, and the plates are read at 450 nm. The assay was normalised by determining the biotin/creatinine ratio in the urine of healthy adults. Urinary biotin excretion was measured in unsupplemented pregnant women. The half-life of biotin excretion after a single oral supplement was determined for healthy volunteers. RESULTS: Urinary biotin excretion in unsupplemented pregnant women was 2.9+/-1.9 micromol/mol creatinine (mean+/-S.D.) and was significantly lower (p<0.001) than those of healthy males and females, which were 9.0+/-5.4 and 7.0+/-2.1 micromol/mol creatinine (mean+/-S.D.), respectively. The half-life of a single oral biotin supplement was 30-40 h, with excretion returning to basal levels at 70 h. CONCLUSION: We have devised a novel binding assay for the direct determination of total biotin excretion in urine, which is suitable for routine clinical laboratory. The assay is inexpensive, simple, rapid, and could be fully automated.     

The separated enantiomers of 2''-deoxy-3''-thiacytidine (BCH 189) both inhibit human immunodeficiency virus replication in vitro.

Racemic 2'-deoxy-3'-thiacytidine (BCH 189) is a dideoxycytidine analog having a sulfur atom in place of the 3' carbon. The enantiomers of BCH 189 have been resolved and found to be equipotent in antiviral activity against human immunodeficiency virus types 1 and 2. However, the (-)-enantiomer (3TC) is considerably less cytotoxic than the (+)-enantiomer.