Pharmacology of 2-[4-(4-chloro-2-fluorophenoxy)phenyl]-pyrimidine-4-carboxamide: a potent, broad-spectrum state-dependent sodium channel blocker for treating pain states

Voltage-gated Na(+) channels may play important roles in establishing pathological neuronal hyperexcitability associated with chronic pain in humans. Na(+) channel blockers, such as carbamazepine (CBZ) and lamotrigine (LTG), are efficacious in treating neuropathic pain; however, their therapeutic utility is compromised by central nervous system side effects. We reasoned that it may be possible to gain superior control over pain states and, in particular, a better therapeutic index, by designing broad-spectrum Na(+) channel blockers with higher potency, faster onset kinetics, and greater levels of state dependence than existing drugs. 2-[4-(4-Chloro-2-fluorophenoxy)phenyl]-pyrimidine-4-carboxamide (PPPA) is a novel structural analog of the state-dependent Na(+) channel blocker V102862 [4-(4-fluorophenoxy)benzaldehyde semicarbazone]. Tested on recombinant rat Na(v)1.2 channels and native Na(+) currents in cultured rat dorsal root ganglion neurons, PPPA was approximately 1000 times more potent, had 2000-fold faster binding kinetics, and > or =10-fold higher levels of state dependence than CBZ and LTG. Tested in rat pain models against mechanical endpoints, PPPA had minimal effective doses of 1 to 3 mg/kg p.o. in partial sciatic nerve ligation, Freund's complete adjuvant, and postincisional pain. In all cases, efficacy was similar to clinically relevant comparators. Importantly, PPPA did not produce motor deficits in the accelerating Rotarod assay of ataxia at doses up to 30 mg/kg p.o., indicating a therapeutic index >10, which was superior to CBZ and LTG. Our experiments suggest that high-potency, broad-spectrum, state-dependent Na(+) channel blockers will have clinical utility for treating neuropathic, inflammatory, and postsurgical pain. Optimizing the biophysical parameters of broad-spectrum voltage-gated Na(+) channel blockers may lead to improved pain therapeutics.     

Epidemiology of congenital malaria in Nigeria: a multi-centre study

Objective To determine the burden of congenital malaria in newborns in Nigeria. Methods In a prospective multi‐centre study, 1875 consecutive mother–baby pairs were enrolled over a continuous 12‐month period. Blood smears were prepared from mothers, neonates, placental aspirates and cord blood within 4 h of delivery. Outcome variables were patent parasitaemia in the mother, placenta, cord and neonate in addition to maternal and neonatal haematocrit. Results Patent parasitaemia was detected in 95 neonates (5.1%). The occurrence varied between study centres, but was found year round in all sites. The mean parasite density among infected neonates was low (48 asexual forms per μl, range 8–200/μl). Maternal and placental parasitaemia were the most important risk factors for patent neonatal parasitaemia (P < 0.0001). Spontaneous clearance of parasitaemia occurred in 62.1% of neonates before day 2. 33.7% were symptomatic within 3 days of birth. Conclusion Congenital malaria is often asymptomatic, clears spontaneously and may not warrant treatment. However, newborns with unexplained fever and refusal to feed in malaria endemic areas should be tested for malaria.     

Adenosine A(2A) and A(2B) receptors mediated nitric oxide production in coronary artery endothelial cells.

The present study further examined the functional presence and the signal transduction mechanism(s) for adenosine A(2A) and A(2B) receptors through nitric oxide (NO) and the guanosine 3', 5'-cyclic monophosphate (cGMP) pathway in cultured porcine coronary artery endothelial cells (PCAEC). The application of adenosine receptor agonists, NECA, CGS-21680 and CAD between 10(-7) and 10(-4) M, enhanced the production of NO (measured as nitrite) in a dose-dependent manner. On the basis of EC(50) values, these agonists showed the following order of potency: NECA>CGS-21680>CAD. This order appears to be of the A(2) adenosine receptor subtype. Similarly, the same concentrations of adenosine agonists evoked the production of cGMP in a dose-dependent manner, exhibiting a rank order that is similar to that of NO production. NO synthase inhibitor, N-nitro-L-arginine methylester (L-NAME, 10(-5) M), inhibited the production of NO and cGMP, which was reversed by L-arginine (10(-4) M). Selective A(2A) adenosine receptor antagonists, ZM-241385 and SCH-58261, at 10(-7) M, significantly inhibited the effects of CGS-21680, but only partly inhibited the effect of NECA on NO and cGMP production. Along with the earlier molecular evidence from this laboratory [Am. J. Physiol. 279 (2000) H650], the present data further support the presence of both A(2A) and A(2B) receptors in PCAEC. These results further support that coronary endothelial cells express functional A(2A) and A(2B) adenosine receptors, leading to GMP production through the NO-synthase-linked mechanism. This is the first direct evidence where an A(2B) adenosine receptor has been linked to NO production in cultured endothelial cells and could play a role in coronary artery physiology and pathophysiology.     

Realist evaluation of faculty development for medical educators: What works for whom and why in the long-term

Purpose: Realism is a perspective in which entities exist independently of being perceived or independently of our theories about them. The realist framework with its principle of explanatory causation was used for an in-depth exploration of faculty development (FD) since, despite the widespread investment in FD, the evidence that it enhances the effectiveness of teaching in the long-term is still limited. The study aimed to develop realist theories that explain the connections between contexts (C), mechanisms (M) and outcomes (O) to find out what works for whom and why in FD.

Methods: Purposive sampling was used to select two medical schools from each of the four UK regions (total 8 of the 33 UK medical schools) for interview of a faculty development coordinator and a medical educator at each school. Sixteen interviews were carried out. Data were coded and summarized under contexts, mechanisms, and outcomes (CMO) to derive realist theories.

Results: We identified contexts that facilitated FD mechanisms of engagement, motivation, positive perception and professionalization, which led to educators’ outcomes of improved confidence, competence, credibility and career progression.

Conclusion: Four realist theories, which support the effectiveness of FD in the long-term, were derived, enabling recommendations for FD stakeholders.     

Comparative study of glycosylated haemoglobin and serum fructosamine values in children with protein-energy malnutrition.

Serum fructosamine, glycosylated haemoglobin (HbAic), fasting blood glucose and serum proteins were determined in 50 malnourished children aged 1-5 years and in 25 healthy and nutritionally normal children of the same age group. It was observed that both HbAic and fructosamine values correlated well with the blood glucose values of the patients. It was also observed that the patients had significantly elevated values of HbAic, indicating the existence of glucose intolerance in them. In contrast, the fructosamine values were significantly reduced in the patients and this was attributed to the hypoproteinaemia in such patients. It was concluded that while both HbAic frustosamine correlate well with blood glucose values, HbAic gives a better reflection of the glycaemic status of malnourished children because its level is not significantly altered by hypoproteinaemia. HbAic measurement may, therefore, be a more reliable indicator of glucose status than serum fructosamine in children with protein-energy malnutrition.     

Assessment of the knowledge and beliefs of Finnish medical students regarding HIV infection and participation in AIDS vaccine trials

This study sought to determine the level of general knowledge about HIV infection among Finnish medical students and their willingness to participate in AIDS vaccine trials. One hundred and sixty-two volunteer medical students at the University of Kuopio in the 2nd and 5th years of training filled self-administered questionnaires. The overall response rate among the 2nd year students was 77%, and among the 5th year students 70%. Knowledge was scored on a percentage scale. The mean score on general knowledge about HIV among 2nd year students was 75.6 (SD=0.23) while in the 5th year it was 87.8 (SD 0.18). Fifty-four students (77%) from the 5th year and 66 (72%) from the 2nd year indicated their willingness to participate (WTP) in AIDS vaccine trials (p=0.09). Medical curricula should be constantly revised to keep medical students up-to-date about recent advances in HIV/AIDS research.     

Instructions to authors for case reporting are limited: A review of a core journal list

Background

Case reports are frequently published in the health care literature, however advice on preparing such reports using the "instructions to authors" pages of journals is alleged to be limited. However, to our knowledge, this has not been formally evaluated. As roles of case reports may vary according to the case and the clinical specialities, one might expect the advice to authors to vary according to journal clinical grouping.

Methods

We surveyed the current advice available to authors of case reports from 'instructions to authors' pages of a core collection of 249 journals ('Hague' list). These were examined and compared for advice or recommendation on writing case reports. Of these, 163 (65%) published case reports and provided instructions on this publication type. Data were extracted on items of style and content of case reports, using a piloted data extraction form.

Results

Journals that published case reports were grouped into medical (n = 81, 50%), surgical (n = 38, 23%) and generic or multidisciplinary (n = 44, 27%) categories. There was a difference among the medical, surgical and generic or multidisciplinary journals in the maximum number of words and pages allowed but no difference in the number of figures, tables, references, authors, abstract or synopsis, indexing or key words and consent. Additionally, there was no statistically significant difference among the three different categories of journals regarding the content of the case reports.

Conclusions

Of the journals reviewed, we found that 'instructions to authors' pages provided limited and varied information for preparing a case report. There is a need for consensus, and more consistent guidance for authors of case report.