pH-dependent effects of lidocaine on defibrillation energy requirements in dogs

Lidocaine increases the energy required for ventricular defibrillation in dogs. Because sodium channel-blocking agents that are weak bases have pH-dependent electrophysiologic effects, we investigated the pH dependence of lidocaine (pKa, 7.9) on internal defibrillation energy requirements in 28 dogs with atrial spring and left ventricular patch electrodes. Results of defibrillation testing were used to derive 50% and 90% successful energy requirements (ED50 and ED90) using logistic regression and were compared with analysis of variance. Acidosis produced by hydrochloric acid infusion decreased the arterial pH from 7.40 +/- 0.05 (SD) to 7.18 +/- 0.03 (n = 8, p less than 0.01), but no significant change in ED90 was observed (14 +/- 4 to 16 +/- 6 J). Lidocaine infusion to therapeutic levels (4.2 +/- .07 micrograms/ml) at normal pH (7.42 +/- 0.02) increased ED90 from 13 +/- 3 to 17 +/- 3 J (n = 6, p less than 0.05), and subsequent acidosis (pH 7.19 +/- 0.02, p less than 0.01) exacerbated this effect of lidocaine on ED90 (22 +/- 5 J, p less than 0.05). Alkalosis produced by respirator hyperventilation increased the arterial pH from 7.41 +/- 0.03 to 7.60 +/- 0.03 (n = 8, p less than 0.01), with a fall in ED90 from 13 +/- 4 to 8 +/- 3 J (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of Renal Impairment on the Pharmacokinetics and Tolerability of Tiagabine

Summary: Purpose: We wished to determine the effect of renal impairment on the pharmacokinetics and tolerability of the new antiepileptic drug tiagabine (TGB).
Methods: We assessed TGB pharmacokinetics and tolerability in 25 subjects with various degrees of renal function (based on creatinine clearance, n = 4–6 per group) from healthy (group I) to requiring hemodialysis (group V) in a single and multiple dose (every 12h), one-period (groups I-IV) or a single dose, two-period (group V) study (4-mg oral doses of TGB · HCl). Blood samples were collected after the first dose (both periods for group V) and after the last dose on day 5 (groups I-IV). TGB plasma concentrations and plasma protein binding were determined by high-performance liquid chromatography (HPLC) and ultrafiltration, respectively.
Results: TGB was well tolerated by all study subjects. The pharmacokinetics of TGB were similar in all subjects; no pharmacokinetic parameter (based on either total or unbound concentrations) was statistically correlated with creatinine clearance. For total TGB in plasma, single-dose mean values of the maximum plasma concentration, clearance, and half-life (t1/2) ranged from 52 to 108 ng/ml, from 7.14 to 11.02 I/h, and from 6.4 to 8.4 h, respectively.
Conclusions: TGB pharmacokinetics and tolerability were independent of renal function; therefore, dosage adjustment is unnecessary for epilepsy patients with renal impairment.     

Ligament tissue engineering: an evolutionary materials science approach

The anterior cruciate ligament (ACL) is important for knee stabilization. Unfortunately, it is also the most commonly injured intra-articular ligament. Due to poor vascularization, the ACL has inferior healing capability and is usually replaced after significant damage has occurred. Currently available replacements have a host of limitations, this has prompted the search for tissue-engineered solutions for ACL repair. Presently investigated scaffolds range from twisted fiber architectures composed of silk fibers to complex three-dimensional braided structures composed of poly (l-lactic acid) fibers. The purpose of these tissue-engineered constructs is to apply approaches such as the use of porous scaffolds, use of cells, and the application of growth factors to promote ligament tissue regeneration while providing mechanical properties similar to natural ligament.     

Recent developments in molecular action of antihormones

 Antihormones are by definition antagonists of steroid hormone action. They interact with the ligand binding domains of steroid hormone receptors and competitively inhibit the action of the receptors by mechanisms that are not quite understood. In certain cases antihormones also exhibit agonistic activity especially in connection with certain naturally occurring receptor mutants. These observations together with findings of indiscriminate interaction of antihormones with several classes of steroid receptors have necessitated a search of more effective and reliable antihormones. Recent advances in the resolution of the crystal structure of the ligand binding domains of certain members of the steroid receptor family and identification of non-liganded activation of steroid receptors have produced considerable information that can be harnessed into a fruitful search for a new generation of antihormones. Received: 19 June 1997 / Accepted: 10 October 1997     

Three-dimensional,bioactive, biodegradable,polymer-bioactive glass composite scaffolds with improved mechanical properties support collagen synthesis and mineralization of human osteoblast-like cells in vitro

In the past decade, tissue engineering-based bone grafting has emerged as a viable alternative to biological and synthetic grafts. The biomaterial component is a critical determinant of the ultimate success of the tissue-engineered graft. Because no single existing material possesses all the necessary properties required in an ideal bone graft, our approach has been to develop a three dimensional (3-D), porous composite of polylactide-co-glycolide (PLAGA) and 45S5 bioactive glass (BG) that is biodegradable, bioactive, and suitable as a scaffold for bone tissue engineering (PLAGA-BG composite). The objectives of this study were to examine the mechanical properties of a PLAGA-BG matrix, to evaluate the response of human osteoblast-like cells to the PLAGA-BG composite, and to evaluate the ability of the composite to form a surface calcium phosphate layer in vitro. Structural and mechanical properties of PLAGA-BG were measured, and the formation of a surface calcium phosphate layer was evaluated by surface analysis methods. The growth and differentiation of human osteoblast-like cells on PLAGA-BG were also examined. A hypothesis was that the combination of PLAGA with BG would result in a biocompatible and bioactive composite, capable of supporting osteoblast adhesion, growth and differentiation, with mechanical properties superior to PLAGA alone. The addition of bioactive glass granules to the PLAGA matrix resulted in a structure with higher compressive modulus than PLAGA alone. Moreover, the PLAGA-BA composite was found to be a bioactive material, as it formed surface calcium phosphate deposits in a simulated body fluid (SBF), and in the presence of cells and serum proteins. The composite supported osteoblast-like morphology, stained positively for alkaline phosphatase, and supported higher levels of Type I collagen synthesis than tissue culture polystyrene controls. We have successfully developed a degradable, porous, polymer bioactive glass composite possessing improved mechanical properties and osteointegrative potential compared to degradable polymers of poly(lactic acid-glycolic acid) alone. Future work will focus on the optimization of the composite scaffold for bone tissue-engineering applications and the evaluation of the 3-D composite in an in vivo model.     

Training the "clinical scientist" through a combined industrial/academic fellowship

A novel two-year fellowship program is described which provides specialized training both in clinical drug research and drug development methodology for pharmacists with previous clinical experience. Pharmaceutical industry, university and hospital research facilities are used as the training laboratories, and collectively offer theoretical as well as practical research skills development. Traditional didactic and laboratory training are provided within university and hospital environments with emphasis in the conduct of clinical trials. Extramural experience with pharmaceutical industry provides a corollary experience which includes exposure to ethical, legal and regulatory issues involving both investigational and marketed drugs. Following successful completion of the fellowship, the pharmacist is expected to have developed the fundamental skills necessary for a career in academia, pharmaceutical industry, or clinical practice.     

Expert for Whom? Court-Appointed Versus Party-Appointed Experts

We investigated differences in judges' attitudes between court-appointed and party-appointed forensic psychiatric expert evidence, including who commissioned the report and how this impacted on the judges' perception of the evidence presented. We also investigated the experts' views on being either a party-appointed or court-appointed expert. This survey has no explicit preconceptions. It sought to gather information empirically. The attitudes towards the experts are seen both from the legal professionals' view and from that of the experts themselves. Two groups, one of 107 forensic psychiatric experts (39 psychologists, 65 psychiatrists and three non-specialist medical doctors), and one of 157 legal professionals (44 judges, 74 attorneys and 39 prosecutors) responded to an online survey. We found that 88% of the experts had been appointed by the court and of these, 73% preferred to be court-appointed. Fifty-one per cent had also been party-appointed and the most common principal was the defence attorney (46%). Sixty-two per cent of the judges who had an opinion stated that the party-appointed experts did not assist the court. This indicates that the judges clearly preferred independent court-appointed experts.     

Longitudinal Assessment of Neuroanatomical and Cognitive Differences in Young Children With Type 1 Diabetes: Association With Hyperglycemia

Significant regional differences in gray and white matter volume and subtle cognitive differences between young diabetic and nondiabetic children have been observed. Here, we assessed whether these differences change over time and the relation with dysglycemia. Children ages 4 to <10 years with (n = 144) and without (n = 72) type 1 diabetes (T1D) had high-resolution structural MRI and comprehensive neurocognitive tests at baseline and 18 months and continuous glucose monitoring and HbA_1c performed quarterly for 18 months. There were no differences in cognitive and executive function scores between groups at 18 months. However, children with diabetes had slower total gray and white matter growth than control subjects. Gray matter regions (left precuneus, right temporal, frontal, and parietal lobes and right medial-frontal cortex) showed lesser growth in diabetes, as did white matter areas (splenium of the corpus callosum, bilateral superior-parietal lobe, bilateral anterior forceps, and inferior-frontal fasciculus). These changes were associated with higher cumulative hyperglycemia and glucose variability but not with hypoglycemia. Young children with T1D have significant differences in total and regional gray and white matter growth in brain regions involved in complex sensorimotor processing and cognition compared with age-matched control subjects over 18 months, suggesting that chronic hyperglycemia may be detrimental to the developing brain.