Contribution of solid-state properties to the aqueous solubility of drugs.

This study investigates the influence of the solid-state properties melting point (T(m)), enthalpy of melting (DeltaH(m)) and entropy of melting (DeltaS(m)) of a drug on its intrinsic solubility (S(0)). For this purpose, 26 chemically and structurally diverse drugs covering the oral drug space were selected and the S(0), T(m), DeltaH(m) and DeltaS(m) were determined experimentally. The influence of T(m), DeltaH(m) and DeltaS(m) on S(0) was studied using regression analysis. The overall improvement of the predictions were 0.3 log units, however, five compounds (astemizole, glyburide, fenbufen, gliclazide and griseofulvin) were improved by more than one log unit. T(m) and DeltaH(m) had a larger effect than DeltaS(m) on the solubility predictions. The well-known general solubility equation (GSE) and the Dannenfelser semi-empirical equation for the calculation of DeltaS(m) were evaluated using our data set. While predictions of drug solubility obtained using the GSE were acceptable, the use of the experimental DeltaS(m) values instead of the constant 56.5 J mol(-1)K(-1) improved the accuracy of the prediction. The Dannenfelser equation underestimated the DeltaS(m) for most compounds with on average 15 J mol(-1)K(-1). Our results show that solid-state properties should be considered for improved performance of future models for prediction of drug solubility. In addition our study provides accurate experimental data on intrinsic solubility for 26 compounds, supplying a useful external data set for validation of drug solubility models.     

Illness-related behaviour and utilization of oral health services among adult city-dwellers in Burkina Faso: evidence from a household survey

Background  

In sub-Saharan Africa, the availability and accessibility of oral health services are seriously constrained and the provision of essential oral care is limited. Reports from the region show a very low utilization of oral health care services, and visits to dental-care facilities are mostly undertaken for symptomatic reasons. The objectives of the present study were to describe the prevalence of oral symptoms among adults in Ouagadougou, capital city of Burkina Faso and the use of oral health services and self-medication in response to these symptoms and to measure the associations between predisposing, enabling and needs factors and decisions to seek oral health care.     

Determination of the velocity associated with VO2max

PURPOSE: The theoretical velocity associated with VO2max (vVO2max) defined by Daniels (1985) is extrapolated from the submaximal VO2-velocity relationship. VO2 is generally determined by assuming that the aerobic response reacts like a linear first-order system at the beginning of square-wave exercise with a steady-state reached by the 4th minute. However, at supra-ventilatory threshold work rates, the steady state in VO2 is delayed or not attained. METHODS: The present study was carried out to compare three values for vVO2max determined with Daniels' method, but with VO2 either measured at the 4th minute (vVO2max4), the 6th minute (vVO2max6), or after the attainment of the true steady-state (vVO2maxSS). The metabolic response during square-wave exercise at each of the three vVO2max were also assessed. RESULTS: These velocities were significantly different (P < 0.05), but vVOmaxSS and vVO2max6 were highly correlated (r = 0.98; P < 0.05). Blood lactate concentrations measured after exercise at velocities very close to the three vVO2max were similar and the end-exercise VO2 were not different from VO2max, but the time required to elicit 95% VO2max during these three square-wave tests were significantly different. CONCLUSION: Therefore, when vVO2max is determined by extrapolation from the submaximal VO2-velocity relationships, submaximal VO2 should be measured beyond the 6th minute of square-wave exercise (at least if it takes 30 s to reach the desired velocity) to ensure that all vVO2max reported in future studies describe a similar quantitative index.     

Myocardial and coronary effects of propofol in rabbits with compensated cardiac hypertrophy

BACKGROUND: Myocardial effects of propofol have been previously investigated but most studies have been performed in healthy hearts. This study compared the cardiac effects of propofol on isolated normal and hypertrophic rabbits hearts. METHODS: The effects of propofol (10-1,000 microM) on myocardial contractility, relaxation, coronary flow and oxygen consumption were investigated in hearts from rabbits with pressure overload-induced left ventricular hypertrophy (LVH group, n = 20) after aortic abdominal banding and from sham-operated control rabbits (SHAM group, n = 10), using an isolated and erythrocyte-perfused heart model. In addition, to assess the myocardial and coronary effects of propofol in more severe LVH, hearts with a degree of hypertrophy greater than 140% were selected (severe LVH group, n = 7). RESULTS: The cardiac hypertrophy model induced significant left ventricular hypertrophy (136+/-21%, P < 0.05). The pressure-volume relation showed normal systolic function but an altered diastolic compliance in hypertrophic hearts. Propofol only decreased myocardial contractility and relaxation at supratherapeutic concentrations (> or = 300 microM) in SHAM and LVH groups. The decrease in myocardial performances was not significantly different in SHAM and LVH groups. Propofol induced a significant increase in coronary blood flow which was not significantly different between groups. In severe LVH group, the degree of hypertrophy reached to 157+/-23%. Similarly, the effects of concentrations of propofol were not significantly different from the SHAM group. CONCLUSIONS: Propofol only decreased myocardial function at supratherapeutic concentrations. The myocardial and coronary effects of propofol were not significantly modified in cardiac hypertrophy.     

Overestimation of Bispectral Index in Sedated Intensive Care Unit Patients Revealed by Administration of Muscle Relaxant

Background: Electromyographic activity has previously been reported to elevate the Bispectral Index (BIS) in patients not receiving neuromuscular blockade while under sedation in the intensive care unit. This study aimed to investigate the magnitude of the decrease of BIS following administration of muscle relaxant in sedated intensive care unit patients.

Methods: The authors prospectively investigated 45 patients who were continuously sedated with midazolam and sufentanil to achieve a Sedation-Agitation Scale value equal to 1 and who required administration of muscle relaxant. BIS (BIS(R) version 2.10), electromyography, and acceleromyography at the adductor pollicis muscle were recorded simultaneously before and after neuromuscular blockade. Sixteen of these 45 patients were also studied simultaneously with the new BIS(R) XP.

Results: After administration of a muscle relaxant, BIS (67 +/- 19 vs. 43 +/- 10, P < 0.001) and electromyographic activity (37 +/- 9 vs. 27 +/- 3 dB, P < 0.001) significantly decreased. Multiple regression analysis showed that the decrease of BIS following administration of myorelaxant was significantly correlated to BIS and electromyographic baseline values. Using standard BIS range guidelines, the number of patients under light or deep sedation versus general anesthesia or deep hypnotic state was markedly overestimated before administration of myorelaxant (53 vs. 2%, P < 0.001).     

Structural Requirements for Interaction with the Oligopeptide Transporter in Caco-2 Cells

Pharmaceutical Research -