Extensive and enantioselective presystemic metabolism of dl-threo-methylphenidate in humans

1. Two pilot studies were carried out to investigate the enantioselective pharmacokinetics of methylphenidate (MPH) in children with attention deficit-hyperactivity disorder (ADHD). A more definitive study, which included administration of an intravenous dose, was carried out in healthy young men. 2. Serial plasma samples were harvested from predose to 8 hours in the first pilot study, predose to 12 hours in the second pilot study and predose to 16 hours in the definitive study. Plasma levels of the separate isomers d-MPH and 1-MPH were determined by an enantioselective gas chromatographic method. 3. In the first pilot study, 6 boys with ADHD each received his regular dose of MPH (10mg n = 5, 5mg n = 1), which contained equal proportions of d-MPH and 1-MPH in an immediate release formulation (MPH-IR). No MPH was detectable in the predose plasma. Thereafter, plasma levels of the more active d-MPH were 4 to 10 fold higher than those of 1-MPH. Plasma levels of 1-MPH were so low that it was not possible to monitor them beyond 4 hours in some children. 4. In the second pilot study, 5 boys and 1 girl with ADHD each received their regular dose (20mg) of a slow release formulation (MPH-SR). No MPH was detectable in the predose plasma. Thereafter, plasma levels of the more active d-MPH were 5 to 10 fold higher than those of 1-MPH. It was possible to monitor plasma levels of 1-MPH over the full 12 hour period of study in 5 of the 6 children.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of phosphatidylcholine on intra-abdominal adhesion formation and peritoneal macrophages

Phosphatidylcholine (PC) is the predominant constituent of the surface-active material coating peritoneal mesothelium. Its effects on surgically induced adhesion formation and on peritoneal macrophage viability and superoxide production were studied in rats. Rats treated with intraperitoneal PC liposomes showed more adhesions than controls (p less than 0.01). In vitro incubation with PC had no effect on macrophage viability, but significantly diminished superoxide production (p less than 0.05 and less). It is concluded that PC in its insoluble form is of no value in the prophylaxis of adhesions after abdominal and pelvic surgery and that with the use of the intraperitoneal route it is probably contraindicated in patients undergoing continuous ambulatory peritoneal dialysis.     

Is documentation of TOLAC counseling a good measure of quality of care?

Objective: The objective of this study is to determine whether chart documentation of patient counseling on trial of labor after cesarean (TOLAC) during prenatal care is associated with patient knowledge of risks and benefits of TOLAC and repeat cesarean delivery (RCD).

Study design: Prenatal patients eligible for TOLAC completed a questionnaire that assessed their knowledge of basic maternal and neonatal risks and benefits of TOLAC versus planned repeat cesarean delivery. Patient electronic medical records were reviewed for documentation of TOLAC counseling. Women were included at both early and late time points in pregnancy to include those who both had and had not undergone counseling.

Results: Patients with documented completed TOLAC counseling did not perform better on the knowledge survey. Patients who had documentation of counseling on specific subjects such as TOLAC success rates, risk of uterine rupture, and downstream health risks of cesarean section were no more likely to answer questions on these topics correctly than patients without counseling. However, patients with documented completed counseling generally felt that they were well informed.

Conclusion: Chart documentation of TOLAC counseling was not correlated with patient knowledge. Patients may not be gaining the knowledge from counseling that providers believe is important for informed decision making.     

Transcutaneous bilirubinometry is a reliably conservative method of assessing neonatal jaundice

Objective: In order to reduce invasive testing in newborns prior to discharge, we tested the direction of the correlation between transcutaneous bilirubin (TcB) and total serum bilirubin (TSB), the likelihood of missing high TSBs with a raised threshold for confirmatory testing, and also calculated potential cost savings from fewer laboratory testing.

Methods: We performed a cross-sectional analysis of single paired TcB and TSB results measured at 36?±?2?h of life in neonates?≥37 weeks admitted only to the Level 1 nursery. TcB was measured using the BiliChek® meter.

Results: Of the 552 infants, 512 (92.8%) had TSB levels below TcB values. Correlation between TcB and TSB was 0.69. If TSB confirmation was to be performed at 11.7 mg/dL (medium risk threshold for phototherapy), the negative predictive value was 99.4%, with a potential cost savings of $6555.00 ($1500.00 per 100 patients). Of the 495 infants with TcB?<11.7?mg/dL, only 3 had TSB levels higher than 11.7?mg/dL, and none met phototherapy threshold for low risk infants.

Conclusions: TcB screening at our institution has a high negative predictive value, and can be used as a stand-alone test until values are close to phototherapy threshold, thus reducing invasive testing and cost.     

Risk perception of future cardiovascular disease in women diagnosed with a hypertensive disorder of pregnancy

Objective: The objective of this study is to evaluate a woman’s risk perception for future cardiovascular disease (CVD) after being diagnosed with a hypertensive disorder of pregnancy.

Methods: A prospective cohort of women diagnosed with a hypertensive disorder of pregnancy (HDP) was studied. Each woman completed two surveys, one prior to hospital discharge and one 2 weeks later, designed to assess knowledge of and risk perception for future CVD based on their recent diagnosis of a HDP. Rates of postpartum depression were also assessed.

Results: Of the 146 subjects included, 28% were diagnosed with preeclampsia with severe features, 52.1% with preeclampsia with mild features, and 19.9% had chronic hypertension. Women with severe features and those delivering preterm were more likely to report a perception of increased risk of both recurrent HDP in a future pregnancy (p?=?0.004 and 0.005, respectively) and hypertension later in life (p?=?0.01 and 0.03, respectively). Women delivering preterm were more likely to report an accurate perception of increased risk of myocardial infarction and stroke compared to those delivering at term (p?=?0.006 and 0.002, respectively).

Conclusions: Disease severity and preterm delivery were associated with a higher likelihood of the perception of an increased risk for both recurrent HDP and hypertension in the future. Only preterm delivery was associated with a higher risk perception for stroke and myocardial infarction. Interventions targeted at improved health awareness in women diagnosed with HDP are warranted.     

Development and validation of bioanalytical method for the determination of asulacrine in plasma by liquid chromatography

Asulacrine (9-[(2-methoxy-4-methylsulphonylamino)phenylamino]-N,5-dimethyl-4-acridinecarboxamide), an analogue of the antileukaemia drug amsacrine, has high antitumour activity in mice and has also shown clinical activity. A simple method is described for the quantitation of asulacrine in plasma by liquid chromatography. Chromatographic separation was achieved on a reversed phase C 18 column (250 mm x 4.6mm, particle size 5 microm, Gemini) using isocratic elution (acetonitrile and 0.01 M sodium acetate buffer pH 4.0, 45/55, v/v) at a flow rate of 1 ml/min. Asulacrine and internal standard (the ethylsulphonanilide analogue) were measured using UV detection at 254 nm. The total chromatographic run-time was 8 min with asulacrine and internal standard eluting at approximately 4.7 and approximately 6.5 min, respectively. Limit of quantification was 0.1microg/ml. The linearity range of the method was 0.1-10 microg/ml (r2=0.9995). Mean recoveries from plasma were 100-105%. Intra-batch and inter-batch precision was 7.1 and 7.8%, respectively, and intra-batch and inter-batch accuracy (relative error) was 4.9 and 8.4%, respectively (n=8 in all cases). The bench top, freeze thaw, short-term storage and stock solution stability evaluation indicated no evidence of degradation of asulacrine. The validated method is simple, selective and rapid and can be used for pharmacokinetic studies in mice.     

Indomethacin–Saccharin Cocrystal: Design,Synthesis and Preliminary Pharmaceutical Characterization

Purpose To design and prepare cocrystals of indomethacin using crystal engineering approaches, with the ultimate objective of improving the physical properties of indomethacin, especially solubility and dissolution rate. Materials and Methods Various cocrystal formers, including saccharin, were used in endeavours to obtain indomethacin cocrystals by slow evaporation from a series of solvents. The melting point of crystalline phases was determined. The potential cocrystalline phase was characterized by DSC, IR, Raman and PXRD techniques. The indomethacin–saccharin cocrystal (hereafter IND–SAC cocrystal) structure was determined from single crystal X-ray diffraction data. Pharmaceutically relevant properties such as the dissolution rate and dynamic vapour sorption (DVS) of the IND–SAC cocrystal were evaluated. Solid state and liquid-assisted (solvent-drop) cogrinding methods were also applied to indomethacin and saccharin. Results The IND–SAC cocrystals were obtained from ethyl acetate. Physical characterization showed that the IND–SAC cocrystal is unique vis-à-vis thermal, spectroscopic and X-ray diffraction properties. The cocrystals were obtained in a 1:1 ratio with a carboxylic acid and imide dimer synthons. The dissolution rate of IND–SAC cocrystal system was considerably faster than that of the stable indomethacin γ-form. DVS studies indicated that the cocrystals gained less than 0.05% in weight at 98%RH. IND–SAC cocrystal was also obtained by solid state and liquid-assisted cogrinding methods. Conclusions The IND–SAC cocrystal was formed with a unique and interesting carboxylic acid and imide dimer synthons interconnected by weak N−H⋯O hydrogen bonds. The cocrystals were non-hygroscopic and were associated with a significantly faster dissolution rate than indomethacin (γ-form). Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.