Gabapentin prophylaxis for postoperative nausea and vomiting in abdominal surgeries: a quantitative analysis of evidence from randomized controlled clinical trials.

INTRODUCTION: Postoperative nausea and vomiting (PONV) is frequently encountered in the surgical recovery room. Abdominal surgery is one important risk factor for increased incidence of PONV. Gabapentin, an anticonvulsant with known postoperative analgesic properties, has shown some activity against PONV. Results from clinical trials evaluating the anti-emetic efficacy of gabapentin are conflicting. The present meta-analysis was performed to examine this issue. METHODS: Seventeen randomized placebo-controlled trials reporting PONV with preoperative gabapentin administration in patients undergoing abdominal surgery were included for analysis. Outcomes evaluated were nausea, vomiting, composite PONV and the use of rescue anti-emetic medication in the postoperative period. RESULTS: The pooled relative risk (RR), estimated using the random effects model of the metafor package for R, was 0.76 (95% CI 0.58-0.98) for nausea, 0.62 (0.45-0.85) for vomiting, 0.71 (0.39-1.28) for data represented as composite PONV (possibly biased by a single study, as observed in the sensitivity analysis), and 0.6 (0.41-0.89) for rescue anti-emetic use. There was a significant RR reduction for nausea and vomiting when propofol was not used as induction and/or maintenance for anaesthesia. In the abdominal hysterectomy subgroup, there was a significant RR reduction for vomiting but not for nausea. DISCUSSION: The present analysis provides evidence supporting preoperative gabapentin as a pharmacotherapy for prevention of PONV in patients undergoing abdominal surgeries. Future studies comparing preoperative gabapentin with 5HT3 antagonists are needed to precisely define its role in PONV.

Hydroxychloroquine's Efficacy as an Antiplatelet Agent Study in Healthy Volunteers: A Proof of Concept Study.

BACKGROUND: With the inflammatory model of atherosclerosis taking center stage, anti-inflammatory drugs hold a promising place in the therapy of cardiovascular disease (CVD). Recent studies showed that hydroxychloroquine (HCQ) was protective against thrombovascular events in lupus erythematosus and traditional cardiovascular risk factors in patients with rheumatoid arthritis. Some preliminary experimental data have shown that it may prevent platelet activation too. OBJECTIVE: To evaluate the antiplatelet activity of HCQ when given alone and in combination with aspirin (ASA) and compare it with ASA alone and ASA plus clopidogrel (CLOP) in healthy human volunteers. METHODS: In part 1 of the study, 8 volunteers were given HCQ for 7 days. In part 2, 12 volunteers were randomly assigned in a 1:1:1 ratio to the 3 groups in which 2 of the 3 treatments, ASA, ASA plus CLOP, and ASA plus HCQ, were given in the 2 treatment periods separated by a 14-day washout period using the incomplete block design. Inhibition of platelet aggregation (IPA) was measured by light transmission aggregometry. RESULTS: When arachidonic acid (AA) was used as agonist, HCQ given alone showed a significant reduction in platelet aggregation (11.0% ± 4.2%, P = .03). The IPA was significantly increased when ASA plus HCQ was compared with ASA alone (31.2% ± 8.1%, P = .002). This synergistic effect was not seen with adenosine diphosphate and collagen as agonists. Levels of serum 11-dehydrothromboxane B2, a stable marker of thromboxane A2 production, were not significantly different between the groups. There was also a significant decrease in fibrinogen and erythrocyte sedimentation rate values when HCQ was used alone or in combination with ASA. CONCLUSION: This study suggests that HCQ has antiplatelet properties possibly through the AA pathway (downstream to thromboxane A2 production). With possible additional beneficial effects over the traditional CVD risk factors, larger studies in the future might explore HCQ's potential as an antiplatelet agent.

Single Ascending Dose Safety and Pharmacokinetics of CDRI-97/78: First-in-Human Study of a Novel Antimalarial Drug.

Background. CDRI 97/78 has shown efficacy in animal models of falciparum malaria. The present study is the first in-human phase I trial in healthy volunteers. Methods. The study was conducted in 50 healthy volunteers in a single, ascending dose, randomized, placebo-controlled, double blind design. The dose ranges evaluated were from 80 mg to 700 mg. Volunteers were assessed for clinical, biochemical, haematological, radiographic, and electrocardiographic parameters for any adverse events in an in-house facility. After evaluation of safety study results, another cohort of 16 participants were administered a single oral dose of 200 mg of the drug and a detailed pharmacokinetic analysis was undertaken. Results. The compound was found to be well tolerated. MTD was not reached. The few adverse events noted were of grade 2 severity, not requiring intervention and not showing any dose response relationship. The laboratory and electrocardiographic parameters showed statistically significant differences, but all were within the predefined normal range. These parameters were not associated with symptoms/signs and hence regarded as clinically irrelevant. Mean values of T 1/2, MRT, and AUC0-∞ of the active metabolite 97/63 were 11.85 ± 1.94 h, 13.77 ± 2.05 h, and 878.74 ± 133.15 ng·h/mL, respectively Conclusion. The novel 1,2,4 trioxane CDRI 97/78 is safe and will be an asset in malarial therapy if results are replicated in multiple dose studies and benefit is shown in confirmatory trials.

Perioperative mortality score: data collection and cost.

The perioperative mortality score aims to predict mortality in elderly patients undergoing noncardiac surgery using three preoperative risk factors (age, albumin and American Society of Anesthesiologists physical status) and then modify this risk assessment if any of three postoperative complications occur (unplanned intensive care unit admission, systemic inflammation and acute renal failure). In order to determine the cost of routine perioperative mortality score calculation in future research, we audited the incidence of clinician-initiated preoperative albumin, pre- and postoperative creatinine and postoperative white cell count testing in patients aged > or = 70 years presenting for elective and emergency noncardiac surgery requiring at least overnight admission over a three-month period. We recruited 637 noncardiac surgical patients. All laboratory tests required for perioperative mortality score calculation were performed in only 47% of patients and the total cost of testing all untested patients was A$12,057 (A$18,927 per 1000 patients). Preoperative hypoalbuminaemia was present in 11% of tested patients, acute renal impairment in 24% of tested patients and high white cell count in 33% of tested patients. These results may be used to inform future research or clinical use of the score.

Continuity conditions and torsion angles from ssNMR orientational restraints.

The backbone torsion angle pair (varphi,psi) at each amino acid of a polypeptide is a descriptor of its conformation. One can use chemical shift and dipolar coupling data from solid-state NMR PISEMA experiments to directly calculate the torsion angles for the membrane-spanning portion of a protein. However, degeneracies inherent in the data give rise to multiple potential torsion angles between two adjacent peptide planes (a diplane). The molecular backbone structure can be determined by gluing together the consecutive diplanes, as in the PIPATH algorithm [T. Asbury, J.R. Quine, S. Achuthan, J. Hu, M.S. Chapman, T.A. Cross, R. Bertram, PIPATH: an optimized alogrithm for generating alpha-helical structures from PISEMA data, J. Magn. Reson. 183 (2006) 87-95.]. The multiplicities in torsion angles translate to multiplicities in diplane orientations. In this paper, we show that adjacent diplanes can be glued together to form a permissible structure only if they satisfy continuity conditions, described quantitatively here. These restrict the number of potential torsion angle pairs. We rewrite the torsion angle formulas from [J.R. Quine, M.T. Brenneman, T.A. Cross, Protein structural analysis from solid-state NMR-drived orientational constraints, Biophys. J. 72 (1997) 2342-2348.] so that they automatically satisfy the continuity conditions. The reformulated torsion angle formulas have been applied recently in the PIPATH algorithm [T. Asbury, J.R. Quine, S. Achuthan, J. Hu, M.S. Chapman, T.A. Cross, R. Bertram, PIPATH: an optimized alogrithm for generating alpha-helical structures from PISEMA data, J. Magn. Reson. 183 (2006) 87-95.] and will be helpful in other applications in which diplane gluing is used to construct a protein backbone model.

PIPATH: an optimized algorithm for generating alpha-helical structures from PISEMA data.

An optimized algorithm for finding structures and assignments of solid-state NMR PISEMA data obtained from alpha-helical membrane proteins is presented. The description of this algorithm, PIPATH, is followed by an analysis of its performance on simulated PISEMA data derived from synthetic and experimental structures. pipath transforms the assignment problem into a path-finding problem for a directed graph, and then uses techniques of graph theory to efficiently find candidate assignments from a very large set of possibilities.

Intensity and mosaic spread analysis from PISEMA tensors in solid-state NMR.

The solid-state NMR experiment PISEMA, is a technique for determining structures of proteins, especially membrane proteins, from oriented samples. One method for determining the structure is to find orientations of local molecular frames (peptide planes) with respect to the unit magnetic field direction, B0. This is done using equations that compute the coordinates of this vector in the frames. This requires an analysis of the PISEMA function and its degeneracies. As a measure of the sensitivity of peptide plane orientations to the data, we use these equations to derive a formula for the intensity function in the powder pattern. With this function and other measures, we investigate the effect of small changes in peptide plane orientations depending on the location of the resonances in the powder pattern spectrum. This gives us an indication of the change in lineshape due to mosaic spread and a way to interpret these in terms of an orientational error bar.