Relationships of the area under the curve/MIC ratio to different integral endpoints of the antimicrobial effect: gemifloxacin pharmacodynamics in an in vitro dynamic model

Most integral endpoints of the antimicrobial effect are determined over an arbitrarily chosen time period, such as the dosing interval (tau), regardless of the actual effect duration. Unlike the tau-related endpoints, the intensity of the antimicrobial effect (I(E)) does consider its duration-from time zero to the time when bacterial counts on the regrowth curve achieve the same maximal numbers as in the absence of the antimicrobial. To examine the possible impact of this fundamental difference on the relationships of the antimicrobial effect to the ratio of the area under the concentration-time curve (AUC) to the MIC, a clinical isolate of Staphylococcus aureus was exposed to simulated gemifloxacin pharmacokinetics over a 40-fold range of AUC/MIC ratios, from 11 to 466 h. In each run, I(E) and four tau-related endpoints, including the area under the time-kill curve (AUBC), the area above the curve (AAC), the area between the control growth and time-kill curves (ABBC), and the ABBC related to the area under the control growth curve (AUGC), were calculated for tau = 24 h. Unlike the I(E), which displayed pseudolinear relationships with the AUC/MIC ratio; each tau-related endpoint showed a distinct saturation at potentially therapeutic AUC/MIC ratios (116 to 466 h) when the antimicrobial effect persisted longer than tau. This saturation results from the underestimation of the true effect and may be eliminated if ABBC, AAC, and AUBC (but not AUGC) are modified and determined in the same manner as the I(E) to consider the actual effect duration. These data suggest a marginal value of the tau-related endpoints as indices of the total antimicrobial effect. Since all of them respond to AUC/MIC ratio changes less than the I(E), the latter is preferable in comparative pharmacodynamic studies.     

Use of modeling techniques to aid in antibiotic selection

Over the past decade, the use of modeling techniques in the development of novel antibiotics has been primarily associated with in vitro dynamic models. These models allow comparisons among different antibiotics by simulating human pharmacokinetics. Although dynamic models have been used extensively, their full potential has not been achieved because of inadequate experimental design and/or suboptimal quantitation of bacterial killing/regrowth curves inherent in many studies. These issues are discussed in this review, which is based on recent pharmacodynamic findings with novel fluoroquinolones.     

Assessment of explanted PTCA balloons

The data presented here are part of a on-going study to define the surface characteristics and properties of explanted PTCA catheters in a further effort to address some of the ramifications of the re-use issue. PTCA balloon catheter were examined after angioplasty in one hundred and sixty-eight patients (n = 168). This series included six balloon types from three manufacturers. The fresh fixed and dehydrated balloons were examined at first with light microscopy and then in a scanning electron microscope. X-ray semiquantitative microanalysis and FT-IR-ATR analysis were also performed on the balloons. Because most blood proteins are water soluble, we examined unfixed balloons with a protein silver staining kit for detection of adhered proteins described by Heukeshoven. A further method for protein detection is the Lowry-analysis. With this method water insoluble proteins can be observed. Our study has shown convincingly that all deployed angioplasty catheters were coated with adherent protein layers. Plaque particles were found embedded in the surfaces of most of the balloons examined. Fissuring and micro tearing of balloon surfaces was noted. FT-IR-ATR analyses of the blood contacted balloon surfaces did not show any peaks indicative of proteins on the balloon surface. The silver staining method also did not show any evidence of protein adsorption on the balloons. On the other hand, the Lowry-analysis yielded clear evidence that water insoluble proteins were adherent to the balloon surfaces. The average measured protein concentration was 17 microg/ml.     

Informed Consent

There have been significant changes in the doctor patient relationship with the impact of technology in day-to-day practice. More and more patients are aware of their rights and are keen to make free choice and decision on their treatment. This helps them to choose the treatment of their choice from the options available and to select a physician of their choice. Doctor's decisions are being questioned regarding their correctness and there is a need to educate the patient, on what one offers by way of treatment. In some procedures and types of treatment, patient needs to be educated and informed of the merits and demerits of the treatment available. This will help the patient to make appropriate choice and also to accept some adverse outcome of treatment. Towards this end, all countries are looking afresh at the necessity of Informed Consent. Methods adopted by some countries are highlighted to help our physicians practice them in an appropriate way. A lot of remedial work needs to be done to minimize future litigation, as many doctors misunderstand their legal obligations and haven't caught up with the change in judge's thinking.     

Chloride losing diarrhoea and metabolic alkalosis in an infant with cystic fibrosis

A case of hypochloraemic metabolic alkalosis in an infant with chloride losing ileostomy drainage and cystic fibrosis is described. It is speculated that intestinal loss of chloride played a major role in the development of metabolic alkalosis.     

The role of pancreatic venous sampling in the localization of occult insulinomas

The palpation and enucleation of occult insulinomas (less than 15 mm) can be a difficult surgical problem even with good arteriographic localization. In the authors' limited experience, confirmation of arteriographic findings by pancreatic venous sampling provided little additional localizing information. However, if arteriography is negative or equivocal, venous sampling can indicate the segment of pancreas to be "blindly" resected if the adenoma is not palpable. Venous sampling may be misleading in polyendocrine syndromes because of the frequency of multiple adenomas and variable hormone production.     

Retrovirally mediated RNA interference targeting the M2 subunit of ribonucleotide reductase: A novel therapeutic strategy in pancreatic cancer

BACKGROUND: Ribonucleotide reductase M2 subunit (RRM2) overexpression enhances tumor chemoresistance and cellular invasiveness. We hypothesized that the RNA interference (RNAi) induced by retrovirally delivered small interfering RNA (siRNA) would sensitize pancreatic adenocarcinoma cells to gemcitabine and attenuate their invasive potential. METHODS: Stable suppression of RRM2 expression in PANC1, MIAPaCa2, BxPC3, and Capan2 cells was induced by exposure to a novel replication-deficient retrovirus, engineered to express RRM2-specific siRNA (psiRRM2), and confirmed by Western blot analysis. Single-base mismatch vector (psiControl) served as control. Ribonucleotide reductase activity was quantified, and gemcitabine 50% inhibitory concentrations were calculated. TUNEL staining and caspase profiling were performed after gemcitabine exposure. Cellular invasiveness was quantified in a Matrigel Boyden chamber. NF-kappaB activity and matrix metalloproteinase-9 (MMP-9) expression and activity were measured. RESULTS: RRM2 expression was stably and specifically suppressed in psiRRM2, but not psiControl transfectants. psiRRM2 transfectants exhibited lower 50% inhibitory concentrations, increased gemcitabine-induced apoptosis, and greater caspase-3 activation, relative to psiControl transfectants. Invasiveness was attenuated in psiRRM2 transfectants, as was NF-kappaB activity, MMP-9 expression, and MMP-9 activity, relative to psiControl transfectants. CONCLUSIONS: RRM2 gene silencing attenuates pancreatic adenocarcinoma cellular invasiveness and gemcitabine chemoresistance. Retroviral siRNA delivery can efficiently induce stable RNAi, allowing dissection of gene function and potentially representing a new therapeutic modality.     

ORIGINAL RESEARCH—ED PHARMACOTHERAPY: Do Food and Dose Timing Affect the Efficacy of Sildenafil? A Randomized Placebo‐Controlled Study

IntroductionSildenafil citrate has been used worldwide by men with erectile dysfunction. The prescribing information for sildenafil suggests ingestion 1 hour before sexual activity and also notes reduced maximum plasma concentration and delayed time to maximum concentration following ingestion with a high‐fat meal. The clinical impact of coingestion of food and these factors has never been evaluated.AimTo determine, using a naturalistic study design, whether sildenafil taken 1 hour before or during a meal compared with usual ingestion 30–60 minutes before sexual activity affects efficacy or patient satisfaction.MethodsAfter a 1–2‐week washout, 48 men (29–79 years old), currently satisfied with sildenafil, followed each of four regimens: (A) sildenafil 1 hour before a meal and placebo 30–60 minutes before planned coitus vs. (B) placebo 1 hour before a meal and sildenafil 30–60 minutes before coitus; and (C) sildenafil during a meal and placebo 30–60 minutes before coitus vs. (D) placebo during a meal and sildenafil 30–60 minutes before coitus. Subjects were not instructed to change their regular dietary habits during the course of the study.Main Outcome MeasuresChange from baseline in the International Index of Erectile Function (IIEF) Erectile Function (EF) domain score, responses to Sexual Encounter Profile (SEP) questions 2 (erection sufficient for penetration) and 3 (erection sufficient to complete intercourse), and measures of patient preference and satisfaction.ResultsMean changes in IIEF‐EF domain scores were 11.4 for regimens A and B and 11.2 for C and D. Positive SEP2 responses were recorded for 93.9% and 91.8% of intercourse attempts in A and B and 91.4% and 92.6% in C and D. Corresponding results for SEP3 were 84.7% and 85.9%, and 83.4% and 87.5%, respectively. There were no significant differences between pairs of treatments on satisfaction. The time between sildenafil ingestion and intercourse attempt (0–0.5 to >10 hours) had no significant effect on responses to SEP2, but decreased responses to SEP3 from a maximum of 92.8% at 1.5–2 hours to 81.6% at more than 10 hours (P = 0.003).ConclusionsNo significant loss of efficacy occurs when sildenafil is taken shortly before or with a meal. The duration of action for sildenafil may exceed 10 hours. Zinner N. Do food and dose timing affect the efficacy of sildenafil? A randomized placebo‐controlled study. J Sex Med 2007;4:137–144.     

Extended-Release Trospium Chloride Improves Quality of Life in Overactive Bladder

ObjectivesOveractive bladder syndrome (OAB) is a urinary condition that often exerts detrimental effects on an individual's quality of life (QoL). A once-daily, extended-release (ER) formulation of the quaternary amine trospium chloride has recently been developed for the treatment of OAB. The pooled health-related QoL (HRQoL) data from two multicenter, parallel-group, double-blind Phase III studies with trospium chloride ER 60 mg were analyzed.MethodsSubjects aged ≥18 years with urinary urgency, frequency, and an average of ≥1 urge urinary incontinence episode per day on a 3-day bladder diary were randomized (1:1) to receive once-daily trospium 60 mg ER or placebo for 12 weeks. HRQoL was assessed at baseline and at Week 12 using the King's Health Questionnaire (KHQ) and the OAB questionnaire (OAB-q).ResultsOverall, 1165 subjects were randomized (trospium ER, n = 578; placebo, n = 587). Trospium ER produced significantly greater improvements from baseline than placebo in seven of the nine KHQ domains. At Week 12, the improvement in mean OAB-q HRQoL total score (from approximately 52 at baseline) was significantly greater with trospium ER than with placebo (+25.8 vs. +20.7; P = 0.0003). Improvements from baseline were seen with trospium ER on all eight of the OAB-q symptom bother scales.ConclusionsOnce-daily trospium 60 mg ER improved the QoL of subjects with OAB, as assessed using the KHQ and the OAB-q, in two large Phase III clinical trials.