The conduct of in vitro and in vivo drug-drug interaction studies: a Pharmaceutical Research and Manufacturers of America (PhRMA) perspective.

Current regulatory guidances do not address specific study designs for in vitro and in vivo drug-drug interaction studies. There is a common desire by regulatory authorities and by industry sponsors to harmonize approaches, to allow for a better assessment of the significance of findings across different studies and drugs. There is also a growing consensus for the standardization of cytochrome P450 (P450) probe substrates, inhibitors and inducers and for the development of classification systems to improve the communication of risk to health care providers and to patients. While existing guidances cover mainly P450-mediated drug interactions, the importance of other mechanisms, such as transporters, has been recognized more recently, and should also be addressed. This article was prepared by the Pharmaceutical Research and Manufacturers of America (PhRMA) Drug Metabolism and Clinical Pharmacology Technical Working Groups and represents the current industry position. The intent is to define a minimal best practice for in vitro and in vivo pharmacokinetic drug-drug interaction studies targeted to development (not discovery support) and to define a data package that can be expected by regulatory agencies in compound registration dossiers.     

Influence of dietary soy isoflavones on the accessory sex organs of the Wistar rat.

We evaluated the effects of three rodent diets differing in soybean meal content on the response of the seminal vesicles, prostate and bulbocavernosus/levator ani (BC/LA) muscle to androgens and anti-androgenic compounds in the Hershberger assay. The diets tested were (1) L5, a semi-synthetic phytoestrogen-free diet, (2) DO4, 8.5% (w/w) vegetable protein and (3) DO3, 22.5% (w/w) vegetable protein. We determined the effects of dietary soy isoflavones after ten days of exposure and in animals fed L5 and DO3 diets throughout their lifetime (including the period of treatment with androgenic or anti-androgenic compounds). After ten days of exposure, we observed no effect of diet on the accessory sex organs of male Wistar rats. In contrast, diet affected the androgenic response to testosterone propionate in seminal vesicles and prostate. Seminal vesicles were the most sensitive organs. Vinclozolin caused a dose-dependent decrease in the relative weights of seminal vesicles, prostate and BC/LA regardless of diet. As vegetable proteins may contain high proportions of genistein and daidzein, two well-known oestrogenic endocrine disrupters that may alter the results of reproductive studies, we recommend the use of a standardised open-formula diet without soy isoflavones, such as L5, if the Hershberger assay is to be performed.     

The usefulness of electrical stimulation for assessing pedicle screw placements

The purpose of this study was to further establish the efficacy of pedicle screw stimulation as a monitoring technique to avoid nerve root injury during screw placement. The study population consisted of 662 patients in whom 3,409 pedicle screws were placed and tested by electrical stimulation. If stimulation resulted in a myogenic response at a stimulation intensity of 10 mA or less, the placement of the screw was inspected. Inspection was necessary for 3.9% of the screw placements in 15.4% of the study population. None of the patients in the study experienced any new postoperative neurologic deficits. These findings provide guidelines for the interpretation of stimulation data and support the use of this technique as an easy, inexpensive, and quick method to reliably assess screw placements and protecting neurological function.     

Ploidy profile of morphologically normal squamous epithelium adjacent to high grade cervical intraepithelial neoplasia

We have investigated the ploidy profile of morphologically normal mucosa adjacent to high grade CIN (   n = 16  ) and also from normal cervix ( n = 18). DNA ploidy was assessed using flow cytometry and image analysis. All cases were diploid by both modalities. Our results show that morphologically normal squamous mucosa has a stable ploidy profile even when it lies adjacent to high grade CIN. This finding supports the view that high grade CIN is a neoplastic expansion of transformed cells rather than the result of a field change effect.     

Incidence of urinary incontinence and constipation during pregnancy and postpartum: survey of current findings at the Rotunda Lying-in Hospital

Objective To assess the impact of pregnancy upon continence and constipation.
Design A questionnaire survey.
Setting Maternity wards in the Rotunda Lying In Hospital, Dublin, Republic of Ireland.
Population 7771 women who were delivered of liveborn infants.
Methods Questionnaires were delivered and collected by physiotherapy staff as part of routine postnatal care.
Results Analysis of data using χ² tests showed significant differences between three parity groups [primigravidae, multigravidae (2–4) and multigravidae (5+)] for symptoms of both urinary incontinence (  χ²= 119.54  , df = 2, P = 0.000) and constipation (  χ²= 12.53  , df = 3, P = 0.002); the incidence of both constipation and urinary incontinence increased with parity.
Conclusion The results of this survey have emphasised the relation between parity and postpartum incontinence which stresses the importance of early diagnosis and intervention.