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.     

The Role of Therapeutic Alliance in Network Therapy: A Family and Peer Support-Based Treatment for Cocaine Abuse

The therapeutic alliance is a well-studied construct factor that is important to outcome in many forms of individual therapy. Therapeutic alliance has been rarely studied in group therapy and results in addiction treatment have been mixed. In this paper, we studied the presence of a therapeutic alliance in Network Therapy: an approach that uses peer and family support in addiction treatment. Twenty-one participants undergoing Network Therapy for cocaine addiction were observed on videotape, and were rated on therapeutic alliance using the Working Alliance Inventory and the Penn Helping Alliance Rating Scale. Results showed a significant positive correlation between therapeutic alliance and outcome as measured by the percentage of cocaine-free urine toxicology screens and by eight consecutive cocaine-free urines.     

Methylated DNA collected by tampons--a new tool to detect endometrial cancer.

This proof of principle study aimed to define a new and simple strategy for detection of endometrial cancer using epigenetic markers. We investigated DNA isolated from vaginal secretion collected from tampon for aberrant methylation of five genes (CDH13, HSPA2, MLH1, RASSF1A, and SOCS2) using MethyLight in 15 patients with endometrial cancer and 109 patients without endometrial cancer. All endometrial cancer patients revealed three or more methylated genes, whereas 91% (99 of 109) of the patients without endometrial cancer had no or fewer than three genes methylated in their vaginal secretion. The methods developed in this study provide the basis for a prospective clinical trial to screen asymptomatic women who are at high risk for endometrial cancer.     

Chromosomal instability rather than p53 mutation is associated with response to neoadjuvant cisplatin-based chemotherapy in gastric carcinoma.

PURPOSE: The objective of the study was to evaluate microsatellite alterations [microsatellite instability (MSI) and loss of heterozygosity (LOH)] and mutation in the p53 gene in relation to response and patient survival to a cisplatin-based neoadjuvant chemotherapy in gastric cancer. EXPERIMENTAL DESIGN: Fifty-three pretherapeutic gastric carcinoma biopsies were analyzed with 11 microsatellite markers. The entire coding region of the p53 gene (exons 2-11) was analyzed for mutations by denaturing high-pressure liquid chromatography and sequencing. p53 protein expression was evaluated by immunohistochemistry. Patients were treated with a cisplatin-based, neoadjuvant chemotherapy regimen. Therapy response was evaluated by computed tomography scan, endoscopy, and endoluminal ultrasound. The median follow-up of the patients was 45.6 months. RESULTS: p53 mutations were identified in 19 of the 53 (36%) analyzed tumors. No significant association with response or survival was found for p53 mutation or for p53 protein expression. MSI (either high-grade MSI or low-grade MSI) did not show a correlation with response. With respect to LOH, LOH at chromosome 17p13 showed a significant association with therapy response (P = 0.022) but did not reach statistical significance in terms of patient survival. The global LOH rate, expressed as fractional allelic loss (FAL), was assessed, and tumors were classified into tumors with a high (>0.5), medium (>0.25-0.5), and low (0-0.25) FAL value. A statistically significant association of FAL with therapy response was found (P = 0.003), with a high FAL being related to therapy response. The sensitivity, specificity, positive predictive value, and negative predictive value for FAL > 0.5 were 45%, 93%, 82%, and 72%, respectively. CONCLUSIONS: A high level of chromosomal instability (high FAL value) defines a subset of patients who are more likely to benefit from cisplatin-based neoadjuvant chemotherapy. p53 mutation status is not significantly associated with therapy response and is not a useful marker for response prediction.     

Reversible neuropsychological deficits after mild traumatic brain injury

OBJECTIVES: To determine the influence of motivation on performance in a divided attention test of patients after mild traumatic brain injury (MBI). METHODS: Comparison of the performance of 12 patients with MBI with 10 patients with severe brain injury (SBI) and 11 healthy controls in a computer supported divided attention task before (T1) and after (T2) verbal motivation. RESULTS: At T1, the MBI group performed the same as the SBI group but significantly worse than the controls in all variables. At T2, the MBI group performed worse than the controls at T2 but the results were equal to the results of the controls at T1 and significantly better than the SBI group at T1 or T2. At T2 the MBI group performed at the level of published norms for the rest. CONCLUSION: Before verbal motivation the MBI group's results in the divided attention task were comparable with those from patients with severe brain injury. They failed to exploit their performance potential when it depended on self motivation but were able to perform at the level of the control group when external motivation was applied.     

Sevoflurane, but not propofol, significantly prolongs the Q-T interval

Prolongation of the Q-T interval may be associated with polymorphic ventricular tachycardia known as torsade de pointes, syncope and sudden death. Existing data show that isoflurane prolongs the Q-T interval, whereas halothane shortens it. The aim of this study was to determine whether sevoflurane or propofol affects the Q-T interval. Thirty female patients undergoing gynecologic surgery were randomly assigned to two groups, one receiving inhaled induction with sevoflurane and the other receiving total IV anesthesia with propofol. Before and 20 min after the induction, a six-lead electrocardiogram was recorded, and blood pressure was measured. The Q-T interval and heart rate adjusted Q-T interval (Q-Tc interval) were significantly prolonged during the administration of anesthesia with sevoflurane, while the Q-T interval was significantly shortened, and the Q-Tc interval was statistically unaffected during propofol anesthesia administration. We conclude that, in otherwise healthy female patients, sevoflurane prolongs the Q-Tc. IMPLICATIONS: In this study, we evaluated the effect of sevoflurane induction and anesthesia versus propofol induction and anesthesia on the Q-T interval. Sevoflurane significantly prolonged the Q-T interval and the heart rate adjusted Q-T interval, whereas propofol shortened the Q-T interval but not the heart rate adjusted Q-T interval.     

Acute ovarian torsion in children

BACKGROUND: Acute ovarian torsion (OT) is an uncommon cause of abdominal pain in children and is frequently confused with other conditions. METHODS: We reviewed the records (1983 to 1999) of all children treated for acute OT at our children's hospital. RESULTS: Mean child age (n = 51) was 12.5 +/- 0.3 years. Children presented with either right-sided (n = 29) or left-sided (n = 22) pain. Diagnosis of OT was confirmed preoperatively by ultrasound (73%) or computed tomography (CT) scan (10%) while nine children (17%) with right-sided pain underwent surgery for presumed appendicitis. Despite a relatively short time from diagnosis to surgery, all 51 children required salpingooophorectomy. Contralateral biopsy was performed in 29% and 57% had an appendectomy. Younger children more commonly had either a mature cystic teratoma or torsion with no underlying abnormality as an etiology compared with OT in older children that was more likely to result from either a follicular or corpus luteal cyst. Pathologic examination of the contralateral ovary and appendix was normal in all children who underwent biopsy and appendectomy. CONCLUSION: Ultrasonography with color doppler is helpful for differentiating acute OT from appendicitis. Although the twisted ovary can rarely be salvaged, the etiology is usually benign. Preoperative serum markers and contralateral ovary biopsy may be unnecessary.