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.     

Phase II study of 1alpha-hydroxyvitamin D(2) in the treatment of advanced androgen-independent prostate cancer.

PURPOSE: In this single institution Phase II trial, we evaluated the efficacy of the vitamin D analogue, 1alpha-OH-D(2), in patients with advanced hormone-refractory prostate cancer. Experimental Design: The patients initially received 1alpha-OH-D(2) at 12.5 micro g p.o. every day, which was dose adjusted for hypercalcemia. Given the cytostatic nature of the drug, the primary study end point was progression-free survival for a minimum of 6 months. The secondary end point was further characterization of drug toxicity. RESULTS: A total of 26 patients was enrolled. Using the intent-to-treat population, stable disease was seen for an average of 19.2 weeks (median 12 weeks, range 3-108 weeks). Twenty patients were evaluable for response. The one patient that achieved disease stabilization for >2 years elected to come off-study because of patient preference. His last disease evaluation showed no evidence of progression. No objective responses were seen. Previous and ongoing clinical observations strongly imply that PSA could be a misleading surrogate marker for clinical effect with this type of drug. Therefore, prostate-specific antigen was not used as a marker for disease response. Toxicity was as expected with mild hypercalcemia and associated symptoms like constipation and prerenal azotemia seen in some patients. Six (30%) evaluable patients experienced stable disease for >6 months, suggesting possible cytostatic activity. CONCLUSION: The results of this and other trials suggest further clinical investigation in this disease with vitamin D analogues alone or in combination with other agents, such as chemotherapy, should be pursued.     

Anesthesia practices in the united states common to in vitro fertilization (IVF) centers

Purpose: Our purpose was to characterize and describe anesthesia practice in programs performing IVF in the United States. Methods: We used a telephone survey requiring respondents to be either the program director, a physician, or a nurse familiar with the practice. Two hundred seven (78%) Society of Assisted Reproductive Technology (SART) registered programs agreed to participate. Programs were divided by geographic region and type of practice (academic versus private). Results: Ninety-one private (68%) and 41 academic (56%) programs used personnel provided by the Department of Anesthesiology. Conscious sedation was performed most commonly (95%). The remaining 5% used primarily either general, regional, or local anesthesia. Typical recovery times were 90 to 120 min. Average costs of anesthetic administration were $300–$400 and were similar among groups except for the Eastern academic programs, with a higher mean cost of $543. Programs using personnel from anesthesiology reported higher costs compared to programs utilizing their own staff ($391±15 vs $157±11; P<0.05). Complications were infrequent (<10%); no hospitalizations or serious life-threatening incidents were reported. Conclusions: A large number of programs safely used their own trained personnel to deliver anesthesia, and realized a significant reduction in cost.     

Screening for gestational diabetes mellitus in adolescent pregnancies

Objective: Our purpose was to determine the incidence of gestational diabetes mellitus in an adolescent population and to determine the cost of screening. Study Design: A retrospective review of 509 adolescent pregnancies was performed. The incidence of gestational diabetes mellitus was determined and the cost of screening analyzed. Results: Five hundred nine adolescent pregnancies were screened for gestational diabetes mellitus with a 1-hour, 50 gm oral glucose challenge test. Twenty-three of the screens (4.5%) had positive results at a plasma glucose level of ≥140 mg/dl. Three-hour 100 gm oral glucose tolerance tests were performed on screen-positive women, six of whom were diagnosed with gestational diabetes mellitus, for an incidence of 1.18%. The cost per case diagnosed was $2733. Conclusions: The incidence of gestational diabetes mellitus in an adolescent population is low. The cost of universal screening may be prohibitive in this population. Large prospective studies are needed to better analyze outcome data and efficacy of screening in adolescent pregnancies. (Am J Obstet Gynecol 1998;178:1251-6.)     

State legislator gender and other characteristics associated with sponsorship of child health bills.

OBJECTIVE: To examine the characteristics of state legislators who introduce child health bills. METHODS: We conducted a cross-sectional analysis of all bills introduced in Colorado, Louisiana, and Michigan during the 1997-1998 legislative session. We identified the topic for each bill while blinded to legislator characteristics. The primary study outcome was whether the bill topic related to child health. We also categorized whether the bill was signed into law. We examined associations between the outcomes and characteristics of the sponsoring legislators (gender, political party, terms served, chairpersonship of committees, legislative chamber, membership in the legislature's Black Caucus). RESULTS: During 1997 and 1998, legislators in the 3 study states introduced 9833 bills (1234 in Colorado, 4905 in Louisiana, and 3694 in Michigan). Sixty-five bills (0.66%) related to child health issues. Child health bills comprised a significantly higher proportion of all legislation introduced by female legislators compared with male legislators (1.5% vs 0.5%, P <.001). Of bills introduced by Black Caucus members, 1.4% pertained to child health compared with 0.59% of bills introduced by nonmembers (P <.01). In contrast, 0.23% of bills introduced by committee chairpersons pertained to child health versus 0.96% of bills introduced by nonchair legislators (P <.001). These associations remained statistically significant in multivariate analyses controlling for state effects. Whether child health bills were signed into law was not associated with other legislator characteristics. CONCLUSIONS: This study offers valuable insights about the different roles of women, Black Caucus members, and committee chairpersons in the state legislative process regarding children's health.     

Marked abnormal quadruple screen in a patient with severe preeclampsia at 20 weeks with a triploid fetus.

Severe preeclampsia rarely occurs prior to 20 weeks of gestation except in pregnancies with triploidy. The patient reported herein is a 29-year-old primigravida who developed severe preeclampsia at 20 weeks of gestation. Evaluation of the pregnancy demonstrated a markedly abnormal quadruple screen. Amniocentesis demonstrated a fetus with triploidy, despite a normal appearance.