Explanations and unresolved issues pertaining to the development of the Nuclear Pharmacy Compounding Guidelines

OBJECTIVES: To provide background information related to the development of the Nuclear Pharmacy Compounding Guidelines, to discuss regulatory complexities related to radiopharmaceutical compounding practice, and to summarize the gaps in the current compounding regulations for radiopharmaceuticals. DATA SOURCES: The Guidelines closely follow the provisions of section 503A of the Federal Food, Drug, and Cosmetic Act (FD&C Act), the monographs and chapters related to pharmacy compounding in the United States Pharmacopeia (USP), and the recommended guidelines published by the American Society of Health-System Pharmacists. SUMMARY: The Food and Drug Administration Modernization Act (FDAMA) of 1997 established parameters under which the compounding of drug products is appropriate and lawful, but these criteria expressly do not apply to radiopharmaceuticals. The Nuclear Pharmacy Compounding Practice Committee, a group of nuclear pharmacists convened by the American Pharmaceutical Association, developed the Nuclear Pharmacy Compounding Guidelines to establish a set of principles and guidelines for good radiopharmaceutical compounding practice. The intent of the new document is to provide guidance on radiopharmaceutical compounding practices that have evolved over the last 2 decades and to place them in an appropriate regulatory framework in accordance with previous enforcement policies and guidelines issued by the U.S. Food and Drug Administration (FDA) regarding the exemption of certain pharmacy practices from enforcement of adulteration, misbranding, and new drug requirements. CONCLUSION: The Nuclear Pharmacy Compounding Guidelines, recently released by APhA, is the first official document that provides realistic and practical compounding guidance for nuclear pharmacists. Even though the United States Court of Appeals for the Ninth Circuit recently ruled section 503A of the FD&C Act to be invalid in its entirety, and the Supreme Court upheld that ruling, the compliance policy guides issued by FDA in March 1992 and revised in May 2002 maintain guiding principles on pharmacy compounding similar to those stated in section 503A of the FD&C Act. The Nuclear Pharmacy Compounding Practice Committee is optimistic that the practical information contained in the Guidelines will assist state boards of pharmacy, FDA, and the United States Pharmacopeial Convention in setting appropriate standards for nuclear pharmacy compounding practice that will ensure the continued availability of high-quality compounded radiopharmaceuticals at reasonable cost.     

Thoracic intrathymic thyroid and cervical goiter: single-stage resection

Ectopic thyroid tissue in the chest is rare. We report a case of a euthyroid patient with benign ectopic thyroid tissue presenting as a thymic mass in association with a multinodular goiter. Both disorders were managed successfully by surgical intervention.     

Synaptic vesicle endocytosis: the races,places, and molecular faces

The classical experiments on synaptic vesicle recycling in the 1970s by Heuser and Reese, Ceccarelli, and their colleagues raised opposing theories regarding the speed, mechanisms, and locations of membrane retrieval at the synapse. The Heuser and Reese experiments supported a model in which synaptic vesicle recycling is mediated by the formation of coated vesicles, is relatively slow, and occurs distally from active zones, the sites of neurotransmitter release. Because heavy levels of stimulation were needed to visualize the coated vesicles, Ceccarelli’s experiments argued that synaptic vesicle recycling does not require the formation of coated vesicles, is relatively fast, and occurs directly at the active zone in a “kiss-and-run” reversal of exocytosis under more physiological conditions. For the next thirty years, these models have provided the foundation for studies of the rates, locations, and molecular elements involved in synaptic vesicle endocytosis. Here, we describe the evidence supporting each model and argue that the coated vesicle pathway is the most predominant physiological mechanism for recycling synaptic vesicles.     

Association of human papillomavirus type 58 variant with the risk of cervical cancer

Human papillomavirus (HPV) type 58 has been found to be prevalent among Chinese patients with cervical cancer. This study examined the oncogenic risk of HPV58 variants in Hong Kong, a southern part of China. Altogether, 1924 women were studied: 42.8% with a normal cervix, 16.2% with cervical intraepithelial neoplasia (CIN) I, 12.7% with CIN II, 20.8% with CIN III, and 7.6% with invasive cervical cancer (ICC). The overall prevalence of HPV58 was 11.4% (220) and increased statistically significantly with the severity of neoplasia (P(trend)<.001, chi(2) test for trend). Among HPV58-positive women, the occurrence of E7 632C-->T (T20I) and E7 760G-->A (G63S) variants (T20I/G63S) showed a positive trend of association with the severity of neoplasia (P(trend)<.001, chi(2) test for trend). HPV58 variants carrying these two substitutions showed an odds ratio (OR) for ICC of 26.79 (95% confidence interval = 10.14 to 74.72), and this OR was 6.9-fold higher than the ORs of variants without these substitutions. Patients with CIN III or ICC who were also infected with T20I/G63S variants had a statistically significant younger age at diagnosis than those infected with other variants (median age = 37 years versus 48 years; P =.038, two-sided Mann-Whitney U test). Thus, HPV58 variants carrying E7 T20I/G63S substitutions may be associated with an increased risk for cervical cancer.     

Brain cytochrome P450 aromatase gene isoforms and activity levels in atlantic salmon after waterborne exposure to nominal environmental concentrations of the pharmaceutical ethynylestradiol and antifoulant tributyltin.

In this study, the effects of two environmental endocrine disruptors, the synthetic pharmaceutical estrogen (ethynylestradiol, EE2) and antifoulant (tributyltin, TBT) representing two different modes of action on the endocrine system, were studied on brain steroidogenic pathway of juvenile Atlantic salmon (Salmo salar). Neurosteroidogenesis was studied using brain aromatase gene isoforms and enzyme activity, in parallel with typical xenoestrogen responses, such as brain estrogen receptor (ERalpha) and plasma vitellogenin (Vtg) levels. Fish were exposed to nominal waterborne EE2 (5 and 50 ng/l) and TBT (50 and 250 ng/l) concentrations dissolved in dimethyl sulfoxide (DMSO), singly and in combination. Gene expressions were quantified using real-time PCR with gene-specific primers, aromatase activity was analyzed using the tritiated water-release assay, and plasma Vtg was analyzed using competitive ELISA. Our data show that EE2 induced a concentration-specific modulation of P450aromA, P450aromB, and aromatase activity in addition to ERalpha and plasma Vtg levels in juvenile salmon at day 3 postexposure. TBT exposure caused both the elevation and inhibition of P450aromA, P450aromB, and aromatase activity levels, depending on concentration, at day 7 postexposure. TBT elevated and inhibited ERalpha and plasma Vtg and also antagonized EE2-induced expression of the studied variables at day 7 postexposure. Interestingly, the carrier vehicle DMSO modulated the receptor-mediated and non-receptor-mediated estrogenic responses at day 7 postexposure, compared to day 3. In general, these findings suggest that the exposed animals are experiencing impaired steroidogenesis and modulations of receptor-mediated endocrine responses. Given the integral role of neurosteroids in homeostatic process, growth, metabolism, reproduction, and development of central nervous system and function, these effects may have serious impact on this endocrine pathway and potentially affect organismal reproductive performance and health. In conclusion, the regulation of steroidogenesis is a fundamental mechanism involved in the biosynthesis of important biological compounds, irrespective of organ; therefore, the search for the molecular targets of xenoestrogens, given singly and also in combination, in these pathways will increase our understanding of organismal endocrine disruption and potential consequences.     

Getting by on credit: how district health managers in Ghana cope with the untimely release of funds

Background  

District health systems in Africa depend largely on public funding. In many countries, not only are these funds insufficient, but they are also released in an untimely fashion, thereby creating serious cash flow problems for district health managers. This paper examines how the untimely release of public sector health funds in Ghana affects district health activities and the way district managers cope with the situation.     

Association of the progesterone receptor gene with breast cancer risk: a single-nucleotide polymorphism tagging approach.

Association studies on susceptibility to breast cancer using single nucleotide polymorphisms (SNP) in the progesterone receptor (PGR) gene have been previously published, but the results have been inconclusive. We used a comprehensive SNP-tagging approach to search for low-penetrance susceptibility alleles in a study of up to 4,647 cases and 4,564 controls, in a two-stage study design. We identified seven tagging SNPs using genotype data from the National Institute of Environmental Health Sciences (NIEHS) Environmental Genome Project and typed these, and an additional three SNPs, in 2,345 breast cancer cases and 2,284 controls (set 1). Three SNPs showed no evidence for association and were not studied further, whereas seven SNPs (rs11571171, rs7116336, rs660149, rs10895068, rs500760, rs566351, and rs1042838) exhibited significant associations at P < 0.1 using either a heterogeneity or trend test and progressed to be genotyped in set 2. After both stages, only one SNP was significantly associated with an increased risk of breast cancer - the PGR-12 (rs1042638) V660L valine to leucine polymorphism [VL heterozygotes (odds ratio, 1.13; 95% confidence interval, 1.03-1.24) and the LL homozygotes (odds ratio, 1.30; 95% confidence interval, 0.98-1.73), P(het) = 0.008, P(trend) = 0.002]. Similar estimates were obtained in a combined analysis of our data with those from three other published studies. We conclude that the 660L allele may be associated with a moderately increased risk of breast cancer, but that other common SNPs in the PGR gene are unlikely to be associated with a substantial risk of breast cancer.     

Overexpression of P-glycoprotein is associated with a decreased mitochondrial transmembrane potential in doxorubicin-selected K562 human leukemia cells

We tested the hypothesis of whether overexpression of P-glycoprotein (Pgp) could be coupled with changes in specific mechanisms of antioxidant defense (in particular, transition of mitochondrial transmembrane potential, MTP) in tumor cells chronically exposed to anticancer drugs known to exert their cytotoxicity via oxidative stress. We show elevation of Pgp associated with decreased MTP in doxorubicin-selected K562Dox subline as compared with parental K562 cells. The low MTP was not due to a fewer number of mitochondria in K562Dox cells, nor was it associated with altered content of Bcl-XL protein. We discuss a model for coordinated up-regulation of Pgp and MTP transition in cells that survived chemotherapy-induced oxidative stress.     

Immediate return of nerve function following microsurgical repair

The conduction of motor nerve impulses across the suture line of microsurgically repaired peripheral nerves has previously been demonstrated. The present study was undertaken to test the hypothesis that such conducted impulses would produce physiological responses in the limb distally. Studies of nerve conduction, muscle motor unit activity and paw tremor were carried out before and after division and repair of the sciatic nerves of nine New Zealand white rabbits. The results indicated that immediately after nerve repair stimulation of the proximal nerve can result in physiological neuromuscular responses distally.