ASO Author Reflections: National Analysis of Breast Surgery Malpractice Cases: A Teachable Moment?

Annals of Surgical Oncology -     

Comparison of Plasma Protein Binding of Basic Drugs in Black and White Individuals

Interethnic difference in drug disposition is an important contributing factor to interindividual variation in drug response. Since interethnic differences in the protein binding of drugs may contribute to variation in drug disposition between ethnic groups, we conducted a study in 10 black Americans (A) and mean (plus minusSE) age 26 plus minus 6 years and weight 80 plus minus 9 kg matched against 10 white Americans (C) with a mean age of 28 plus minus 6 years and weight 81 plus minus 9 kg, all within 10% of ideal body weight. Serum alpha-1-acid glycoprotein (AGP) and albumin concentrations were measured using the auramine-O and bromcresol green methods, respectively. Verapamil, propranolol, lidocaine, disopyramide and diazepam binding in plasma were measured with the equilibrium-dialysis method, involving the determination of free and unbound drug concentrations. The unbound fraction of diazepam (A = 1.1 plus minus 0.1%; C = 1.1 plus minus 0.1%), verapamil (A = 9.5 plus minus 0.8%; C = 9.8 plus minus 0.4%), propranolol (A = 14.2 plus minus 1.0%; C = 12.6 plus minus 0.7%), lidocaine (A = 28.5 plus minus 2.1%; C = 25.7 plus minus 1.1%) and diphenhydramine (A = 42.9 plus minus 10.2; C = 30.4 plus minus 7.01%) showed no significant ethnic differences (unpaired t-test). Disopyramide measured at 7 different concentrations (1.0--20.0 &mgr;g/ml) was similar in both groups, as were the plasma concentrations of AGP (A = 100 plus minus 20 mg 100 ml; C = 120 plus minus 20 mg 100 ml) and albumin (A = 4.3 plus minus 0.1 g 100 ml; C = 4.5 plus minus 0.1 g 100 ml). It is therefore concluded that there are no interethnic differences in the protein binding of basic drugs between black Americans and white Americans and that it is not a major contributing factor to any possible interethnic variation in the disposition of responsiveness of these drugs.     

Covalent binding of isomeric benzo[a]pyrene diol-epoxides to DNA

We have compared the abilities of two diol-epoxide derivativesof benzo[a]pyrene (B[a]P) to bind covalently to DNA in a simplein vitro system. Purified DNA in aqueous solution was allowedto react with (±)-7, 8ß-dihydroxy-9ß,10ß-oxy-7,8,9,10-tetrahydroB[a]P (BPDE) or with (±)-9,10ß-dihydroxy-7,8-oxy-7,8,9,10-tetrahydroB[a]P (reverseBPDE) to completion. After repurification of the DNA, bindingwas detected by fluorescence spectroscopy or by absorbance spectroscopy.Both BPDE and reverse BPDE but not their hydrolysis productsexhibited binding which increased linearly with increasing diolepoxide concentration. When DNA modified by reverse BPDE wasenzymatically hydrolysed, two major fluorescent deoxyribonucleoside-adductswere detected by reverse phase h.p.l.c. These were separablefrom the major adduct obtained from BPDE-modified DNA and fromthe major products obtained by hydrolysis of reverse BPDE inthe absence of DNA. Absorbance and fluorescence spectroscopyof modified native DNA suggested that the pyrene nucleus ofreverse BPDE but not of BPDE was intercalated in the DNA doublehelix. This suggestion was supported by fluorescence-quenchingstudies. In the presence of increasing DNA concentrations, covalentbinding of both diol epoxides increased towards an apparentmaximum. Double reciprocal analysis of the data indicated amaximum binding level of 5% of the total dose for BPDE and 4%for reverse BPDE. This suggests that for both diol epoxidesthe ratio of the rate constants for covalent binding and forDNA-enhanced hydrolysis are nearly the same. Covalent bindingof reverse BPDE to DNA was effectively blocked by low concentrationsof Mg²⁺, suggesting that formation of a non-covalent intercalationcomplex may be a prerequisite for covalent reaction.     

Polilactofate microspheres for Paclitaxel delivery to central nervous system malignancies.

PURPOSE: The purpose of this study was to demonstrate that surgically implanted, controlled-release, biodegradable polilactofate microspheres (Paclimer) can be used safely to bypass the blood-brain barrier and deliver paclitaxel to malignant brain tumors. EXPERIMENTAL DESIGN: The rate of paclitaxel release from Paclimer microspheres submerged in PBS was measured in vitro by high-performance liquid chromatography. In vivo studies of Paclimer were performed as intracranial implants in Fischer 344 rats in the presence or absence of 9L gliosarcoma. Mantel-Cox statistics were used to assess the efficacy of Paclimer at extending survival of tumor-bearing animals compared with control implants. Paclimer implants tagged with [(3)H]paclitaxel were used to measure biodistribution of paclitaxel from the Paclimer implant. RESULTS: Paclimer released paclitaxel at a constant rate for up to 3 months in vitro. In vivo, Paclimer implants placed intracranially in rats released active drug for up to 30 days after implantation and doubled the median survival of rats bearing established 9L gliosarcomas (median survival of paclitaxel-treated animals = 35 days; median survival of control-treated animal = 16 days; P < 0.0001). Active drug was distributed throughout the rat brain based on liquid scintillation counting and TLC. Rats implanted with Paclimer demonstrated no overt signs of neurotoxicity and exhibited local cytopathological changes consistent with exposure to an antimicrotubule agent. CONCLUSIONS: Paclimer extends survival in a rodent model of glioma with minimal morbidity and optimal pharmacokinetics.     

Dietary modulation of 7,12-dimethylbenz[a]anthracene (DMBA)-induced adrenal toxicity in female Sprague-Dawley rats.

In this study, dietary modulation of 7,12-dimethylbenz[a]anthracene (DMBA)-induced adrenal toxicity in rats was investigated. Beginning at postnatal day (PND) 21, female Sprague-Dawley rats were fed either soy-containing NIH-31 diet or soy- and alfalfa-free 5K96 diet. On the first day of diestrus when the animals were PND 50 +/- 5, rats received either an oral dose of 80 mg/kg DMBA or sesame oil, the vehicle, and were sacrificed at 24, 36, or 48 h after treatment. Apoptosis was manifested at 24 and 36 h after DMBA treatment in the zona reticularis (ZR) and the zona fasciculata (ZF) of the adrenal cortex; this was followed by severe hemorrhagic necrosis at 48 h. DMBA-induced apoptosis, evaluated by the TUNEL assay, immunohistochemical analysis of activated caspase 3, and the ratio of expression of pro-apoptotic Bax to anti-apoptotic Bcl2, was greater in rats fed NIH-31 diet relative to rats fed 5K96 diet at 24 h after treatment. Four of six DMBA-treated rats fed 5K96 diet had severe adrenal necrosis by 48 h, whereas this lesion was present in only two of six DMBA-treated rats fed NIH-31 diet. DMBA also caused a significant decrease of serum corticosterone relative to controls at 48 h in rats fed 5K96 diet. The present study indicated that diet modulates DMBA-induced adrenal toxicity in female rats, with increased apoptosis early and reduced necrosis later in rats fed a soy-containing diet.     

Effect of chronic alcohol consumption on plasma lipid, vitamins A, and E in Korean alcoholics

This human study was conducted to evaluate the effect of chronic alcohol consumption on plasma concentrations of lipid and the antioxidative system in 44 Korean alcoholics and 45 age-, sex-, and nationality-matched nonalcoholic subjects. Plasma triacylglycerols and atherogenic index were higher in alcoholics than in control subjects. Plasma total cholesterol was not different among groups, but plasma high-density lipoprotein cholesterol was lower in alcoholics. There were positive correlations between ethanol consumption and plasma lipid peroxide and atherogenic index in all subjects; there were negative correlations between ethanol consumption and plasma high-density lipoprotein cholesterol in all subjects. There were no significant differences between alcoholics and control subjects in plasma concentrations of α-tocopherol, although plasma α-tocopherol/lipid tended to be lower in alcoholics. Plasma retinol was lower in alcoholics. These results suggest that chronic ethanol consumption can contribute to increased risk for vascular diseases in Korean alcoholics.     

Quality of life in tuberculosis: Patient and provider perspectives

Tuberculosis (TB) is a persistent problem in the United States; however, little is known about its impact on functioning and quality of life (QOL) among people with TB. The purpose of this study is to describe the impact of TB on patients' QOL by using focus groups to assess the domains of QOL that are affected. Participants included patients (n = 10) who received treatment for active TB and physicians (n = 4) and nurses (n = 9) caring for patients with TB at a public health clinic in Baltimore, Maryland. TB affected all predicted domains of QOL, including general health perceptions, somatic sensation, psychological health, spiritual well-being, and physical, social and role functioning. Social stigmatization, isolation, pill burden, long duration of therapy, sexual dysfunction, loss of income, and fear were additional specific problems related to TB. Surprisingly, 11% (33) of the comments described benefits of TB illness, including increased spirituality and improved life perspectives. In addition, four additional QOL domains and three elements of treatment specific to TB which substantially impact QOL were identified. While patients and clinicians both identified issues in many areas of QOL, only patients mentioned the impact on sexual function, spirituality and improved life perspectives. Despite available curative therapy, TB and its treatment still have significant short and long-term consequences on patients' QOL.