Pharmacokinetics and safety of bromotetrandrine (BrTet, W198) after single-dose intravenous administration in healthy Chinese volunteers

Objective: To investigate the safety and pharmacokinetics of bromotetrandrine (BrTet, W198), a novel inhibitor of P‐glycoprotein (P‐gp), after single‐dose i.v. infusion in healthy Chinese volunteers. Methods: We conducted a randomized, dose‐escalating, phase I clinical study for that purpose. Thirty healthy subjects received BrTet at the doses of 10, 20 or 30 mg/m² by i.v. infusion. Plasma and urine concentrations of bromotetrandrine were determined by using a liquid chromatography–tandem mass spectrometric (LC/MS/MS) method. AUC was calculated by the trapezoidal rule extrapolation method. C_max, T_max, t_1/2α, t_1/2β, Cl and V_d were compiled from the plasma concentration–time data. Results: Bromotetrandrine was generally well tolerated at all doses. No serious or severe adverse events were found in the study. The pharmacokinetic parameters of BrTet after single i.v. infusion doses of BrTet 10, 20 and 30 mg/m² were as follows: T_max were 1·5 h in three groups, C_max were 24·79, 39·59 and 64·31 μg/L, t_1/2α were 0·37, 0·29 and 0·30 h, t_1/2β were 62·88, 56·45 and 52·20 h. AUC_0–194h were 345·83, 688·15 and 1096·28 μg h/L, Cl were 23·68, 25·69 and 25·66 L h/m², V_d were 157·73,156·96 and 140·73 L/m². In urine, the total eliminate rate of originate compound was 0·61 ± 0·19%. Conclusions: This study suggested that bromotetrandrine was well tolerated in healthy volunteers within the dose range evaluated. The pharmacokinetics parameters of bromotetrandrine indicated that the compound was rapidly distributed and accumulated in the tissues, and slowly cleared from plasma, which supported the use of BrTet for a once or twice dosing per chemotherapy cycle.     

Synchronous Bilateral Breast Carcinoma in a Patient with Cowden Syndrome: A Case Report with Morphologic,Immunohistochemical and Genetic Analysis

Abstract: Synchronous bilateral breast carcinoma (SBBC) and early onset are important characteristics of hereditary cases. The lifetime risk for breast carcinoma in Cowden syndrome (CS) is estimated to be 25–50%. We reported a 44‐year‐old woman presenting SBBC and characteristic mucocutaneous lesions of CS, confirmed by PTEN gene mutation analysis. Bilateral modified mastectomy and axillary dissection were performed. Histopathologic examination revealed a moderate‐differentiated invasive ductal carcinoma with mixed features of luminal A immunophenotype (Estrogen and/or Progesterone Receptors >50% and/or Ki67 < 30% of positive cells). The skin lesions showed the characteristic findings of tricholemmoma. Lack of PTEN expression was observed in all specimens. Sequencing analysis confirmed the presence of PTEN splice‐acceptor site mutation in intron 8 (c.1027‐2A>G), a germline mutation which had not been previously reported in CS. The patient received adjuvant chemotherapy and tamoxifen for 5 years. After 5 years of follow‐up, she persists recurrence‐free. SBBC with early onset suggests a hereditary predisposition. Thus, analysis of PTEN expression abnormality, easily assessed by immunohistochemistry, may be of clinical value to screen those patients with CS.     

Grand multiparity: an obstetric or neonatal risk factor?

Grand multiparity has been considered to be a factor in maternal and neonatal morbidity. In addition, families with seven or more children have been associated with low socioeconomic status. To minimize the confounding effect of the socioeconomic status, the outcome of grand multiparity has been investigated in a mostly homogeneous, ultraorthodox Jewish community in Jerusalem, Israel. A total of 5916 deliveries in one community hospital (Bikur Cholim) were studied, of which 893 (13%) occurred in mothers who had given birth to seven or more infants. There was a significant decrease in the incidence of small for gestational age infants among the grand multiparous women (3.6% as opposed to 5.8% in the control population). This difference was independent of maternal age. Moreover, grand multiparous women gave birth to significantly more large for gestational age infants. No increase in obstetric complications or neonatal morbidity and mortality was found among the offspring of the grand multiparous mothers. Having taken socioeconomic status into account, we conclude that grand multiparity does not carry an increased risk of perinatal morbidity or mortality.     

Estimates of the chromium(VI) reducing capacity in human body compartments as a mechanism for attenuating its potential toxicity and carcinogenicity

Estimates of the overall reducing capacity of hexavalent chromium(VI) in some human body compartments were made by relating the specific reducing activity of body fluids, cell populations or organs to their average volume, number, or weight. Although these data do not have absolute precision or universal applicability, they provide a rationale for predicting and interpreting the health effects of chromium(VI). The available evidence strongly indicates that chromium(VI) reduction in body fluids and long-lived non-target cells is expected to greatly attenuate its potential toxicity and genotoxicity, to imprint a threshold character to the carcinogenesis process, and to restrict the possible targets of its activity. For example, the chromium(VI) sequestering capacity of whole blood (187-234 mg per individual) and the reducing capacity of red blood cells (at least 93-128 mg) explain why this metal is not a systemic toxicant, except at very high doses, and also explain its lack of carcinogenicity at a distance from the portal of entry into the organism. Reduction by fluids in the digestive tract, e.g. by saliva (0.7-2.1 mg/day) and gastric juice (at least 84- 88 mg/day), and sequestration by intestinal bacteria (11-24 mg eliminated daily with feces) account for the poor intestinal absorption of chromium(VI). The chromium(VI) escaping reduction in the digestive tract will be detoxified in the blood of the portal vein system and then in the liver, having an overall reducing capacity of 3300 mg. These processes give reasons for the poor oral toxicity of chromium(VI) and its lack of carcinogenicity when introduced by the oral route or swallowed following reflux from the respiratory tract. In terminal airways chromium(VI) is reduced in the epithelial lining fluid (0.9-1.8 mg) and in pulmonary alveolar macrophages (136 mg). The peripheral lung parenchyma has an overall reducing capacity of 260 mg chromium(VI), with a slightly higher specific activity as compared to the bronchial tree. Therefore, even in the respiratory tract, which is the only consistent target of chromium(VI) carcinogenicity in humans (lung and sinonasal cavities), there are barriers hampering its carcinogenicity. These hurdles could be only overwhelmed under conditions of massive exposure by inhalation, as it occurred in certain work environments prior to the implementation of suitable industrial hygiene measures.      

Effect of proton pump inhibitors on the detection of Helicobacter pylori in gastric biopsies.

BACKGROUND: Proton pump inhibitors are known to decrease the activity of Helicobacter pylori organisms within the stomach and to shift their distribution proximally. This effect may reduce the sensitivity of histological examination and rapid urease testing for H. pylori on biopsies taken from recommended sites. It is of particular relevance if a proton pump inhibitor has been prescribed before the patient has undergone diagnostic endoscopy. METHODS: We studied patients referred to our open-access upper gastrointestinal endoscopy service who had either been on no medication (controls) or were already taking proton pump inhibitors. Biopsies taken from the gastric antrum and corpus were used for rapid urease testing and for histological examination. Sera, taken from patients who had no evidence of H. pylori in biopsies, were tested for IgG H. pylori antibodies as an alternative indicator of infection. RESULTS: H. pylori organisms were detected by histological examination in 27 of 40 controls (68%) and in 13 of 25 patients taking proton pump inhibitors (52%). Among patients with positive histology (organisms detected in either antral or corpus biopsies, or both), only the sensitivity of the antral urease test read at 1 h was significantly lower in patients taking proton pump inhibitors than in controls, with no significant difference in sensitivities of the antral urease test at 24 h, of the corpus urease test at 1 or 24 h, or of histology from the antrum or corpus. Of patients with negative histology, none of 13 controls compared with six of 12 patients taking proton pump inhibitors (50%) had positive serology (P = 0.005). Five (83%) of the six histology-negative, seropositive patients taking proton pump inhibitors had histological changes consistent with H. pylori gastritis even though no organisms were detected. CONCLUSIONS: Treatment with a proton pump inhibitor before endoscopy reduces the sensitivity of antral and corpus biopsies for H. pylori detection, both by urease testing and histological examination. If proton pump inhibitors already prescribed cannot be discontinued for an adequate period before endoscopy, patients should have biopsies taken from the corpus as well as from the antrum, and serum should be tested for H. pylori.     

Oxidative stress in term small for gestational age neonates born to undernourished mothers: a case control study

Background  

The objective of this study was to assess the status of oxidative stress in term small for gestational age (SGA) newborn infants born to undernourished mothers by estimating levels of erythrocyte superoxide dismutase (SOD), catalase, reduced glutathione, and serum malondialdehyde (MDA) in cord blood and comparing them to healthy appropriate for gestational age (AGA) controls. This was done in a case control design at a tertiary level teaching hospital.     

Comparison of morphologic features of intact and ruptured aneurysms of infrarenal abdominal aorta

INTRODUCTION: Endovascular aneurysm repair (EVAR) has been suggested as a technique to improve outcome of ruptured abdominal aortic aneurysm (AAA). Whether this technique becomes an established treatment will depend, in part, on the anatomy of ruptured AAA. METHODS: The anatomy of intact and ruptured AAA seen in a university department of vascular surgery over 5 years was reviewed. Aneurysm anatomy was assessed with spiral computed tomographic angiography. Suitability for EVAR was assessed from the dimensions of the proximal neck and common iliac arteries. Neck length less than 15 mm, neck width greater than 30 mm, and common iliac artery diameter greater than 22 mm were declared unsuitable for EVAR. RESULTS: Three hundred sixty-three patients with intact AAA and 46 with ruptured AAA were identified. Larger intact aneurysms were significantly associated with longer renal artery-bifurcation distance and more complex proximal neck architecture. In this sample, patients with ruptured AAA were more likely to have larger aneurysms with shorter and narrower proximal necks. Significantly more intact aneurysms were morphologically suitable for endovascular repair compared with ruptured AAA (78% vs 43%; P <.001). CONCLUSIONS: Ruptured AAA are less likely to be suitable for endovascular repair than are intact AAA, most probably because of larger diameter at presentation. Open repair will likely remain the treatment of choice in most patients with ruptured AAA, because of current morphologic constraints of endovascular repair.     

Effect of publication of the "Practice Parameter for the management of hyperbilirubinemia" on treatment of neonatal jaundice

The aim of this study was to evaluate the change in the treatment of neonatal jaundice following introduction of the "American Academy of Pediatrics' Practice Parameter for the management of hyperbilirubinemia in the healthy term newborn". In a historical control observation cohort study, we examined the rate of phototherapy and exchange transfusions among full-term (> or = 37 wk gestation) and near-term (gestational age between 35 and 37 wk and birthweight > 2000 g) infants in two community hospitals. The study included all consecutive infants born during two 15-mo study periods immediately before and after the introduction of the new guidelines. Data were prospectively recorded in a computerized database. The rate of phototherapy significantly decreased in the second study period from 7.9% (514/6499) to 2.9% (251/8650) (p < 0.0001) among full-term infants, and from 20.9% (102/489) to 9.4% (47/502) (p < 0.0001) in near-term infants. The use of exchange transfusion was significantly higher (p < 0.001) in the first compared to the second period: 0.2% (15/6499) vs 0.03% (3/8650). A significant decrease was found when the data from each hospital were analyzed separately. CONCLUSION: A significant decrease in the use of phototherapy and exchange transfusion occurred after the publication of the new practice parameters. This trend was observed for both term and preterm newborns, although the new guidelines were not intended for infants born before term.