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.     

Gene expression signature predicts recurrence in lung adenocarcinoma.

PURPOSE: Improving outcomes for early-stage lung cancer is a major research focus at present because a significant proportion of stage I patients develop recurrent disease within 5 years of curative-intent lung resection. Within tumor stage groups, conventional prognostic indicators currently fail to predict relapse accurately. EXPERIMENTAL DESIGN: To identify a gene signature predictive of recurrence in primary lung adenocarcinoma, we analyzed gene expression profiles in a training set of 48 node-negative tumors (stage I-II), comparing tumors from cases who remained disease-free for a minimum of 36 months with those from cases whose disease recurred within 18 months of complete resection. RESULTS: Cox proportional hazards modeling with leave-one-out cross-validation identified a 54-gene signature capable of predicting risk of recurrence in two independent validation cohorts of 55 adenocarcinomas [log-rank P=0.039; hazard ratio (HR), 2.2; 95% confidence interval (95% CI), 1.1-4.7] and 40 adenocarcinomas (log-rank P=0.044; HR, 3.3; 95% CI, 1.4-7.9). Kaplan-Meier log-rank analysis found that predicted poor-outcome groups had significantly shorter survival, and furthermore, the signature predicted outcome independently of conventional indicators of tumor stage and node stage. In a subset of earliest stage adenocarcinomas, generally expected to have good outcome, the signature predicted samples with significantly poorer survival. CONCLUSIONS: We describe a 54-gene signature that predicts the risk of recurrent disease independently of tumor stage and which therefore has potential to refine clinical prognosis for patients undergoing resection for primary adenocarcinoma of the lung.     

The decreased molar ratio of phytate:zinc improved zinc nutriture in South Koreans for the past 30 years (1969-1998)

For the assessment of representative and longitudinal Zn nutriture in South Koreans, Zn, phytate and Ca intakes were determined using four consecutive years of food consumption data taken from Korean National Nutrition Survey Report (KNNSR) every 10 years during 1969-1998. The nutrient intake data are presented for large city and rural areas. Zn intake of South Koreans in both large city and rural areas was low during 1969-1988 having values between 4.5-5.6 mg/d, after then increased to 7.4 (91% Estimated Average Requirements for Koreans, EAR = 8.1 mg/d) and 6.7 mg/d (74% EAR) in 1998 in large city and rural areas, respectively. In 1968, Zn intake was unexpectedly higher in rural areas due to higher grain consumption, but since then until 1988 Zn intake was decreased and increased back in 1998. Food sources for Zn have shifted from plants to a variety of animal products. Phytate intake of South Koreans during 1969-1978 was high mainly due to the consumption of grains and soy products which are major phytate sources, but decreased in 1998. The molar ratios of phytate:Zn and millimmolar ratio of phytate×Ca:Zn were decreased due to the decreased phytate intake in South Koreans, which implies higher zinc bioavailability. The study results suggest that Zn nutriture has improved by increased dietary Zn intakes and the decreased molar ratio of phytate:Zn in South Koreans in both large city and rural areas.     

Zinc deficiency negatively affects alkaline phosphatase and the concentration of Ca, Mg and P in rats

Zn is an essential nutrient that is required in humans and animals for many physiological functions, including immune and antioxidant function, growth, and reproduction. The present study evaluated whether Zn deficiency would negatively affect bone-related enzyme, ALP, and other bone-related minerals (Ca, P and Mg) in rats. Thirty Sprague Dawley rats were assigned to one of the three different Zn dietary groups, such as Zn adequate (ZA, 35 mg/kg), pair fed (PF, 35 mg/kg), Zn deficient (ZD, 1 mg/kg) diet, and fed for 10 weeks. Food intake and body weight were measured daily and weekly, respectively. ALP was measured by spectrophotometry and mineral contents were measured by inductively coupled plasma-mass spectrophotometer (ICP-MS). Zn deficient rats showed decreased food intake and body weight compared with Zn adequate rats (p<0.05). Zn deficiency reduced ALP activity in blood (RBC, plasma) and the tissues (liver, kidney and small intestine) (p<0.05). Also, Zn deficiency reduced mineral concentrations in rat tissues (Ca for muscle and liver, and Mg for muscle and liver) (p<0.05). The study results imply the requirement of proper Zn nurture for maintaining bone growth and formation.     

The concentration of the 35-kDa surfactant apoprotein in amniotic fluid from normal and diabetic pregnancies

A specific, enzyme-linked immunoabsorbent assay was used to determine the concentration of the 35,000 mol wt surfactant apoprotein (SP-A) in samples of amniotic fluid obtained from nondiabetic (n = 358) and diabetic (n = 29) women. The enzyme-linked immunoabsorbent assay was performed with rabbit antibodies directed against SP-A present in lavage fluid from a patient with alveolar proteinosis. Amniotic fluid SP-A concentrations increased as a function of gestational age, from less than 3 micrograms/ml at 30-31 wk to 24 micrograms/ml at 40-41 wk, and were positively correlated with the lecithin to sphingomyelin ratio (p less than 0.01). SP-A concentrations also increased as a function of gestational age in shake test positive samples (p less than 0.05), but were unchanged in shake test-negative samples. There was no difference in the surfactant apoprotein concentration of male compared with female fetuses at any gestational age. In amniotic fluid obtained from 20 diabetic women, SP-A levels were significantly less than in nondiabetic pregnancies that were matched for gestational age and sex of the fetus (p less than 0.05). The SP-A concentrations in amniotic fluids obtained from nine women who were diabetic and hypertensive and from 10 hypertensive women were not different from matched controls. The relationships described above were valid whether the SP-A concentration was expressed per mg protein or per ml amniotic fluid. These data are suggestive that the concentration of amniotic fluid SP-A is decreased in diabetic pregnancies.     

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.     

Treatment of metabolic alkalosis with intravenous infusion of concentrated hydrochloric acid

A concentrated hydrochloric acid (1 N) infusion was utilized for treatment on 35 occasions of metabolic alkalosis in 24 patients. The amount of hydrochloric acid to be infused was calculated from total base excess. To avoid over-correction, two thirds of the calculated dosage of hydrochloric acid only was infused. 1 N hydrochloric acid solution was infused at a speed of 1 mEq/min through a roentgenographically confirmed central venous line. Metabolic alkalosis was successfully treated in all instances without any complication. However, increased respiratory stimulation was not demonstrated in these observations. Concentrated hydrochloric acid infusion is a safe, reliable, and effective method of rapid correction of metabolic alkalosis. Because only small volumes are needed, this method is especially useful when fluid intake must be restricted.