Influence of once-monthly rifampicin and daily clofazimine on the pharmacokinetics of dapsone in leprosy patients in Nigeria

Summary In leprosy patients in Nigeria the influence of daily clofazimine and of once-monthly rifampicin on the pharmacokinetics of dapsone has been investigated.Three days after rifampicin the elimination half-life of dapsone was reduced from 40.4 to 25.3 h (n=23). Correspondingly, the plasma dapsone 24 h after the last dose had fallen significantly from 2.63 to 2.02 mg/l. Clofazimine did not cause change in the pharmacokinetics of dapsone.It was concluded that, although rifamipicin had a considerable influence on the pharmacokinetics of dapsone, there is no reason to adjust the dose of dapsone during multidrug therapy of leprosy.     

EEG alterations in patients treated with clozapine in relation to plasma levels

It is well known that psychotropic drugs can induce EEG alterations. Dose dependence seems established; however, there are no data concerning the impact of plasma levels. The authors investigated the influence of clozapine plasma levels on the frequency of EEG alterations. Data from 29 inpatients (18 male, 11 female, 31.7±10.2 years) receiving clozapine in a dose range between 25 and 600 mg were collected prospectively. There was no psychotropic or anticholinergic comedication. All patients had normal EEGs before taking clozapine. Fifteen patients showed pathological changes (group 2) and 14 no changes (group 1). Discriminant analysis showed that EEG changes are dependent on plasma levels (P=0.0009, plasma levels in group 1 mean 81.6 ng/ml, ±SD 64.6, in group 2 235.7 ng/ml, ±169.8). A total of 72.4% of the patients were correctly classified as having either pathological EEG changes or none by this analysis. Variables such as dose, age, sex, weight and duration of treatment were not statistically relevant. It can therefore be suggested that clozapine plasma levels are a valid indicator for the appearance of electrophysiological reactions.     

Benznidazole-induced ultrastructural and biochemical alterations in rat esophagus

Benznidazole (Bz) is a drug used in the chemotherapy of the acute and intermediate phases of Chagas' disease (American Trypanosomiasis), an endemic parasitic disease afflicting more than 16 million people in Latin America. Serious toxic side effects of Bz have been reported in treated human beings and in experimental animals. Bz toxicity would be linked to its nitroreductive bioactivation to reactive intermediates and to the corresponding amine known to occur in vivo and mediated by different enzymatic systems. In the present study the presence of Bz nitroreductases in rat esophagus and the occurrence of Bz induced esophageal cell injury are described. Already 1 and 3 h after an intragastric Bz administration to Sprague-Dawley male rats (240-260 g body weight) at a dose of 100 mg/kg esophageal levels of the drug were 66.4+/-4.0 and 149.2+/-14.3 nmol per g tissue, respectively. The esophageal mucosa homogenates exhibited Bz nitroreductase activity attributable to the participation of cytochrome P450 reductase and xanthine oxidoreductase (XOR). The ultrastructural observation of esophageal tissue from Bz treated animals 24 h after its administration evidenced: detachment and conglomeration of polyribosomes, reduction in the presence of desmosomes and of the amount of bacteria on its surface. The potential significance of these alterations is not fully clear at present. However, these deleterious effects might be additive or synergistic with those induced by the evolution of the disease.     

苄硝唑诱导大鼠结肠超微结构和生化改变

AIM: To study the effects of benznidazole (Bz), a drug used in the chemotherapy of the acute and the intermedi-ate phase of Chagas' disease, on the colon of rats. METHODS: Sprague Dawley male rats received Bz 100 mg/kg ig. After 24 h colons were examined by electron microscopy. Concentrations of Bz in colonic tissue were measured by HPLC. Bz nitroreduction was followed by the decrease in the drug concentration using spectropho-tometry and HPLC or by covalent binding to proteins of reactive products formed under in vivo and in vitro con-ditions. RESULTS: Colon mucosa of Bz-treated rats showed intense ultrastructural alterations: abundant mucus secretion at the level of the Goblet cells and dilatation of the endoplasmic reticulum and the Golgi apparatus in ep-ithelial cells. The concentration of Bz in tissue was (59±18) and (93±14) nmol/g (protein) 1 and 3 h after o-ral administration to rats, respectively. Colonic micro-somes anaerobically activated Bz in the presence of NADPH. This activating nitrored     

Neuropathological,biochemical and genetic alterations in AD

The molecular and cellular processes that lead to the production of the amyloid beta (A beta) peptide and some of the processes associated with A beta fibrillogenesis and neurotoxicity have recently been elucidated. Experimental results have suggested that abnormalities in the processing of the beta-amyloid precursor protein (beta APP) are central to the pathogenesis of Alzheimer's disease (AD). beta APP processing includes two mutually exclusive proteolytic cleavage pathways, one involving the putative gamma-secretase enzyme, the identity of which remains unknown. Recent evidence has suggested the presenilin 1 and presenilin 2 genes are necessary for gamma-secretase activities. Another gene associated with susceptibility to AD is the apolipoprotein E (APOE) gene. Given the important role that abnormal processing of beta APP plays in the genesis of AD, most current efforts are directed at either modulating A beta peptide production or inhibiting its ability to aggregate into fibrils and cause neurotoxicity. To inhibit A beta production, one strategy might be to inhibit either beta-secretase or gamma-secretase. Several approaches to the inhibition of A beta aggregation are under investigation.     

Pharmacokinetics of trimetrexate and dapsone in AIDS patients with Pneumocystis carinii pneumonia

The objective of this study was to determine the pharmacokinetics of trimetrexate and dapsone in AIDS patients with moderate to severe pneumocystis pneumonia. Trimetrexate, leucovorin, and dapsone were administered for 21 +/- 3 days in the following doses: trimetrexate glucuronate, 45 mg/m2; leucovorin, 20 mg/m2; and dapsone, 100 mg daily. The pharmacokinetics of trimetrexate, dapsone, and dapsone's metabolite, monoacetyldapsone, were determined at three separate periods over the course of treatment. Serial blood samples were obtained over 24 hours after dosing and analyzed for trimetrexate, dapsone, and monoacetyldapsone, and pharmacokinetic parameters were determined. The mean parameters obtained for the early, mid-, and late collection periods were the following: trimetrexate: t1/2 = 8.29, 9.15, 10.00 hr; AUC = 16.85, 22.38, 24.49 mg.hr/l; CI = 5.58, 4.14, 3.96 l/hr, respectively. DDS: t1/2 = 14.99, 16.59, 15.13 hr; AUC = 30.60, 35.29, 36.08 mg.hr/l; CI = 3.82, 3.49, 3.01 l/hr, respectively. Monoacetyldapsone: t1/2 = 20.25, 18.66, 16.32 hr; AUC = 24.05, 24.06, 23.86 mg.hr/l, respectively. No statistically significant changes in pharmacokinetics for trimetrexate or dapsone were observed over the 21 +/- 3 day course of treatment. The results suggest that there are no major interactions between trimetrexate and dapsone when administered together in acutely ill patients.     

Immunological and biochemical responses in mice treated with mercuric chloride

Adult B6C3F1 male mice were given water containing 3, 15, and 75 ppm mercury (as mercuric chloride) for 7 weeks. There were dose-related increases in blood and kidney mercury levels but only the former showed a time-dependent change. Mercury was not detected in any of the lymphoid organs except for the spleen. There was no mortality and only minimal histological changes occurred in kidneys of dosed mice. Nonspecific toxicity occurred at the 75 ppm dose level, consisting of small differences in body and organ weights, hematological changes, and general enzyme inhibition in the bone marrow and spleen. However, there were specific immunotoxic and biochemical alterations in lymphoid organs of mice treated at the lower doses of mercury. The immunological defects were consistent with altered T-cell function as evidenced by decreases in both T-cell mitogen and mixed leukocyte responses. There was a particular association between the T-cell defects and inhibition of thymic pyruvate kinase, the rate-limiting enzyme for glycolysis. The differences in the pattern of enzyme responses among lymphoid organs implied that two mechanisms of mercury toxicity were operative--one at high concentrations that caused physicochemical enzyme inhibition and another at low concentrations that caused indirect enzyme inhibition.     

Early nifurtimox-induced biochemical and ultrastructural alterations in rat heart

Nifurtimox (Nfx) and Benznidazole (Bz) are being used for the treatment of the acute phase of Chagas' disease. Recently, they were also considered for use in the indeterminate phase. Both the nitroheterocyclic drugs have serious toxic side effects. The mechanism of Nfx toxicity is associated with the formation of reactive oxygen species (ROS) generated during nitroreduction. Potential effects on cardiac function have not been established yet, despite the well-known cardiopathy often produced by the disease itself. We describe experiments testing some acute effects of Nfx on the male Sprague Dawley rat heart. Nifurtimox was present in the heart at 1, 3 and 6 h after intragastric (i.g) treatment. In vitro studies on Nfx microsomal and cytosolic nitroreductase activities showed that only the microsomal fraction had the ability to nitroreduce it. Cytochrome P450 and cytochrome P450 reductase would be involved in the process as suggested by their response to specific inhibitors. Nifurtimox increased the cardiac protein carbonyl content at 1 and 3 h and decreased the protein sulfhydryl content at 3 h. In addition, 24 h after treatment ultrastructural alterations such as marked cytoplasmic vacuolization, separation and loss of myofibrils and mitochondrial swelling were observed. Results suggest that Nfx administration might aggravate pre-existing adverse cardiac conditions. Human & Experimental Toxicology (2007) 26, 781 -788.     

Methylmercury induced biochemical and histochemical alterations in rat testis

The methylmercurry chloride (MMC) administered at doses of 5 and 10 micrograms/kg over a period of 90 days to male rats caused enzymatic impairments in testicular tissue. The study at intervals of 15, 30, 60 and 90 days showed gradual diminution of testicular weight and gradual decrements in testicular protein and inhibition in testicular succinic dehydrogenase activity. Histochemical and biochemical studies revealed that testicular acid phosphatase activity was also inhibited at both the doses of MMC treatment. The inhibition of enzyme activity in testicular tissues after MMC treatment caused the impairment of both spermatogenesis and steroidogenesis in rats.     

MDT干预模式在急性多发性肋骨骨折患者中的应用

目的:探讨多学科协同治疗(MDT)干预模式在急性多发性肋骨骨折患者中的应用.方法:选取2018-04～2019-10 河南省永城市神火总医院收治的急性多发性肋骨骨折患者102例,根据入院时间进行分组,分为观察组51例和对照组51例.对照组行常规急诊救治模式,观察组采用MDT干预模式,比较两组患者抢救时间、术后并发症发生率.结果:观察组入院后医师到诊时间(17.90±3.21)min、急性检查时间(23.69±3.17)min、急诊室停留时间(40.75±7.39)min均较对照组[(25.64±3.79)min、(40.18±3.22)min、(61.52±7.58)min]短;观察组术后并发症发生率3.92％较对照组17.65％低,差异有统计学意义(P＜0.05).结论:MDT干预模式应用于急性多发性肋骨骨折患者中可有效缩短抢救时间,提高护理质量,还可降低治疗后并发症发生风险.     

Immune alterations in untreated and treated myelodysplastic syndrome

INTRODUCTION: Current literature suggests a variety of immune abnormalities are present in myelodysplastic syndrome (MDS) patients. However, they have not been comprehensively characterized or systematized to date. As a result, their clinical implications remain largely unknown. In addition, an increased incidence of various autoimmune conditions has been documented in MDS patients. AREAS COVERED: The authors offer a comprehensive review of the existing literature on immune mechanisms involved in the pathogenesis of MDS, various immune abnormalities documented in its course, their link with the clonal evolution of MDS as well as immune alterations induced by the existing MDS therapies. EXPERT OPINION: The course of MDS is accompanied by complex immune alterations, including T-cell and NK-cell defects, decreased functional abilities of neutrophils and antigen-presenting cells, altered antibody and cytokine production. While contemporary MDS therapies are shown to possess some immunomodulatory properties, authentic autoimmune conditions have also been documented with lenalidomide and recombinant erythropoietin. Caution should be exerted with the use of these agents in MDS patients with evidence of autoimmune disorders, as exacerbation of autoimmune phenomena can be anticipated. While the heterogeneity of MDS represents an inherent limitation, integration of emerging information from molecular biology, genetics, immunology research and clinical practice could translate into improved outcomes of this disease spectrum.     

Immune alterations in untreated and treated myelodysplastic syndrome

Introduction: Current literature suggests a variety of immune abnormalities are present in myelodysplastic syndrome (MDS) patients. However, they have not been comprehensively characterized or systematized to date. As a result, their clinical implications remain largely unknown. In addition, an increased incidence of various autoimmune conditions has been documented in MDS patients.

Areas covered: The authors offer a comprehensive review of the existing literature on immune mechanisms involved in the pathogenesis of MDS, various immune abnormalities documented in its course, their link with the clonal evolution of MDS as well as immune alterations induced by the existing MDS therapies.

Expert opinion: The course of MDS is accompanied by complex immune alterations, including T-cell and NK-cell defects, decreased functional abilities of neutrophils and antigen-presenting cells, altered antibody and cytokine production. While contemporary MDS therapies are shown to possess some immunomodulatory properties, authentic autoimmune conditions have also been documented with lenalidomide and recombinant erythropoietin. Caution should be exerted with the use of these agents in MDS patients with evidence of autoimmune disorders, as exacerbation of autoimmune phenomena can be anticipated. While the heterogeneity of MDS represents an inherent limitation, integration of emerging information from molecular biology, genetics, immunology research and clinical practice could translate into improved outcomes of this disease spectrum.     

Cadmium-enriched cigarette smoke-induced cytological and biochemical alterations in rat lungs

Male Sprague-Dawley rats were exposed daily for 52 wk in a nose-only exposure system to smoke from the University of Kentucky 2R1 reference cigarettes (SM) or from cigarettes made of cadmium-enriched tobacco (Cd-SM). At sacrifice, the animals were evaluated by bronchoalveolar lavage (BAL) for inflammatory cell response in the lungs, and the cells so obtained were analyzed for phagocytosis of particles (latex and IgG-coated SRBCs) and for their ability to release oxidants upon phagocytic challenge. Additionally, lung tissues were analyzed for Cd levels and lung homogenate fractions were assayed for aryl hydrocarbon hydroxylase (AHH) as well as total and selenium-dependent glutathione peroxidase (GSH-Px) activities. BAL cell counts showed a significant influx of inflammatory cells into the lungs of the Cd-SM group but not the SM group. The proportion of neutrophils in the BAL cells of the Cd-SM group was elevated to 40 +/- 9%, compared with less than 2% in the SM group. Phagocytosis of both types of particles by macrophages from SM and Cd-SM groups was similar to that of the control groups, except that a greater uptake of latex particles was seen in Cd-SM macrophages. The release of oxidants (superoxides and hydrogen peroxide) by the BAL cells was severely impaired in the Cd-SM group, whereas a slight stimulation was seen in the SM group. Pulmonary GSH-Px activity was the same in all groups. A significant induction of the pulmonary AHH activity was observed in the SM group only. The Cd levels in the lungs were approximately 8- and 200-fold greater than controls in SM and Cd-SM groups, respectively. These observations suggest a significant influence of tobacco Cd on the toxicity of cigarette smoke.     

Triclosan elicited biochemical and transcriptomic alterations in Labeo rohita larvae

In the current study, Triclosan (TCS, a commonly used antimicrobial agent) induced alterations in biochemical parameters and gene expression were recorded in the larvae of Labeo rohita after 96 h exposure and 10 days recovery period to find out health status biomarkers. 96 h exposure to 0.06, 0.067 and 0.097 mg/L TCS significantly declined the levels of glucose, triglycerides, urea and uric acid and activity of alkaline phosphatase (ALP), glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT). There was a non-significant decline in the levels of cholesterol and total protein but albumin and total bilirubin showed no change. After 10 days of recovery period, trend was opposite for glucose, urea and ALP only. Decline in the expression of trypsin and pancreatic amylase and elevation in creatine kinase during exposure to TCS showed a reverse trend after recovery period. However, concentration dependent elevation of chymotrypsin persisted till the end of recovery period. Principal Component Analysis (PCA) showed association of total protein, ALP, GOT, creatine kinase and pancreatic amylase with PC1 after exposure as well as recovery period. Therefore, these can be considered as important biomolecules for identification of health status of TCS stressed fish.