Pharmacokinetics of clavulanic acid-potentiated ticarcillin in renal failure

The serum kinetics of an intravenous bolus of a combination of ticarcillin (TIC) (3 g) and clavulanic acid (CLAV) (0.2 g) have been determined in a number of patients with different degrees of renal failure as characterized by creatinine clearance. The volume of distribution for both drugs was unaffected by renal failure. Indices of serum and renal drug clearance were related to the degree of renal failure. TIC was cleared more slowly than CLAV. Anephric patients may have a higher serum clearance of CLAV than patients categorized by creatinine clearance as having severe renal failure; this could be due to an increase in metabolic clearance. Haemodialysis effectively clears both drugs. "Rebound" serum concentrations were consistently observed for TIC, but were observed in only one patient for CLAV. Continuous ambulatory peritoneal dialysis results in significant recovery of both drugs. The dosing requirements for the combination of TIC and CLAV in patients with renal failure are considered.     

Spectrophotometric evaluation of carboxyhemoglobin in blood of mice after exposure to marijuana or tobacco smoke in a modified Walton horizontal smoke exposure machine

Carboxyhemoglobin (COHb) values were determined in mice exposed to varying amounts of marijuana and tobacco cigarette smoke utilizing a spectrophotometric technique. Mice were exposed to smoke inhalation in a modified Walton horizontal smoke exposure machine, whereby rodents can be exposed to multiples of 1-min smoke exposure cycles. Smoke exposure was intermittent; during the first 30 sec of each 1-min cycle, the subjects were exposed to smoke diluted either 1:10 or 1:5 with air. During the second half of the cycle the animals were given fresh air. There was a positive linear relationship between COHb values obtained and the number of puffs of marijuana smoke administered via either 2, 4, 6, or 8 "puffs" of marijuana smoke. COHb levels in plasma did not increase in animals given multiple 8-puff episodes of smoke daily as long as a 60-min period was interposed between smoking episodes. COHb values in mice exposed to tobacco smoke were significantly higher than those in mice receiving equal numbers of exposures to marijuana smoke. Mean COHb values of mice receiving 8 consecutive puffs of marijuana smoke were 18.6 and 22.0% saturation, but CO was rapidly cleared from the blood. This rapid clearance suggests that the binding affinity of CO for mouse hemoglobin may be be weaker than that of human hemoglobin. Mice similarly exposed to 6 or 8 puffs of tobacco smoke had mean COHb values of 24.6 and 28.5% saturation, respectively. No acute lethal effects were observed in mice receiving multiple daily episodes of 8 puffs per episode of marijuana smoke, whereas mice exposed to a single 8-puff episode of tobacco smoke suffered about 50% acute lethal effects.     

Factors influencing the clinical efficacy of activated charcoal

The use of activated charcoal as part of the treatment of intoxicated patients has increased dramatically over the last ten years. Activated charcoal is currently suggested as therapy to prevent the absorption of orally ingested compounds, and is gaining popularity as a method of increasing systemic drug clearance. This review presents variables that should be considered when activated charcoal is used in the treatment of intoxicated patients. Variables that may alter the efficacy of charcoal therapy include the preparation and dose of charcoal used, the intoxicants involved, stomach contents, the gastrointestinal pH, concurrently administered materials, and time from toxin ingestion to charcoal administration. As a general guideline, a single, large dose should be administered with a cathartic as soon as possible after oral ingestion to prevent drug absorption. When charcoal is used to enhance systemic drug clearance, the dosage regimen should be individualized, based on the drugs involved and the patient's gastrointestinal tract function, fluid and electrolyte status, and the severity of intoxication.     

Quantitative analysis of liver GST-P foci promoted by a chemical mixture of hexachlorobenzene and PCB 126: implication of size-dependent cellular growth kinetics

The objectives of this study were twofold: (1) evaluating the carcinogenic potential of the mixture of two persistent environmental pollutants, hexachlorobenzene (HCB) and 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126), in an initiation-promotion bioassay involving the development of π glutathione S-transferase (GST-P) liver foci, and (2) analyzing the GST-P foci data using a biologically-based computer model (i.e., clonal growth model) with an emphasis on the effect of focal size on the growth kinetics of initiated cells. The 8-week bioassay involved a series of treatments of initiator, two-thirds partial hepatectomy, and daily oral gavage of the mixture of two doses in male F344 rats. The mixture treatment significantly increased liver GST-P foci development, indicating carcinogenic potential of this mixture. Our clonal growth model was developed to simulate the appearance and development of initiated GST-P cells in the liver over time. In the model, the initiated cells were partitioned into two subpopulations with the same division rate but different death rates. Each subpopulation was further categorized into single cells, mini- (2–11 cells), medium- (12–399 cells), and large-foci (>399 cells) with different growth kinetics. Our modeling suggested that the growth of GST-P foci is size-dependent; in general, the larger the foci, the higher the rate constants of division and death. In addition, the modeling implied that the two doses promoted foci development in different manners even though the experimental foci data appeared to be similar between the two doses. This study further illustrated how clonal growth modeling may facilitate our understanding in chemical carcinogenic process. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Economic Evaluations of Pathology Tests, 2010-2015: A Scoping Review

Background

Concerns about pathology testing such as the value provided by new tests and the potential for inappropriate utilization have led to a greater need to assess costs and benefits. Economic evaluations are a formal method of analyzing costs and benefits, yet for pathology tests, questions remain about the scope and quality of the economic evidence.

Risk creating and risk reducing: Community perceptions of supervised consumption facilities for illicit drug use

Progressive public health authorities in high-income countries have advocated supervised consumption facilities, where people who use illicit drugs can consume them in a hygienic, supervised environment, as a way of reducing drug-related risks to both people who use drugs and communities. However, the planning of such facilities has often met with strong reactions from the local community. ‘Not in my backyard’ (NIMBY) type reactions are frequently encountered and public opinion polling is limited in its ability to provide detailed insights into the reasons why people support or oppose these facilities in Toronto and Ottawa. We explore perceptions of residents and business representatives to the proposed implementation of supervised consumption facilities, and examine their perceptions of risks from these facilities. We collected qualitative data from 2008–2010 using focus groups and interviews with 38 residents and 17 business representatives in these two large Canadian cities lacking supervised consumption facilities. We used thematic analysis to examine expressed benefits and risks regarding supervised consumption facilities amongst community members. These participants saw these facilities as potentially risk-reducing, but recognised that the facilities could also create risks for their communities. While community members accepted that facilities could have positive health effects, they expressed a level of concern regarding the risk of public nuisance associated with supervised consumption facilities that seemed unwarranted based on the existing evidence. Discussions on the risks involved in the establishment of supervised consumption facilities should move beyond a focus on the benefits to facility users, to exploring community-level benefits and risks, and integrate evidence regarding actual risk experiences from other locations. Similar approaches may apply to NIMBY concerns related to other contentious issues.     

Vitamin E inhibition of lipid peroxidation and ethanol-mediated promotion of esophageal tumorigenesis.

Promotion of chemically induced esophageal cancer by ethanol may include the generation of highly reactive free radicals and thus may be preventable by the antioxidant vitamin E. In the present study, female C57BL/6 mice received N-nitrosomethylbenzylamine (NMBzA, 0.2 mg/kg ig) three times a week for three weeks. After this esophageal carcinogenic treatment, mice were fed a nutritionally adequate liquid diet with 30% of the calories supplied by ethanol or an isocaloric carbohydrate with or without supplemental alpha-tocopherol (142 mg/kg diet). As a marker of in vivo lipid peroxidation, exhaled ethane was collected and measured 24 hours "before" the mice were killed after 20 weeks of dietary treatment. Hepatic malondialdehyde, lipid fluorescence, and conjugated dienes were determined as markers of products of lipid peroxidation and serum aminotransferases as indexes of liver toxicity. Hepatic liver concentrations of vitamins A and E and the size and frequency of esophageal tumors were also assessed. Ethanol consumption after NMBzA administration significantly increased (p less than 0.05) the size and frequency of esophageal tumors. These ethanol-promoted effects were accompanied by increases in indexes of in vivo and accumulated products of lipid peroxidation. Similarly treated animals that received supplemental dietary vitamin E showed significant reductions (p less than 0.05) in mean tumor size and frequency of tumors as well as a decrease in the indexes of hepatic lipid peroxidation. The results suggest that promotion of NMBzA-induced esophageal tumors by ethanol may in part result from increased lipid peroxidation and that vitamin E reduces carcinogenicity of NMBzA or ethanol promoter effects by inhibiting lipid peroxidation.     

Ethanol-induced changes in the intestinal mucosa-associated immune system of young and mature mice

Alcoholics have frequent bronchial and intestinal bacterial-associated infections compromising the mucosal-associated lymphoid tissues. Alcoholics also suffer undernutrition due to changes in their lifestyles. Thus, we studied the intestinal mucosa-associated lymphoid tissues using two types of diets in young and mature mice. The objective was to elucidate if ethanol consumption alters the T and B cell populations in the intestine, and if the alteration could be associated with the age and/or the nutritional status of the host. There was an increase in the number of CD8⁺ cells per field in the intestinal lamina propria (ILP) of young mice consuming ethanol, with no changes in CD4⁺ and IgA⁺ cells in the ILP and CD4⁺ and CD8⁺ cells in the intestinal intraepithelium (IE). There was also an increase in the number of CD4⁺ and CD8⁺ cells in the ILP of well-nourished mature mice consuming ethanol, and an increase in the number of CD4⁺ cells in the ILP of undernourished mice. An increase in the number of CD8⁺ cells in the IE was also detected in the well-nourished group consuming ethanol. Therefore, we conclude that ethanol administration alters the intestinal mucosa-associated lymphoid tissue.     

How can biologically-based modeling of arsenic kinetics and dynamics inform the risk assessment process? - A workshop review

Quantitative biologically-based models describing key events in the continuum from arsenic exposure to the development of adverse health effects provide a framework to integrate information obtained across diverse research areas. For example, genetic polymorphisms in arsenic metabolizing enzymes can lead to differences in target tissue dosimetry for key metabolites causative in toxic and carcinogenic response. This type of variation can be quantitatively incorporated into pharmacokinetic (PK) models and used together with population-based modeling approaches to evaluate the impact of genetic variation in methylation capacity on dose of key metabolites to target tissue. The PK model is an essential bridge to the pharmacodynamic (PD) models. A particular benefit of PD modeling for arsenic is that alternative models can be constructed for multiple proposed modes of action for arsenicals. Genomics data will prove useful for identifying the key pathways involved in particular responses and aid in determining other types of data needed for quantitative modeling. These models, when linked with PK models, can be used to better understand and explain dose- and time-response behaviors. This in turn assists in prioritizing modes of action with respect to their risk assessment relevance and future research. This type of integrated modeling approach can form the basis for a highly informative mode-of-action directed risk assessment for inorganic arsenic (iAs). This paper will address both practical and theoretical aspects of integrating PK and PD data in a modeling framework, including practical barriers to its application.