Rhodamine B increases hypothalamic cell apoptosis and disrupts hormonal balance in rats

ObjectiveTo investigate whether orally exposure to rhodamine B could be changes the expression of Bax, Bcl-2 of the hypothalamic, and also levels of Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) in female rats.MethodsTwenty eight virgin female Wistar rats were divided into four groups, including control group, group exposed to dose of 4.5, 9 and 18 milligram/200 gram body weight (mg/200 g BW) of rhodamine B daily for 36 days. The hypothalamic expressions of Bax and Bcl-2 were examined immunohistochemically. The levels of serum FSH and LH were determined by the enzyme-linked immunosorbent assay (ELISA) technique.ResultsThe level of Bax was significantly higher in the rhodamine B treatment group compred to control group (P<0.05). Out of the 4.5, 9, and 18 mg/200 g BW doses of rhodamine B treatment, only the two highest doses significantly decreased the Bcl-2 levels compared to the control group (P<0.05). The serum FSH and LH levels were significantly lower in all dose's rhodamine B treatment groups compared with the control (P<0.05).ConclusionIn conclusion, rhodamine B increases hypothalamic cell apoptosis and disrupts hormonal balance in rats.     

The role of investigative molecular toxicology in early stage drug development

Molecular toxicology, the application of molecular biology principles and technologies to preclinical safety assessment, represents a key tool for understanding mechanisms of toxicity and assessing the risks associated with specific toxicities. The application of gene expression markers to early stage preclinical safety assessment has the potential to impact pipelines in two main areas: lead optimisation and issue management. Lead optimisation focuses on deprioritising leads with significant, development-limiting toxicological liabilities while advancing those compounds with the greatest chance of successfully navigating the gauntlet of preclinical and clinical safety studies. Issue management utilises mechanistic toxicology studies to position non-development-limiting findings prior to the onset of Good Laboratory Practice studies in full development, and can help to identify and validate gene expression markers predictive of adverse events to avoid issues in second-generation projects. In this review, the authors describe the application of molecular toxicology to a standard pharmaceutical testing funnel, provide examples of the successful application of gene expression markers, and discuss the potential for future impact in several broad categories of clinically relevant toxicity.     

Lessons Learned from the Reimbursement Profile of a Mature Private Medical Toxicology Practice: Office-Based Practice Pays

We previously reported the financial data for the first 5 years of one of the author’s medical toxicology practice. The practice has matured; changes have been made. The practice is increasing its focus on office-based encounters and reducing hospital-based acute care encounters. We report the reimbursement rates and other financial metrics of the current practice. Financial records from October 2009 through September 2013 were reviewed. This is a period of 4 fiscal years and represents the currently available financial data. Charges, payments, and reimbursement rates were recorded according to the type and setting of the medical toxicology encounter: forensic consultations, outpatient clinic encounters, nonpsychiatric inpatient consultations, emergency department (ED) consultations, and inpatient psychiatric consultations. All patients were seen regardless of ability to pay or insurance status. The number of billed Current Procedural Terminology (CPT) codes for office-based encounters increased over the study period; the number of billed CPT codes for inpatient and ED consultations reduced. Office-based encounters demonstrate a higher reimbursement rate and higher payments. In the fiscal year (FY) of 2012, office-based revenue exceeded hospital-based acute care revenue by over $140,000 despite a higher number of billed CPT encounters in acute care settings, and outpatient payments were 2.39 times higher than inpatient, inpatient psychiatry, observation unit, and ED payments combined. The average payment per CPT code was higher for outpatient clinic encounters than inpatient encounters for each fiscal year studied. There was an overall reduction in CPT billing volume between FY 2010 and FY 2013. Despite this, there was an increase in total practice revenue. There was no change in payor mix, practice logistics, or billing/collection service company. In this medical toxicology practice, office-based encounters demonstrate higher reimbursement rates and overall payments compared to inpatient and ED consultations. While consistent with our previous studies, these differences have been accentuated. This study demonstrates the results of changes to the practice—reduced inpatient/ED consultations and increased outpatient encounters. These practice changes resulted in higher overall revenue despite a lower patient volume. In this analysis, the office-based practice of medical toxicology has higher reimbursement rates, nearly 2.5 times higher, when compared to hospital-based acute care consultations.     

The toxicology and immunology of detergent enzymes

Detergent enzymes have a very good safety profile, with almost no capacity to generate adverse acute or chronic responses in humans. The exceptions are the limited ability of some proteases to produce irritating effects at high concentrations, and the intrinsic potential of these bacterial and fungal proteins to act as respiratory sensitizers, demonstrated in humans during the early phase of the industrial use of enzymes during the 1960s and 1970s. How enzymes generate these responses are beginning to become a little clearer, with a developing appreciation of the cell surface mechanism(s) by which the enzymatic activity promotes the T-helper (T_H)-2 cell responses, leading to the generation of IgE. It is a reasonable assumption that the majority of enzyme proteins possess this intrinsic hazard. However, toxicological methods for characterizing further the respiratory sensitization hazard of individual enzymes remains a problematic area, with the consequence that the information feeding into risk assessment/management, although sufficient, is limited. Most of this information was in the past generated in animal models and in vitro immunoassays that assess immunological cross-reactivity. Ultimately, by understanding more fully the mechanisms which drive the IgE response to enzymes, it will be possible to develop better methods for hazard characterization and consequently for risk assessment and management.     

A “good practice” approach to the quality and consistency of morphological examination of the internal head structures of the term rabbit fetus

Variation in the interpretation of the regulatory guidelines has resulted in a diversity of techniques employed to examine the internal structures of the foetal rabbit head.Examination of the foetal rabbit brain, using a single transverse section as the sole technique, is considered not to be sufficiently thorough to be regarded as an adequate examination method. It is not compliant with published EPA and OECD guidelines covering required examination of the internal head structures, nor is it considered to conform to the spirit of the safety assessment required by the ICH guideline.Fixation of approximately half of the heads in each litter to allow the examination of multiple transverse sections enables the major structures within the head to be assessed effectively. This method is compliant with current guidelines, represents “good practice” and should be consistently adopted for the examination of the internal head structures of the term rabbit foetus.     

Fentanyl: A Review for Clinical and Analytical Toxicologists

Fentanyl is a highly potent, short acting synthetic analgesic indicated as a preanesthetic medication. It is available for intravenous injection, as a transdermal patch and a lozenge dosage form. Fentanyl displays a large apparent volume of distribution, short plasma half life and extensive biotransformation. It is a popular drug of abuse among health care professionals. Diversion of pharmaceutical fentanyl preparations, as well as the availability of illicitly synthesized potent and highly toxic fentanyl analogs have resulted in numerous overdose deaths. Analysis of fentanyl and fentanyl analogs requires highly selective and sensitive methodologies. This review is intended as a quick reference source for clinical and analytical toxicologists.     

Mass methanol poisonings in the Czech Republic

Abstract

The article provides detailed information on the case of 2012–2013 Czech mass methanol poisoning caused by the consumption of spirits with methanol added during manufacture. The article compares basic characteristics of methanol and ethanol. It also gives toxicological properties of methanol and describes therapy of methanol afflicted patients with the medicinal product Fomepizole. Having provided an overview of the short-term remedies to the Czech 2012–2013 poisoning problems, the authors suggest long-term measures for prevention of possible future mass poisoning cases like legislative changes and extension of school education with courses on ethanol and methanol effects in human organism.     

Hazards after the storm: Floodwater drainage pump stations and exposure to hydrogen sulfide

A hurricane can present unique hazards that exist long after the strong winds and heavy rains have subsided. These hazards may not only be physical, but chemical as well. Hydrogen sulfide (H₂S) represents an important and potentially overlooked hazard that can be naturally produced in floodwaters following a hurricane. In August of 2012, in the wake of Hurricane Isaac, Plaquemines Parish, Louisiana was submerged under a blanket of floodwater. To remove floodwaters that had breached the levee system designed to keep water out, temporary drainage pump stations were installed at strategic locations. The transfer of floodwaters at these drainage stations resulted in the generation of elevated concentrations of airborne H₂S at the pumping stations. The generation of H₂S at these pumping stations represented a potential inhalation hazard for workers; thus, awareness for possible H₂S exposure at these installments is crucial.     

中药新药毒性与抗癌效应研究

开发有效、低毒的抗癌中药的有效途径为：①采取药效与毒性相结合的研究方法,比较研究原药材、毒性成分（组分）和去毒药材的抗癌效果,建立科学的存效脱毒（减毒）方法。②建立符合中医理论的“抗癌中药癌症毒理实验动物模型”来评价抗癌中药的毒性。③以中医药理论为基础、以疗效为中心,确定抗癌新药的“效_毒”关系、建立与中医理论相适应的动物模型及多种靶点筛选模型,开展抗癌中药新药的疗效及机制研究。     

The toxicological significance of post-mortem drug concentrations in bile

Context: Some authors have proposed that post-mortem drug concentrations in bile are useful in estimating concentrations in blood. Both The International Association of Forensic Toxicologists (TIAFT) and the US Federal Aviation Administration recommend that samples of bile should be obtained in some circumstances. Furthermore, standard toxicological texts compare blood and bile concentrations, implying that concentrations in bile are of forensic value.

Aim: To review the evidence on simultaneous measurements of blood and bile drug concentrations reported in the medical literature.

Methods: We made a systematic search of EMBASE 1980–2016 using the search terms (“bile/” OR “exp drug bile level/concentration/”) AND “drug blood level/concentration/”, PubMed 1975–2017 for (“bile[tw]” OR “biliary[tw]”) AND (“concentration[tw]” OR “concentrations[tw]” OR “level[tw]” OR “levels[tw]”) AND “post-mortem[tw]” and also MEDLINE 1990–2016 for information on drugs whose biliary concentrations were mentioned in standard textbooks. The search was limited to human studies without language restrictions. We also examined recent reviews, indexes of relevant journals and citations in Web of Science and Google Scholar. We calculated the bile:blood concentration ratio. The searches together yielded 1031 titles with abstracts. We scanned titles and abstracts for relevance and retrieved 230, of which 161 were considered further. We excluded 49 papers because: the paper reported only one case (30 references); the data referred only to a metabolite (1); the work was published before 1980 (3); the information concerned only samples taken during life (10); or the paper referred to a toxin or unusual recreational drug (5). The remaining 112 papers provided data for analysis, with at least two observations for each of 58 drugs.

Bile:blood concentration ratios: Median bile:blood concentration ratios varied from 0.18 (range 0.058–0.32) for dextromoramide to 520 (range 0.62–43,000) for buprenorphine. Median bile concentrations exceeded blood concentrations by one order of magnitude for several drugs, including dihydrocodeine, quetiapine and sildenafil; and by two orders of magnitude of for buprenorphine, colchicine and 3,4-methylenedioxy-methamphetamine (MDMA), among others. The minimum and maximum values for the ratio differed by a factor of three or more in three-quarters of the cases where data were available and by a factor of 10 or more for over half of the analytes.

Limitations: The data were difficult to find. Medline does not explicitly index the term “drug bile concentration”. It may well be that other reports exist, although they would not alter our major conclusion. Many of the papers that contributed data failed to specify the source of the blood samples or the post-mortem interval, so that no judgment was possible regarding post-mortem redistribution in whole blood or bile.

Conclusions: For most drugs, there are wide ranges of bile:blood concentration ratios, which means that bile and blood concentrations are generally poorly correlated. Bile concentration measurements cannot readily be used to establish post-mortem blood concentrations; nor can they be extrapolated to ante-mortem concentrations. However, because drug concentrations in bile often exceed those in blood, bile may allow qualitative identification of drugs present, even when the blood concentration is below the limit of detection.