Phase I metabolic profiling of the synthetic cannabinoids THJ-018 and THJ-2201 in human urine in comparison to human liver microsome and cytochrome P450 isoenzyme incubation

International Journal of Legal Medicine - Despite the increasing relevance of synthetic cannabinoids as one of the most important classes within “New Psychoactive Substances”, there is...     

Toxicological findings in suicides – frequency of antidepressant and antipsychotic substances

The role of psychoactive substances in the treatment of mental disorders and the risk of suicide are major public health issues. This cross-sectional study examined the prevalence of antidepressants and antipsychotics detected in toxicological screenings in suicides. Cases from the Institute of Legal Medicine of the Charité-University Medicine Berlin were reviewed over a 4-year-period. All cases (n = 477) with positive toxicology for antidepressants and antipsychotics in blood or organ tissue were included. Frequencies of the detected substances in non-suicide cases (n = 212; male n = 177, 55.2%; female n = 95, 52.5%) and suicide cases (n = 235; male n = 149, 63.4%; female n = 86, 36.6%) were examined. Tricyclic antidepressants (48.1%) were found most frequently in suicides, followed by atypical neuroleptics (37.0%), selective serotonin reuptake inhibitors (28.1%), typical neuroleptics (17.4%), tetracyclic antidepressants (16.2%) and other substances (8.9%). Alcohol was detected in 37.2% of suicides. The leading cause of death was drug poisoning (35.6%) followed by polytrauma (26.8%) and death by hanging (18.5%). A mental disorder (depression, schizophrenia, bipolar disorder, suicidality) was known in 22.9% of suicides. The most common location of death was the person’s own house (63.8%) followed by public places (28.1%) and hospitals (8.1%) The five most common substances in the suicide group were doxepin (20%) citalopram (15.3%), mirtazapine (14.9%), quetiapine (13.6%) and amitriptyline (12.3%). Toxicological findings from cross-sectional studies provide insight into how often certain types of antidepressants and antipsychotics are associated with suicide. A complementary approach is valuable for assessing the risk of suicide during medical treatment because the various available approaches (analysis of suicidal behavior/ideation, toxicity of drugs) each have strengths and limitations.     

Stigma and Knowledge as Determinants of Recommendation and Referral Behavior of General Practitioners and Internists

Background

Despite reported effectiveness, weight loss surgery (WLS) still remains one of the least preferred options for outpatient providers, especially in Germany. The aim of this study was to examine the effect of stigma and knowledge on recommendation of WLS and referral to a surgeon by general practitioners (GPs) and internists.

Method

The sample consists of 201 GPs and internists from Germany. The questionnaire included questions on the perceived effectiveness of WLS, the frequency of recommendations of WLS, and the frequency of referral to WLS. Stigma, as well as knowledge was also assessed in this context. Linear and logistic regression models were conducted. A mediation analysis was carried out within post hoc analysis.

Results

Knowledge (b?=?0.258, p?<?0.001) and stigma towards surgery (b?=??0.129, p?=?0.013) were related to the frequency of recommendation of WLS. Additionally, respondents, who were more likely to express negative attitudes towards WLS, were less likely to recommend WLS and thus refer patients to WLS (b?=??0.107, p?<?0.05). Furthermore, respondents with more expertise on WLS were more likely to recommend and thus refer patients to WLS (b?=?0.026, p?<?0.05).

Conclusion

This study showed that stigma plays a role when it comes to defining treatment pathways for patients with obesity. The question remains how this might influence the patients and their decision regarding their treatment selection. Interventions are required to make treatment decisions by physicians or patients independent of social pressure due to stigma.

     

Analysis of MDR genes expression and cross-resistance in eight drug resistant ovarian cancer cell lines

Ovarian endometriomas affect a substantial proportion of women of reproductive age who may have a potential risk of diminished ovarian reserve (DOR) after ovarian cystectomy. Here, we investigated the risk factors for pre-surgical DOR in patients with ovarian endometriomas and for DOR after laparoscopic ovarian cystectomy for endometriomas and evaluated the feasibility of the pre-surgical prediction of post-surgical DOR based on the Bologna criteria. A total of 143 patients with ovarian endometriomas who underwent laparoscopic cystectomy from January 2009 to May 2015 at our hospital were prospectively enrolled and evaluated. Serum anti-Müllerian hormone (AMH) concentrations were measured pre-surgically and at 3 and 6 months after surgery. In accordance with the Bologna criteria, the patients whose AMH concentrations were <1.1 ng/mL before surgery and 3 or 6 months after surgery were classified into pre- and post-surgical adverse DOR (aDOR) groups, respectively. Thirty-one (21.7 %) of 143 patients were classified as pre-surgical aDOR. Patient age and serum follicle-stimulating hormone level were significantly positively correlated with pre-surgical aDOR [odds ratios (ORs), 1.26 and 1.16; p < 0.001 and p = 0.003, respectively]. Among the remaining 112 patients, 38 patients (33.9 %) had post-surgical aDOR 3 and 6 months after surgery. Bilateral cystectomy was positively correlated with post-surgical aDOR (at 3 months: OR, 4.7; p = 0.001; at 6 months: OR, 3.71; p = 0.006); conversely, pre-surgical serum AMH concentrations were negatively correlated with post-surgical aDOR (at 3 months: OR, 0.65; p = 0.005; at 6 months: OR, 0.43; p < 0.001). The optimal cut-off point of pre-surgical AMH concentrations for predicting aDOR at 3 and 6 months in the patients undergoing unilateral cystectomy was 2.1 ng/mL. In contrast, the optimal cut-off points at 3 and 6 months in the patients undergoing bilateral cystectomy were 3.0 and 3.5 ng/mL, respectively. Our data suggest that the pre-surgical serum AMH concentrations and bilateral cystectomy are significant factors for the risk of aDOR following surgery and that predicting post-surgical aDOR according to the Bologna criteria could be feasible using pre-operative measurements of serum AMH concentrations.     

High‐flow nasal cannula therapy and apnea time in laryngeal surgery

In small children, high‐flow nasal cannula therapy may prolong apnea time even when an inspiratory oxygen fraction below 100% is used. This will be beneficial in prolonged intubation attempts, but especially during procedures requiring prolonged apnea time, leading to fewer airway manipulations and markedly enhanced surgical conditions.     

Detection of Clostridium difficile toxin: comparison of enzyme immunoassay results with results obtained by cytotoxicity assay

Several kinds of laboratory techniques are available to detect Clostridium difficile toxin in fecal samples. Because questions have been raised about the reliability of immunoassays compared to the accepted standard, cytotoxicity assay, we studied three enzyme immunoassays (EIAs) and one rapid EIA, which demonstrated relatively good sensitivities and specificities compared to cytotoxicity assay.     

Mechanisms of toxicity associated with six tyrosine kinase inhibitors in human hepatocyte cell lines

Tyrosine kinase inhibitors have revolutionized the treatment of certain cancers. They are usually well tolerated, but can cause adverse reactions including liver injury. Currently, mechanisms of hepatotoxicity associated with tyrosine kinase inhibitors are only partially clarified. We therefore aimed at investigating the toxicity of regorafenib, sorafenib, ponatinib, crizotinib, dasatinib and pazopanib on HepG2 and partially on HepaRG cells. Regorafenib and sorafenib strongly inhibited oxidative metabolism (measured by the Seahorse‐XF24 analyzer) and glycolysis, decreased the mitochondrial membrane potential and induced apoptosis and/or necrosis of HepG2 cells at concentrations similar to steady‐state plasma concentrations in humans. In HepaRG cells, pretreatment with rifampicin decreased membrane toxicity (measured as adenylate kinase release) and dissipation of adenosine triphosphate stores, indicating that toxicity was associated mainly with the parent drugs. Ponatinib strongly impaired oxidative metabolism but only weakly glycolysis, and induced apoptosis of HepG2 cells at concentrations higher than steady‐state plasma concentrations in humans. Crizotinib and dasatinib did not significantly affect mitochondrial functions and inhibited glycolysis only weakly, but induced apoptosis of HepG2 cells. Pazopanib was associated with a weak increase in mitochondrial reactive oxygen species accumulation and inhibition of glycolysis without being cytotoxic. In conclusion, regorafenib and sorafenib are strong mitochondrial toxicants and inhibitors of glycolysis at clinically relevant concentrations. Ponatinib affects mitochondria and glycolysis at higher concentrations than reached in plasma (but possibly in liver), whereas crizotinib, dasatinib and pazopanib showed no relevant toxicity. Mitochondrial toxicity and inhibition of glycolysis most likely explain hepatotoxicity associated with regorafenib, sorafenib and possibly pazopanib, but not for the other compounds investigated.