Idiosyncratic drug reactions (IDRs) are unpredictable adverse drug reactions. Their exact mechanisms are unknown but most appear to be immune-mediated. Mechanistic studies require valid animal models, but there are very few available and none for the study of drug-induced agranulocytosis. Thus, the first part of my thesis has focused on the development of an animal model of agranulocytosis. We pursued many attempts to develop one in rabbits, guinea pigs, and rats by treatment with aminopyrine, amodiaquine, and clozapine and manipulating the factors hypothesized to be involved in the mechanism of IDRs such as reactive metabolite formation/detoxication and immune stimulation. Clozapine-induced agranulocytosis is not associated with immune memory, which suggests that it may not be immune-mediated. Therefore, other factors, specifically selenium and vitamin C deficiencies, were assessed as possible risk factors for clozapine-induced agranulocytosis. Despite many attempts, we were not able to develop an animal model of idiosyncratic drug-induced agranulocytosis. The second part of this thesis was focused on investigating the effects of clozapine on neutrophils. It is known that the reactive metabolite of clozapine increases neutrophil apoptosis in vitro; however, it was not clear that the conditions of these experiments reflect in vivo conditions. Therefore, the effect of clozapine on neutrophil kinetics in vivo was examined. We found that clozapine treatment decreased the half-life of circulating neutrophils and increased the rate of release of neutrophils in rabbits. Thus, even though these animals did not develop agranulocytosis clozapine did appear to cause neutrophil damage that was compensated for by an increased production of neutrophils. Failure of the bone marrow to keep up with the increased rate of neutrophil destruction in certain individuals could result in agranulocytosis. Alternatively, damage to neutrophils could lead to an immune response in some patients that results in agranulocytosis. The failure to develop an animal model of drug-induced agranulocytosis despite many attempts using interventions based on the current mechanistic hypotheses suggests that these hypotheses are wrong. However, it is also possible that we are just unable to overcome the default response of immune tolerance; future studies will examine this possibility and the mechanism of clozapine-induced neutrophil damage.

Diss. (sammanfattning) Uppsala : Univ., 2003. / Härtill 5 uppsatser.

Thesis (M.S.)--University of Michigan, 1963.

Thesis (M.S.)--University of Michigan, 1963.

Mitochondrial complex I, a large respiratory enzyme located in the inner mitochondrial membrane, catalyses electron transfer from NADH to ubiquinone while concomitantly translocating protons across the membrane to sustain ATP synthesis. A crucial aspect of the pharmacology of complex I is drug-induced mitochondrial dysfunction, particularly its role in liver toxicity. Complex I inhibition causes an energy deficit and can lead to adverse changes in the status of the mitochondrial [NADH]/[NAD+] pool and increased reactive oxygen species production, causing widespread damage. A library of molecules that are known candidates for causing complex I-driven drug- induced mitochondrial dysfunction was compiled using database and literature searches and then tested with assays on isolated mammalian complex I, mitochondrial membranes and cultured mammalian cells. The results extend the knowledge of complex I-linked drug toxicity and define a proof-of-principle methodology for the investigation of further unknown candidate molecules. Using this methodology, the Screen-Well V2 library from Enzo Life Sciences, containing 786 FDA-approved drugs, was used to investigate the role of complex I-linked drug toxicity on a wider scale. The results show that complex I is targeted by many structurally unrelated pharmacological compounds, but whether catalysis is inhibited in vivo requires drug transport into the mitochondrion, limiting the adverse physiological consequences in most cases tested. Furthermore, three structure-activity relationship studies were carried out on specific classes of complex I inhibitors: rotenoid natural product compounds, a family of pyrazole-based compounds under investigation as anticancer drugs, and variants on the drug Mubritinib. These studies identified structural determinants of binding to complex I and improve our understanding of complex I inhibition.

Since their introduction to the United States in 2008, synthetic cannabinoids became the most widely used recreational drug behind marijuana, then regressed to an estimated prevalence of less than 1%. Contrary to expectations for a drug declining in use, emergency department presentations and acute poisonings related to the use of synthetic cannabinoids are increasing. Alongside this phenomenon, a growing body of literature is beginning to uncover a relationship between psychosis and synthetic cannabinoid use. A current gap in the literature exists surrounding harm prevention methods and targeted intervention strategies for users of synthetic cannabinoids. To date, no known studies have examined individuals with a history of use of these substances and investigated the reasons they decided to discontinue recreational use. The purpose of the current study was to fill this gap in the literature while also further confirming and expanding existing research on the characterization of synthetic substance use, perceived harm of synthetic cannabinoids, and users’ knowledge about synthetic cannabinoids. Cross sectional survey methods in a non-experimental comparative design was utilized with participants recruited through the online crowd sourcing platform Amazon MTurk. Significant motivating factors for both discontinuation and continuation of synthetic cannabinoid use were found including personal experience, accessibility, preference towards other substance, and questions surrounding the source and purity of the synthetic cannabinoids. It was also found that individuals who currently use synthetic cannabinoids have less general knowledge about the substance class when compared to individuals who have discontinued use. These results suggest that psychoeducational campaigning surrounding general knowledge about the substance class as well as information on the physiological effects of synthetic cannabinoids may be an effective harm reduction method.

Drug-induced gene expression profiles are rich information sources that can help to measure the effect of a drug on the transcriptional state of cells. However, the available experimental data only covers a limited set of conditions such as treatment time, dosages, and cell lines. This poses a challenge for neural network models to learn embeddings that can be generalized to new experimental conditions. In this project, we focus on the cell line as the confounder variable and train an Adversarial Neural Network to extract transcriptional effects that are conserved across multiple cell lines, and can thus be more confidently generalized to the biological setting of interest. Additionally, we investigate several methods to test whether our approach can simultaneously learn biologically valid embeddings and deconfound the effect of cell lines on the data distribution

Methotrexate has proven to be effective in treating rheumatoid arthritis (RA), and is believed to be nononcogenic in the low weekly dose typically employed in the patients with RA. We report, however, a patient with RA in whom a rapidly enlarging diffuse large B-cell lymphoma developed in the left upper lung after weekly treatment with methotrexate for 5 years. The patient had a positive serum IgG for Epstein-Barr virus but a negative in situ hybridization of the resected specimen. Methotrexate therapy was discontinued, and the patient elected for clinical observation instead of chemotherapy or radiation therapy. There has been no clinically detectable recurrence of the lymphoproliferative disorder for 2 years. We believe that methotrexate has an oncogenic potential even in low weekly dosing in a subset of patients with RA and latent Epstein-Barr virus infection. The strongest causal link is demonstrated by the persistent tumor remission after stopping treatment with methotrexate.

The aims of the research were to establish whether diphenylhydantoin and phenobarbitone are teratogenic in mice both in vivo and in an in vitro whole embryo culture system, to investigate possible mechanisms of teratogenicity and to examine whether the methods used in this study, may form a basis for developing systems of more extensive drug teratogenicity screening.

No description available.