Receptor antagonism, therapy

In acute overdose, peak serum levels > 100 pg ml may be predictive of arrhythmias and seizures. The use of sustained-release formulations and the presence of pharmacobezors in the gut may make it difficult to determine peak serum levels. Sinus tachycardia is the most common cardiac sign of theophylline toxicity. Ventricular and supraventricular tachycardia, ectopic beats, hypotension, and cardiac arrest may occur. Metabolic acidosis, hypokalemia, hypercalcemia, and hyperglycemia may be seen. Tremulousness and agitation frequently occur. Intractable seizures may occur in severe intoxications, probably secondary to adenosine receptor antagonism in the brain. Onset of seizures is a poor prognostic indicator. Persistent vomiting is commonly seen and may interfere with attempts at therapy. 

Serendipitous ob.servation of beneficial effects of aminoadamantanes in Parkinson s disease patients undergoing antiviral therapy led to the conclusion that these tompound.s may pos.sess dopaminomimetic or possibly cholinoiytic properties. The fact that administration of clinically relevant do.ses of memantine results primarily in NMDA receptor antagonism was discovered only in the late 1980s (Bormann, 1989). 

Using PET, Farde et al. found that D2 receptor occupancy in schizophrenic patients was reduced by 20-67% of the pretreatment levels in those successfully treated with clozapine. It was reduced to 80-90% of original values that occurred with other typical neuroleptics. He concluded that D2 receptor antagonism alone does not explain the efficacy of clozapine therapy. At low doses (125-172 mg/day), clozapine occupied more than 80% of 5-HT 2A receptors. 

Chintala, M., Shimizu, K., Ogawa, M., Yamaguchi, H., Doi, M., and Jensen, P. (2008) Basic and translational research on proteinase-activated receptors antagonism of the proteinase-activated receptor 1 for thrombin, a novel approach to antiplatelet therapy for atherothrombotic disease. Journal of Pharmaceutical Sciences, 108 (4), 433-438. 

Most recently, a phase-I-study defined a dose of 13-ris-retinoic acid that was tolerable in patients after myeloablative therapy, and a phase-III-trial showed that postconsolidation therapy with 13-cis-retinoic acid improved EFS for patients with high-risk neuroblastoma [7]. Preclinical studies in neuroblastoma indicate that ATRA or 13-cw-RA can antagonize cytotoxic chemotherapy and radiation, such that use of 13-cis-RA in neuroblastoma is limited to maintenance after completion of cytotoxic chemotherapy and radiation. It is likely that recurrent disease seen during or after 13-cis-RA therapy in neuroblastoma is due to tumor cell resistance to retinoid-mediated differentiation induction. Studies in neuroblastoma cell lines resistant to 13-cw-RA and ATRA have shown that they can be sensitive, and in some cases collaterally hypersensitive, to the cytotoxic retinoid fenretinide. Here, fenretinide induces tumor cell cytotoxicity rather than differentiation, acts independently from RA receptors, and in initial phase-I-trials has been well tolerated. Clinical trials of fenretinide, alone and in combination with ceramide modulators, are in development. 

Unfortunately although much is known about the pathways and receptors involved in extrapyramidal activity and the mechanism of the EPSs that follow neuroleptic therapy and even the possible origin of negative symptoms in the prefrontal cortex, the precise site of origin and NT involvement in the overriding positive symptoms is less clear. Until that is corrected, permutations of NT antagonisms are likely to multiply with the neuroleptics. 

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