Antipsychotic drugs ziprasidone

C. Prakash, A. Kamel, J. Gummerus, K. Wilner, Metabobsm and Excretion of a New Antipsychotic Drug, Ziprasidone, in Humans , Drug Metab. Dispos. 1997,25, 863 - 872. 

Hyperlipidemia associated with antipsychotic drugs has been reviewed (SEDA-29, 64). Haloperidol and the atypical antipsychotic drugs ziprasidone, risperidone, and aripiprazole would be associated with lower risks of hyperlipidemia, whereas chlorpromazine, thioridazine, and the atypical drugs quetiapine, olanzapine, and clozapine would be associated with higher risks. However, severe clozapine-induced hypercholesterolemia and hypertriglyceridemia has been reported in a patient taking clozapine (55). 

The atypical antipsychotic drug ziprasidone (105)(514) was approved for the treatment of schizophrenia in the United States in early 2001. Studies of the biotransformation of this benzoisothiazolederivative reveal that it is extensively metabolized in rats (515,516) and in... 

Prakash, C., Kamel, A., Gummerus, J., and Wilner, K. (1997) Metabolism and excretion of the antipsychotic drug, ziprasidone, in humans. Drug Metab. Dispos. 25, 863-872. 

In the synthesis of an intermediate to the antipsychotic drug ziprasidone, Krapcho conditions produced an unexpected side reaction.31 In trying to decarboxylate compound 53 to produce 54, by-products 55 and 56 were formed instead. Their formation was likely a result of the electron withdrawing substituents on the benzene ring. Although these products were unwanted and not part of the overall synthetic pathway, their formation is an interesting potential application of the Krapcho reaction when applied to compounds with electron withdrawing substituents, and could prove useful. 

A search of Medline, EMBASE and PsycLIT was conducted in August 2000, using the following terms Amisulpride, clozapine, olanzapine, risperidone, sertindole, zotepine, ziprasidone, economics, healthcare, costs. All manufacturers of atypical antipsychotic drugs were contacted in April 2000 and asked to supply primary reference data on their product, and all companies had complied with this request by August 2000. A further manual search was conducted of files and journals kept in the National Centre for Information on Psychotropics at the Maudsley Hospital. Reference sections from all retrieved papers were scrutinized for further relevant references. 

To further illustrate the diversity of hydrolytic opening reactions, we turn our attention to an isothiazole ring as found in the antipsychotic agent ziprasidone (11.129). This drug is subject to various reactions of oxidation and reduction, but also undergoes hydrolytic cleavage of the C=N bond of the isothiazole ring. Evidence for this reaction was afforded by detection of radioactive metabolite 11.130, a sulfonamide, in the urine of patients dosed... 

Gl dysmotility Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Use quetiapine, ziprasidone, risperidone, olanzapine, aripiprazole, and others cautiously in patients at risk for aspiration pneumonia. Hypersensitivity reactions Patients who have demonstrated a hypersensitivity reaction (eg, blood dyscrasias, jaundice) with a phenothiazine should not be re-exposed to any phenothiazine unless the potential benefits of treatment outweigh the possible hazards. 

Schizophrenia - When deciding among the alternative treatments available for schizophrenia, consider ziprasidone s greater capacity to prolong the QT/QTc interval compared with other antipsychotic drugs. 

Until recently, lithium carbonate was the universally preferred treatment for bipolar disorder, especially in the manic phase. With the approval of valproate, aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone for this indication, a smaller percentage of bipolar patients now receive lithium. This trend is reinforced by the slow onset of action of lithium, which has often been supplemented with concurrent use of antipsychotic drugs or potent benzodiazepines in severely manic patients. The overall success rate for achieving remission from the manic phase of bipolar disorder can be as high as 80% but lower among patients who require hospitalization. A similar situation applies to maintenance treatment, which is about 60% effective overall but less in severely ill patients. These considerations have led to increased use of combined treatment in severe cases. After mania is controlled, the antipsychotic drug may be stopped and benzodiazepines and lithium continued as maintenance therapy. 

Ziprasidone is apparently well tolerated, with a limited potential to cause extrapyramidal adverse effects or weight gain (4). Out-patients who partly respond to conventional antipsychotic drugs, risperidone, or olanzapine may have improved control of psychotic symptoms after switching to ziprasidone, according to the results of a reanalysis of 6-week, multicenter, randomized, open, parallel-group studies in patients with schizophrenia who had previously taken conventional antipsychotic drugs (n = 108), olanzapine (n = 104), or risperidone (n = 58) these results have been published in two different journals (5, 6). 

Stimmel GL, Gutierrez MA, Lee V. Ziprasidone an atypical antipsychotic drug for the treatment of schizophrenia. Clin Ther 2002 24(l) 21-37. 

The same group of antipsychotic drugs have been evaluated for their effects on working memory (276,277) in a visual spatial version of the delayed non-matching to position paradigm (278,279). Haloperidol and risperidone exhibit marked inhibitory effects in low doses, whereas considerably higher doses of clozapine, olanzapine, and ziprasidone are required to produce similar effects (276). Sertindole and quetiapine are inactive at the doses tested (276). Long-term treatment reveals a continued memory impairment of memory by haloperidol, the development of tolerance to the effects of clozapine on memory, and continued lack of impairment by sertindole (277). 

Although the term neuroleptic initially encompassed this whole unique syndrome and is still used as a synonym for antipsychotic, it now is used to emphasize the more neurological aspects of the syndrome i.e., the parkinsonian and other extrapyramidal effects). Except for clozapine, arip-iprazole, quetiapine, ziprasidone, and low doses of olanzapine and risperidone, antipsychotic drugs available in the U.S. also have effects on movement and posture and can be called neuroleptic. The more general term antipsychotic is preferable, as reinforced by the growing number of modern atypical antipsychotic drugs with little extrapyramidal action. 

Adverse Neurological Effects Many neurological syndromes, particularly involving the extrapyramidal motor system, occur following the use of most antipsychotic drugs, especially with the high-potency D -receptor antagonists (tricyclic piperazines and butyrophenones). Acute adverse extrapyramidal effects are less likely with aripiprazole, clozapine, quetiapine, thioridazine, and ziprasidone, or low doses of olanzapine or risperidone. 

---