What Is the Clinical Global Impression?

Ziprasidone, a new type of atypical antipsychotic with excellent curative effect, is marketed globally after clozapine, risperidone, olanzapine, and quetiapine The fifth atypical antipsychotic (World Clinic Drugs). It is also the only atypical antipsychotic that has inhibitory effects on NE and 5-HT reuptake. Ziprasidone hydrochloride is used to treat schizophrenia. It has a good effect on acute or chronic, initial or recurrent schizophrenia; it is effective on schizophrenia-related symptoms (including audiovisual hallucinations, delusions, lack of motivation, and social avoidance).

Ziprasidone hydrochloride

Ziprasidone, a new type of atypical antipsychotic with excellent curative effect, is marketed globally after clozapine, risperidone, olanzapine, and quetiapine. The fifth atypical antipsychotic (World Clinic Drugs). It is also the only atypical antipsychotic that has inhibitory effects on NE and 5-HT reuptake. Ziprasidone hydrochloride for treatment

Ziprasidone treatment caused prolonged QTc, which was about 9-14 milliseconds longer than the effect of the four control drugs (risperidone, olanzapine, quetiapine, and haloperidol) on QTc, but shorter than thioridazine 14 milliseconds. Some drugs that can prolong the QT / QTc interval are considered to be twisted with the tip

The following adverse reactions have been reported in foreign clinical trials:

Patients with schizophrenia : Discontinuation rates due to adverse reactions in the ziprasidone and placebo groups were 4.1% (29/702) and 2.2% (6/273), respectively. The main adverse reaction was rash. Seven patients discontinued (1%) due to rash in the ziprasidone group and zero in the placebo group. Common adverse reactions with a incidence greater than 5% in short-term placebo-controlled trials are shown in the table below. Common adverse reactions in schizophrenia patients taking ziprasidone (N = 702) for short periods (4-6 weeks): lethargy: the percentage of patients reporting adverse reactions was 14%, compared to this in the placebo group (N = 273) 7%;

Ziprasidone is an atypical antipsychotic and its structure is different from that of phenothiazine or butyrylbenzene. In vitro studies show that ziprasidone has a high affinity for dopamine D2, D3, serotonin 5HT2A, 5HT2C, 5HT1A, 5HT1D, 1-adrenergic receptors, and moderate affinity for histamine H1 receptors, including No other receptors / binding sites, including M cholinergic receptors, showed affinity. Ziprasidone has antagonistic effects on dopamine D2, 5HT2A, and 5HT1D receptors, and has an agonistic effect on 5HT1A receptors. Ziprasidone inhibits the reuptake of serotonin and norepinephrine by synapses. Consistent with other anti-schizophrenia drugs, the mechanism of action of ziprasidone is unclear. Studies have suggested that its anti-schizophrenic effect may be exerted by antagonism of the dopamine D2 and 5HT2 receptors, and antagonism of other similar affinity receptors may be the cause of other therapeutic effects and side effects. Antagonism to the H1 receptor may be the cause of drowsiness with ziprasidone, and antagonism to the 1-adrenergic receptor may be the cause of orthostatic hypotension. Before clinical trials abroad, the following studies were performed on this product: 3 short-term (4 and 6-week studies) and 1 long-term (52-week studies) controlled study evaluated ziprasidone treatment for DSM-III-R schizophrenia Of inpatients with diagnostic criteria for autism or schizoaffective disorder. Several assessment tools were used in these studies to assess psychotic symptoms and signs, including the Concise Mental Illness Rating Scale (BPRS) and Positive and Negative Symptom Rating Scale ( PANSS), these two scales include a number of psychopsychological items, often used in studies to evaluate the efficacy of drugs in the treatment of mental illness. Another traditional assessment tool is the Clinical Global Impressions Scale (CGI), which reflects the overall clinical status of patients with experienced assessors who are very familiar with the symptoms of schizophrenia. In addition, in some clinical studies, the Negative Symptom Scale (SANS) and the Montgomery Depression Scale (MADRS) have been used. In this 52-week placebo-controlled maintenance treatment study (N = 294), ziprasidone doses of 20, 40, and 80 mg bid were significantly better at preventing disease recurrence than placebo, total BPRS scores, and mental health. Symptom factor scores, CGI, PANSS total scores, and negative symptom scores, as well as overall impression scale scores due to social functioning, were significantly better than placebo. The proportion of ziprasidone and placebo treatment discontinued due to adverse reactions was 7-10%, compared with 15% in the placebo group. Two multicenter, placebo-controlled studies evaluated ziprasidone in patients with acute schizophrenia with clinically significant depressive symptoms (MADRS (greater than or equal to) 14), treated with ziprasidone Depressive symptoms improved significantly in one study. In one study, ziprasidone dose was 60 mg twice daily; in another study, ziprasidone dose was 80 mg twice daily; MADRS score versus placebo Compared with the group, the difference in curative effect was statistically significant (p <0.05).

Ziprasidone should not be used in combination with drugs that extend the QT interval. Ziprasidone mainly acts on the central nervous system, and should be used with caution in combination with other drugs that act on the central nervous system. Ziprasidone may induce hypotension and therefore may enhance the efficacy of certain antihypertensive drugs. Ziprasidone may antagonize the effects of L-dopamine and dopamine agonists. The effects of other drugs aligning rapamidone: carbamazepine: carbamazepine is a CYP 3A4 inducer, taking 200 mg carbamazepine twice a day for 21 consecutive days, the AUC of ziprasidone was reduced by about 35%. The higher the carbamazepine dose, the more the AUC of ziprasidone decreased. Ketoconazole: Ketoconazole is a potent CYP3A4 inhibitor. Patients take 400mg of ketoconazole daily for 5 consecutive days. The AUC and Cmax of ziprasidone increase by about 35-40%. Other CYP 3A4 inhibitors have similar effects. Cimetidine: 800 mg of cimetidine, once daily for 2 days, has no effect on the pharmacokinetics of ziprasidone. Antacids: 30 mL antacids combined with rapacidone have no effect on pharmacokinetics. In addition, in a controlled clinical trial, a population pharmacokinetic analysis of patients with schizophrenia showed that pharmacokinetics of ziprasidone in combination with benztropine, propranolol, and lauracillo There was no significant change in kinetics. Effects of ziprasidone on other drugs: In vitro tests have shown that ziprasidone does not interfere with its metabolism when combined with drugs that are primarily cleared by CYP 1A2, CYP 2C9, CYP 2C19, CYP 2D6, and CYP 3A4. There are few interactions between ziprasidone and other drugs due to displacement. Lithium: Ziprasidone (40 mg bid), combined with lithium (450 mg bid) for 7 days, will not affect the steady-state plasma concentration or renal clearance of lithium. Oral contraceptives: The combination of ziprasidone (20 mg bid) with the oral contraceptives ethinylestradiol (0.03 mg) and levonorgestrel (0.15 mg) will not affect the pharmacokinetics of these two oral contraceptives . Dextromethorphan: Consistent with the results of in vitro tests, a study conducted in healthy volunteers showed that ziprasidone does not change the process of the metabolism of dextromethorphan, the substrate of CYP 2D6, to its main metabolite, dexorphane . There was no significant change in the dextromethorphan / dextrin ratio in urine.

The pharmacological activity of ziprasidone mainly comes from the original drug. After oral administration of ziprasidone hydrochloride, it is well absorbed through the gastrointestinal tract and widely distributed. Peak plasma concentrations are reached in 6-8 hours, steady-state blood concentrations are reached in 1-3 days, and the plasma protein binding rate is greater than 99%. The apparent volume of distribution is 1.5 L / kg, the absolute bioavailability of 20 mg of the drug taken at meals is about 60%, and food can increase the absorption of the product about 2 times. Within the recommended clinical dose range, ziprasidone has an average terminal half-life (T?) Of approximately 7 hours and an average apparent systemic clearance of 7.5 mL / min / kg. The plasma protein binding rate is greater than 99%. After oral ziprasidone is mainly metabolized by the liver, only a small amount of the original drug is excreted in urine (<1%) and feces (<4%). Ziprasidone is eliminated by three metabolic pathways, resulting in four major circulating metabolites: benzoisothiazole (BITP) sulfoxide, BITP-sulfone, ziprasidone sulfoxide, and S-methyl-dihydroazide Laxone. Drugs excreted in the urine and feces are approximately 20% and 66%, respectively, and protoform ziprasidone in the serum is approximately 44%. In vitro studies on human hepatocyte components show that S-methyl-dihydrozirasidone is produced in two steps. In vitro studies on human liver microsomes and recombinant enzymes showed that the CYP enzyme of oxidative metabolism ziprasidone is mainly CYP 3A4, and the effect of CYP 1A2 is weak. In vivo secretion and metabolism data show that less than 1/3 of ziprasidone is eliminated by cytochrome P450 oxidation metabolism, and about 2/3 of ziprasidone is eliminated by aldehyde oxidase metabolism. The clinical significance of aldehyde oxidase inhibitors or agonists is unknown. Age, gender, and ethnicity have no effect on the pharmacokinetics of rapacetone and do not require dose adjustment. Smoking: In vitro studies on human hepatocyte enzymes have shown that ziprasidone is not a substrate for the CYP 1A2 enzyme and smoking should have no effect on the pharmacokinetics of ziprasidone. The results of the population pharmacokinetic study were consistent with the results of the in vitro study. The population pharmacokinetic study showed that smoking and non-smokers had no effect on the pharmacokinetics of rapacidone. Kidney injury: Ziprasidone has a high metabolic rate, and the protodrug secreted by the kidney is less than 1%. The kidney pharmacokinetics of ziprasidone alone have no significant effect. There is no need to adjust the dosage according to the degree of renal function damage. Liver injury: Ziprasidone is mainly cleared by the liver, and liver damage can lead to increased AUC of ziprasidone. Multi-dose (20 mg, 2 times daily for 5 consecutive days) studies of 13 Childs-Pugh type A and B necrotizing hepatitis subjects showed that Childs-Pugh type A and B subjects were related to phase Compared with matched controls (n = 14), AUC0-12 increased by 13% and 34%, respectively. The half-life of patients with liver damage was 7.1 hours, compared with 4.8 hours for controls. Toxicological studies conducted in dogs showed that intrahepatic cholestasis, elevated serum ALT, and alkaline phosphatase occurred when oral medication was administered at a dose that was twice the maximum clinical exposure (plasma AUC). Experience with ziprasidone in patients with severe liver dysfunction is inadequate, so ziprasidone should be used with caution in this group of patients.

Genotoxicity: In the Ames test, ziprasidone can increase the rate of back mutation of a Salmonella typhimurium strain without metabolic activation. The mouse lymphoma cell gene mutation test and human lymphocyte chromosome aberration test result were positive, and the mouse micronucleus test result was negative. Reproductive toxicity: SD rats can see mating time prolonged when the ziprasidone dose is 10-160 mg / kg / day (calculated as mg / m2, which is equivalent to 0.5-8 times the maximum recommended human dose of 200 mg / day). Fertility decreased at a dose of 160 mg / kg / day and no effect on fertility was seen at a dose of 40 mg / kg / day. Male rats did not see reduced fertility after mating with unadministered female rats at a dose of 160 mg / kg / day, so ziprasidone may only affect fertility in female rats. In a 6-month rat test, the dose was 200 mg / kg (calculated as mg / m2, which is equivalent to 10 times the maximum recommended human dose of 200 mg / day), and there was no effect on the testes. . Zirasidone was administered at a dose of 10-160 mg / kg / day during teratogenicity in rats. Fetal weight loss and delayed bone ossification were seen, but no deformity was seen. The dose was 5 mg / kg / day with no effect on development. Maternal toxicity is seen at doses of 40 and 160 mg / kg. Administration of ziprasidone 30 mg / kg / day in rabbits during the teratogenic allergy period (calculated as mg / m2, which is equivalent to 3 times the maximum recommended human dose of 200 mg / day) shows an increase in the incidence of fetal structural abnormalities, which has no effect on development The dose was 10 mg / kg / day. Rats were given ziprasidone 10 mg / kg / day (calculated as mg / m2, equivalent to 0.5 times the maximum human recommended dose of 200 mg / day) or higher during perinatal period, and the number of stillbirths increased. The number of surviving animals decreases. At a dose of 5 mg / kg / day (calculated as mg / m2, which is equivalent to 0.2 times the maximum recommended human dose of 200 mg / day), it can be seen that the offspring have delayed development and impaired neurobehavioral function. Carcinogenicity: Long-Evans rats and CD-1 mice were administered ziprasidone at 2, 6, 12 mg / kg / day or 50, 100, 200 mg / kg / day (calculated as mg / m2, (Equivalent to 0.1-0.6 times and 1-5 times the maximum recommended human dose of 200 mg / day, respectively) for 24 consecutive months. Compared with the control group, no increase in tumor incidence was observed in rats and male mice. In female mice, the incidence of pituitary adenoma, pituitary cancer, and breast cancer increased in a dose-dependent manner. Pituitary and mammary hyperplasia can be seen in rodents given other antipsychotic drugs over time, and they are thought to be prolactin-mediated. Mice were given ziprasidone at a dose of 100, 200 mg / kg / day for 1 month, and the serum prolactin levels of female mice were increased, while male mice had no effect. No changes in prolactin were observed when ziprasidone was administered by the rat admixture method. The relevance of prolactin-mediated endocrine tumors in rodents to human drug use risk is unknown.

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