SEARCH · PubMed Health

Results for “clozapine”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources

PubMed2025

The time has come for revising the rules of clozapine blood monitoring in Europe. A joint expert statement from the European Clozapine Task Force.

The European Clozapine Task Force is a group of psychiatrists and pharmacologists practicing in 18 countries under European Medicines Agency (EMA) regulation, who are deeply concerned about the underuse of clozapine in European countries. Although clozapine is the most effective antipsychotic for people with treatment-resistant schizophrenia, a large proportion of them do not have access to this treatment. Concerns about clozapine-induced agranulocytosis and stringent blood monitoring rules are major barriers to clozapine prescribing and use. There is a growing body of evidence that the incidence of clozapine-induced agranulocytosis is very low after the first year of treatment. Maintaining lifelong monthly blood monitoring after this period contributes to unjustified discontinuation of clozapine. We leverage recent and replicated evidence on the long-term safety of clozapine to call for the revision and updating of the EMA's blood monitoring rules, thus aiming to overcome this major barrier to clozapine prescribing and use. We believe the time has come for relaxing the rules without increasing the risks for people using clozapine in Europe.

Clozapine↗

PubMed1992

Serotonergic drugs do not substitute for clozapine in clozapine-trained rats in a two-lever drug discrimination procedure.

The atypical neuroleptic clozapine has been shown to have cue properties in two-lever drug discrimination procedures. Although it has been demonstrated that clozapine acts at several types of receptors in vitro and in vivo, including dopamine, serotonin [5-hydroxytryptamine (5-HT)], and acetylcholine receptors, the mechanism of action for its discriminative stimulus properties has not yet been determined. The present study examined the effects of haloperidol (D2 dopamine antagonist), ritanserin (5-HT2 antagonist), 1-alpha H,3-alpha,5-alpha H-tropan-3yl-3,5-dichlorobenzoate (MDL 72222) (5-HT3 antagonist), and buspirone (5-HT1A agonist) in stimulus substitution tests with rats trained to discriminate clozapine (5.0 mg/kg, IP) from vehicle in a two-lever drug discrimination procedure under a fixed ratio 30 schedule of food reinforcement. Analysis of the results revealed that, while clozapine produced dose-dependent responding on the clozapine lever, haloperidol and the three serotonin drugs failed to produce full substitution for clozapine at any of the doses tested. These results suggest that the discriminative stimulus properties are not mediated by D2 dopamine receptor blockade, antagonism at 5-HT2 or 5-HT3 receptors, or agonistic activity at 5-HT1A receptors. The neural basis of clozapine's discriminative stimulus properties has not yet been determined.

Animals↗

PubMed1992

Metabolism of clozapine by neutrophils. Possible implications for clozapine-induced agranulocytosis.

Many types of adverse drug reactions appear to involve reactive metabolites which, by their very nature, usually have short biological half-lives. Therefore, reactive metabolites formed by neutrophils, or neutrophil precursors in the bone marrow, would seem more likely to be responsible for drug-induced agranulocytosis than metabolites formed in the liver. We have found that several drugs associated with a relatively high incidence of drug-induced agranulocytosis are metabolised by activated neutrophils to chemically reactive metabolites. In preliminary experiments with clozapine, we found that clozapine was metabolised by neutrophils. It also reacted with hypochlorous acid, the principal oxidant generated by neutrophils, to form a reactive intermediate. This intermediate has a half-life of 1 minute in buffer, but reacts very rapidly with glutathione. We believe that this intermediate is a nitrenium ion. Such a metabolite could be responsible for clozapine-induced agranulocytosis, either by direct toxicity or through an immune-mediated mechanism.

Agranulocytosis↗

PubMed1992

Clinical and biologic response to clozapine in patients with schizophrenia. Crossover comparison with fluphenazine.

Twenty-one patients with schizophrenia who met criteria for neuroleptic treatment resistance or intolerance participated in a crossover, placebo-controlled, double-blind comparison of long-term typical neuroleptic and clozapine treatment. Clozapine significantly reduced total as well as positive and negative symptoms in comparison with both fluphenazine and placebo. Of the 21 patients, eight (38%) showed clozapine superiority on the basis of prospective response criteria. High levels of extrapyramidal side effects during fluphenazine treatment and later onset of illness were clinical predictors of clozapine superiority. Clozapine and fluphenazine equally reduced plasma homovanillic acid levels in comparison with placebo, although fluphenazine but not clozapine increased plasma prolactin level. A striking biologic difference between clozapine and fluphenazine was clozapine's enhancement of indexes of noradrenergic activity. Superior clozapine response was predicted by low ratios of cerebrospinal fluid homovanillic acid to 5-hydroxyindoleacetic acid, consistent with the notion that balance between dopaminergic and serotoninergic systems is important for clozapine's mechanism of action.

Adult↗

PubMed1992

Clozapine treatment of psychosis in Parkinson's disease: a report of five consecutive cases.

BACKGROUND: Clozapine has gained acceptance as an antipsychotic in treatment-resistant schizophrenia. Its low propensity to induce extrapyramidal side effects makes clozapine an attractive treatment for patients with Parkinson's disease and dopaminomimetic psychosis. Recent evidence demonstrates that Parkinson's patients are exquisitely sensitive to both the antipsychotic and the potential extrapyramidal effects of clozapine. The uncontrolled studies suggest that low-dose clozapine may be efficacious in this population. The dose range, side effect profiles, and length of treatment varied in these reports. METHOD: We report our experience with five patients with Parkinson's disease and psychosis who were treated with clozapine in an open trial. RESULTS: Three patients were successfully treated with clozapine (25-100 mg/day, mean = 66.7 mg) without worsening their parkinsonism. Adverse effects unrelated to the motor disability required discontinuation of clozapine in the other two patients. At 1- to 2-year follow-up, each patient had required increased dosages of clozapine (75-150 mg/day, mean = 125 mg) for continued management of their psychosis and parkinsonism. The higher dose range was well tolerated. CONCLUSION: These results suggest that clozapine may effectively treat psychosis in Parkinson's disease.

Aged↗

PubMed1992

The discriminative stimulus effects of clozapine in pigeons: involvement of 5-hydroxytryptamine1C and 5-hydroxytryptamine2 receptors.

Pigeons were trained to discriminate i.m. injections of the atypical antipsychotic clozapine (1.0 mg/kg) from saline in a two-key operant procedure. In substitution tests, compounds that shared antagonistic action at 5-hydroxytryptamine (5-HT)1C and 5-HT2 receptors produced discriminative stimulus effects similar to clozapine: cyproheptadine, metergoline, mianserin, pizotifen and fluperlapine. 5-HT antagonists selective for 5-HT2 vs. 5-HT1C receptors (e.g., ketanserin, pirenperone, risperidone and methiothepin) failed to produce substantial clozapine-appropriate responding. Other serotonergic compounds failed to produce substantial clozapine-appropriate responding: the 5-HT3 antagonist, ondansetron; the 5-HT1A agonists, (+-)-8-hydroxy-2-(di-n-propylamino)tetralin and BMY 14802; the 5-HT1A/1B agonist, RU24969; the 5-HT1A partial agonist, NAN190; the 5-HT1C/2 antagonist, mesulergine; the 5-HT1 agonist, I-5-hydroxytryptophane; and the 5-HT1C/2 agonist, quipazine. Other reference compounds such as the typical antipsychotics, chlorpromazine and thioridazine; the selective dopamine D-2 antagonists, droperidol and sulpiride; the dopamine D-1 antagonist, SCH 23390; the antimuscarinics, atropine and scopolamine; the antihistamines, pyrilamine and diphenhydramine; the alpha-1 antagonist, prazosin; and the antidepressants, imipramine and chloromipramine also failed to produce clozapine-appropriate responding. Promethazine, cinanserin and amitriptyline produced only partial generalization to the clozapine cue. The results suggest that blockade of both 5-HT2 and/or 5-HT1C receptors is important in the pharmacological mediation of the discriminative stimulus effects of clozapine. Blockade of 5-HT2 receptors appears not to be sufficient to produce clozapine-like discriminative stimulus effects. The precise role of 5-HT1C receptors in the clozapine discriminative stimulus is unclear due to the lack of compounds selective for this receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1978

Clozapine concentrations in brain regions: relationship to dopamine metabolite increase.

Levels of clozapine in rat striatum and tuberculum olfactorium were quantitated by a gas chromatographic technique. The relationship of the increase in 3,4-dihydroxyphenylacetic acid (DOPAC) in these regions produced by clozapine to the concentration of clozapine was explored. One hour after 10, 20 or 40 mg/kg clozapine i.p. the concentration of drug increased in proportion to the dose and at each dose was similar in striatum and T.O. The percent increase in DOPAC in both areas was related to the clozapine concentration in a typical dose--response manner and was greater in the striatum than the T.O. A relatively high concentration of clozapine (40 micron) was required to produce a half-maximal elevation of DOPAC. Striatal clozapine levels were similar in acutely and chronically treated animals. The concentrations of clozapine in striatum and T.O. reflect the dose injected and do not account for its atypical properties.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1992

Neuroleptics increase c-fos expression in the forebrain: contrasting effects of haloperidol and clozapine.

The mechanisms by which the atypical neuroleptic clozapine produces its therapeutic effects in the treatment of schizophrenia without causing the extrapyramidal side effects that are characteristic of most antipsychotic drugs remain unclear. Recently, a single injection of the typical antipsychotic haloperidol has been shown to increase c-fos expression in the striatum [Dragunow et al. (1990) Neuroscience 37, 287-294]. C-fos is a proto-oncogene that encodes a 55,000 mol. wt phosphoprotein, Fos, which is thought to assist in the regulation of "target genes" containing an AP-1 binding site. Because a wide variety of physiological and pharmacological stimuli increase c-fos expression, it has been proposed that Fos immunohistochemistry might be useful in mapping functional pathways in the central nervous system. The present experiments examined some potential neuroanatomical differences in the actions of clozapine and haloperidol by comparing their effects on c-fos expression in the medial prefrontal cortex, nucleus accumbens, striatum and lateral septum. The effects of the selective dopamine receptor antagonists SCH 23390 (D1) and raclopride (D2) were also examined. Haloperidol (0.5, 1 mg/kg) and raclopride (1, 2 mg/kg) produced large increases in the number of Fos-containing neurons in the striatum and nucleus accumbens. SCH 23390 (0.5, 1 mg/kg) reduced the number of Fos-positive neurons in the nucleus accumbens and striatum, and had no effect in the other regions. Neither haloperidol nor raclopride increased the number of Fos-positive neurons in the medial prefrontal cortex. Haloperidol, but not raclopride, produced a modest increase in c-fos expression in the lateral septal nucleus. Clozapine (10, 20 mg/kg) was without effect in the striatum; however, it significantly increased the number of Fos-positive neurons in the nucleus accumbens, medial prefrontal cortex and lateral septal nucleus. Destruction of mesotelencephalic dopaminergic neurons with 6-hydroxydopamine abolished the increase in Fos expression in the nucleus accumbens and striatum produced by haloperidol and raclopride, and also blocked the clozapine-induced increase in the nucleus accumbens. However, the inductive effects of clozapine and haloperidol on c-fos expression in the lateral septal nucleus and of clozapine in the medial prefrontal cortex were not affected by the 6-hydroxydopamine lesions. These results suggest that clozapine's unique therapeutic profile may be related to its failure to induce Fos in the striatum as well as its idiosyncratic actions in the lateral septum and medial prefrontal cortex. The effects of clozapine in these latter regions do not appear to be mediated by dopaminergic mechanisms.

Animals↗

PubMed1992

[A new therapeutic approach tp drug-resistant schizophrenia: clozapine. Long-term prospective study in 16 patients].

Clozapine, a dibenzodiazepine derivative, has potent antipsychotic activity; but bone marrow suppression resulting in agranulocytosis has been associated with clozapine treatment and has restricted the administration of this drug to treatment-resistant schizophrenic patients. This report describes preliminary results of an open prospective study of the effects of clozapine on symptomatology and social function in 16 treatment-resistant schizophrenic patients. Authors prospectively followed up for 18 months 16 DSM III-R schizophrenic patients who had failed to respond to various neuroleptics (n: 7.2 +/- 2.8); when clozapine treatment was initiated, the mean duration of the illness was 14.2 (+/- 6.7) years. Total BPRS, BPRS "positive" and "negative" symptoms scores were used for evaluation. Social integration and side effects were also studied. 14 of 16 patients are still receiving clozapine; 1 out of 14 patients has a more than 60% decrease in total BPRS, 11 out of 14 have 30 to 60% decrease in total BPRS and 2 out of 14 have less than 30% decrease in total BPRS. Improvements in both total and positive symptoms BPRS scores were observed within the first month of treatment (p < 0.001); improvement in negative symptoms was noted within the third month (p < 0.02). At the end of the follow up period, 43% of patients showed marked improvement in family life and 21% found a job during the study. Beyond noteworthy improvement of clinical symptoms in these patients who presented with severe schizophrenia, clozapine also significantly reduced the use of concomitant medication. Side effects are studied but none required treatment disruption; neurological side effects were less reported than with usual neuroleptics. It is concluded that clozapine offers particular benefits for some treatment-resistant schizophrenic patients; however the increased comparative risk requires a restricted use of clozapine to selected patients.

Adult↗

PubMed1979

Effects of clozapine on the activity of central dopaminergic and noradrenergic neurons.

The effects of clozapine on the spontaneous firing rate of noradrenergic (NE, locus coeruleus), dopaminergic (DA, zona compacta, ventral tegmental area) and non-dopaminergic (zona reticulata) neurons was studied in chloral hydrate anesthetized rats. Clozapine administered intraperitoneally significantly increased the spontaneous activity of NE and DA neurons. After a cumulative dose of 8 mg/kg clozapine, the increase of mean firing rate per min of zona compacta and ventral tegmental area neurons attained almost similar values. Amphetamine reversed the clozapine-induced stimulation of NE and DA neurons. Zona reticulata neurons were depressed by clozapine. Neither amphetamine nor physostigmine were effective in antagonizing the inhibition. Our results suggest that clozapine blocks central NE and DA receptors. Furthermore, they fail to reveal a smaller sensitivity of the striatum as compared to the limbic system to the effects of clozapine.

Amphetamine↗

PubMed1992

Determination of clozapine and its major metabolites in human serum using automated solid-phase extraction and subsequent isocratic high-performance liquid chromatography with ultraviolet detection.

An isocratic high-performance liquid chromatographic (HPLC) method with ultraviolet detection is described for the quantification of the atypical neuroleptic clozapine and its major metabolites, N-desmethylclozapine and clozapine N-oxide, in human serum or plasma. The method included automated solid-phase extraction on C18 reversed-phase material. Clozapine and its metabolites were separated by HPLC on a C18 ODS Hypersil analytical column (5 microns particle size; 250 mm x 4.6 mm I.D.) using an acetonitrile-water (40:60, v/v) eluent buffered with 0.4% (v/v) N,N,N',N'-tetramethylethylenediamine and acetic acid to pH 6.5. Imipramine served as internal standard. After extraction of 1 ml of serum or plasma, as little as 5 ng/ml of clozapine and 10 or 20 ng/ml of the metabolites were detectable. Linearity was found for drug concentrations between 5 and 2000 ng/ml as indicated by correlation coefficients of 0.998 to 0.985. The intra- and inter-assay coefficients of variation ranged between 1 and 20%. Interferences with other psychotropic drugs such as benzodiazepines, antidepressants or neuroleptics were negligible. In all samples, collected from schizophrenic patients who had been treated with daily oral doses of 75-400 mg of clozapine, the drug and its major metabolite, N-desmethylclozapine, could be detected, while the concentrations of clozapine N-oxide were below 20 ng/ml in three of sixteen patients. Using the method described here, data regarding relations between therapeutic or toxic effects and drug blood levels or metabolism may be collected in clinical practice to improve the therapeutic efficacy of clozapine drug treatment.

Chromatography, High Pressure Liquid↗

PubMed1976

In vivo actions of clozapine and haloperidol on the turnover rate of acetylcholine in rat striatum.

We have measured acetylcholine (ACh) content and turnover rate (TRACh) in striatum and cortex of rats receiving haloperidol and clozapine i.p. Both clozapine (30 mumol/kg) and haloperidol (10 mumol/kg) reverse the decrease in striatal TRACh elicited by apomorphine (11 mumol/kg) while each antipsychotic affects the steady state and the TRACh in striatum differently. Haloperidol fails to change striatal ACh content but increases the TRACh; chozapine (15 and 30 mumol/kg) neither decreases the content of ACh nor changes the TRACh in striatum. Moreover, 60 or 90 mumol/kg of clozapine causes a 40% decrease in ACh content without affecting the TRACh. Clozapine, but not haloperidol, antagonizes the increase in ACh content and the decrease in TRACh elicited by arecoline (64 mumol/kg) and oxotremorine (9 mumol/kg) in striatum. Clozapine resembles trihexylphenidyl (14 mumol/kg) and benztropine (12 mumol/kg) because it decreases the ACh content of striatum without changing the TRACh. Moreover, clozapine and benztropine reverse the increase in striatal TRACh elicited by haloperidol. The increase in striatal TRACh elicited by haloperidol could be of value to explain the extrapyramidal action of this drug. The anticholinergic action of clozapine could explain the absence of extrapyramidal side effects observed with this drug.

Animals↗

PubMed1992

Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine. Relation to extrapyramidal side effects.

Positron emission tomography and selective radioligands were used to determine D1 and D2 dopamine receptor occupancy induced by neuroleptics in the basal ganglia of drug-treated schizophrenic patients. In 22 patients treated with conventional dosages of classical neuroleptics, the D2 occupancy was 70% to 89%. Patients with acute extrapyramidal syndromes had a higher D2 occupancy than those without side effects. This finding indicates that neuroleptic-induced extrapyramidal syndromes are related to the degree of central D2 occupancy induced in the basal ganglia. In five patients treated with clozapine, the prototype atypical antipsychotic drug, a lower D2 occupancy of 38% to 63% was found. This finding demonstrates that clozapine is also "atypical" with respect to the central D2 occupancy in patients. During treatment with clozapine, there is a low frequency of extrapyramidal syndromes, which accordingly may reflect the comparatively low D2 occupancy induced by clinical doses of clozapine. Classical neuroleptics, like haloperidol or sulpiride, did not cause any evident D1 occupancy, but the thioxanthene flupentixol induced a 36% to 44% occupancy. In four patients treated with clozapine, the D1 occupancy was 38% to 52%. The D1 occupancy induced by clozapine and flupentixol may contribute to the antipsychotic effect of these drugs.

Adolescent↗

PubMed1976

Effect of clozapine on the metabolism of serotonin in rat brain.

Clozapine, but not chlorpromazine, haloperidol, thioridazine, or loxapine, increases the concentrations of tryptophan, serotonin, and 5-hydroxyindoleacetic acid in the brain of the rat. This effect of clozapine is due to an increased serotonin synthesis as demonstrated by an enhanced accumulation of 3H-serotonin in the brain after i.v. infusion of 3H-tryptophan. Clozapine also elevates the plasma concentration of free tryptophan, and reduces the plasma concentration of total tryptophan. Therefore, clozapine may increase the brain serotonin concentration by enhancing the availability of tryptophan in the brain, thereby promoting serotonin synthesis. Measurement of the rate of disappearance from the brain of 3H-serotonin or of endogenous serotonin after synthesis inhibition with 6-fluorotryptophan shows that clozapine has no direct effect on the release and degradation of serotonin. The effect of clozapine on brain serotonergic systems may possibly be related to the pronounced sedative and sleep-inducing properties of this drug.

Animals↗

PubMed1978

A psychophysiological investigation of the long-term effects of clozapine upon sleep patterns of normal young adults.

A 25-night single-blind cross over design was employed to determine the long-term effects of clozapine on the sleep patterns of six normal young adults. Subjects received 12.50 mg placebo on the first and last five nights, whereas on the intermediate 15 nights 12.5 mg clozapine was administered. The subjects slept in the laboratory on the third and fourth nights to obtain baseline recordings, and on the eight, twelfth, sixteenth, and twentieth nights to determine the effects of clozapine on sleep variables. Recordings on nights 21 and 25 were used to assess withdrawal effects. Percentage stage 1 sleep and indices of body movements during sleep were significantly reduced, suggesting that clozapine may have sleep-inducing properties. There were no significant rebound of stage REM sleep during drug withdrawal despite a small but significant reduction in stage REM during drug administration. Numerous side effects, indicative of sleepiness, were reported on the mornings following drug administration, and there was evidence of a rapid tolerance to clozapine. These findings may limit the efficacy of clozapine as an hypnotic agent over an extended period of time. Further research on insomniac subjects is therefore indicated.

Adult↗

PubMed2026

Effect of atenolol versus ivabradine on heart rate variability in patients of schizophrenia with clozapine-induced tachycardia: a randomized controlled trial.

BACKGROUND: A third of schizophrenia cases are resistant to antipsychotics, where clozapine is the only FDA-approved medication. Clozapine use is often limited by intolerable adverse effects. Persistent tachycardia occurs in approximately 25-54% patients receiving clozapine. Heart rate variability (HRV) is a non-invasive, clinically relevant marker of autonomic nervous system functioning. Atenolol and Ivabradine are usually prescribed for clozapine-induced tachycardia (CIT), although evidence guiding their optimal use remains limited. AIM: This study aimed to compare the effects of atenolol versus ivabradine on HRV in patients with treatment-resistant schizophrenia (TRS) receiving clozapine. METHODS: This open-label randomised clinical trial, conducted at a tertiary-care center over 20 months, involved TRS patients on clozapine for more than three months and having persistent tachycardia. Twenty patients received atenolol 25mg once-daily, while twenty received ivabradine 5mg twice-daily for two months. The primary outcome was the change in the frequency domain of HRV, while the secondary outcomes were time-domains, central and peripheral blood pressure, pulse rate and treatment-emergent adverse events (TEAE). RESULTS: While both drugs significantly reduced pulse-rates (atenolol: -20.56±13.00, p<0.001; ivabradine: -21.855±12.873, p<0.001). Within-group analysis showed that, the atenolol group had significant improvements in high-frequency [HF] power (p=0.048) and LF/HF ratio (p=0.044), along with a non-significant trend towards increased total power (p=0.053); no significant within-group changes were observed in the ivabradine group. CONCLUSION: No significant between-group differences in HRV parameters were established between atenolol and ivabradine. Ivabradine could be a viable option in patients where atenolol is either contraindicated or not tolerated. Future larger multicentric studies are needed for greater generalisability. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT06505668.

Humans↗

PubMedDate not supplied

Differential blockade of octopamine and dopamine receptors by analogues of clozapine and metoclopramide.

1. Sulpiride, but not procainamide, antagonizes the excitatory effects of (+/-)-octopamine receptors in the Tapes ventricle. Neither compound attenuates dopamine excitation. 2. Clozapine will attenuate the effects of (+/-)-octopamine and (-)-alpha-methyl octopamine at the octopamine receptor but not the excitatory effect of dopamine at dopamine receptors. 3. Clozapine is more potent than its 2-positional isomer HF 2046 in attenuating octopamine excitation. However, HF 2046, unlike clozapine, will attenuate the excitatory effects of dopamine. 4. These data indicate that replacement of the 8-chloro substituent in the clozapine nucleus with a 2-chloro substituent decreases the ability of the compound to blockaed octopamine receptors. However, the 2-chloro-substituted compound (HF 2046) now has the added ability to blockade excitatory dopamine receptors. 5. The greater potency of clozapine than HF 2046 as an octopamine antagonist suggests that it is the 8-chloro-substituted aromatic ring of clozapine which overlaps the aromatic site usually occupied by the octopamine aromatic ring.

Animals↗

PubMed1992

A clozapine treatment program for patients living in the community.

Clozapine treatment for schizophrenic patients living in the community requires strategies to ensure safe use of the medication and to foster patients' emerging social and living skills. The authors describe a clozapine treatment program in a community mental health center that includes a weekly clozapine support group meeting followed by drawing of blood for monitoring of side effects. Case managers and other program staff remind patients to take clozapine as prescribed and help them comply with hematological monitoring requirements, manage side effects, deal with the emotional aspects of improvement, and benefit from emerging capabilities. About 75 percent of the center's patients who have been offered clozapine have decided to take the medication, and almost all patients in the clozapine treatment program have experienced significant symptom relief and functional development with manageable side effects.

Activities of Daily Living↗