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At least 19 recordsLinked to original sources
PubMed1999

Low-dose loxapine in the treatment of schizophrenia: is it more effective and more "atypical" than standard-dose loxapine?

Loxapine is chemically related to clozapine and shares with it and other atypical antipsychotic drugs relatively greater affinity for serotonin (5-HT)2A than for dopamine D2 receptors. However, as is the case for risperidone, the occupancy of 5-HT2A and D2 receptors can range from partial to full, depending upon the dose. It was, therefore, of interest to determine whether loxapine at low doses (< 50 mg/day) might be at least as or more effective and more tolerable than usual clinical doses (> or = 60 mg/day). We retrospectively examined data from 75 patients treated with loxapine and found psychopathology data from 10 and 12 patients treated with low-dose or standard-dose loxapine, respectively. No data were available on the other 53 patients, 28 of whom were initially treated with low-dose and 25 with standard-dose loxapine. For those treated for at least 6 weeks, there was evidence of equivalent efficacy for both low- and standard-dose loxapine with regard to improvement in Brief Psychiatric Rating Scale (BPRS) and Global Assessment Scale scores. There were 6 patients with a history of neuroleptic resistance among the 22 completers. Four of the low-dose group (40%) and 8 of the standard-dose group (67%) had at least a 20% decrease in BPRS total scores. Further study of the dose-response curve for loxapine and its usefulness in treating neuroleptic-resistant schizophrenia is indicated.

Adult↗
PubMed1979

Determination of therapeutic and toxic concentrations of doxepin and loxapine using gas-liquid chromatography with a nitrogen-sensitive detector, and gas chromatography-mass spectrometry of loxapine.

A gas-liquid chromatographic procedure is presented for the determination of therapeutic and toxic serum levels of doxepin and loxapine, using a nitrogen-phosphorus-sensitive detector. Amitriptyline is used as the internal standard. The method is accurate, sensitive and specific with no derivatization required prior to analysis. An advantage of the procedure is the small serum sample size needed for analysis and the selectivity and sensitivity of the detector, with the limit of detection being 3 and 2 microgram/l for doxepin and loxapine, respectively. Nine cases of doxenin and loxapine misuse are presented. Serum doxepin concentrations ranged from 113 to 439 microgram/l, with a loxapine concentration of 192 microgram/l observed in one patient. The presence of the tricyclics was identified and confirmed by gas chromatography-mass spectrometry and the mass spectrum of loxapine is reported.

Adult↗
PubMed2003

A comparison of the effects of loxapine with ziprasidone and thioridazine on the release of dopamine and acetylcholine in the prefrontal cortex and nucleus accumbens.

RATIONALE: Atypical, but not typical, antipsychotic drugs (APDs), produce preferential increases in dopamine (DA) and acetylcholine (ACh) release in rat medial prefrontal cortex (mPFC) compared to the nucleus accumbens (NAC). The increase in DA release has been attributed, in part, to their greater serotonin (5-HT)(2A) relative to D(2) receptor occupancy, while the basis for the increase in ACh has not yet been determined. Loxapine, a dibenzoxazepine congener of clozapine, is generally considered to be a typical APD because it produces significant extrapyramidal symptoms (EPS) in humans, at generally recommended clinical doses (60-100 mg/day), and catalepsy in rodents, although several studies have found it to be effective at lower doses which do not produce significant EPS. Moreover, loxapine, like its congener clozapine, has higher affinity for serotonin (5-HT)(2A) than dopamine D(2) receptors, in vitro, suggesting the possibility it could be an atypical APD with clozapine-like potential. OBJECTIVES: The purpose of this study was to compare the effects of loxapine on DA and ACh release in the mPFC and NAC with those of ziprasidone, a novel atypical APD, and thioridazine, which is generally classified as a typical APD. RESULTS: Loxapine, 0.03-10 mg/kg, increased prefrontal dopamine release with the magnitude of this increase exceeding that in the NAC, at all doses, other than the 10 mg/kg dose. The effect of loxapine (0.3 mg/kg) on DA release in the prefrontal cortex was attenuated by WAY 100635 (0.2 mg/kg), a 5-HT(1A) antagonist, as is the case for other atypical APDs. Ziprasidone (0.1-3 mg/kg) also preferentially increased DA release in the mPFC compared to NAC. Thioridazine (5 and 20 mg/kg) did not increase DA release in either the mPFC or NAC. Loxapine (3 mg/kg) and ziprasidone (1 and 3 mg/kg), but not thioridazine (10 and 20 mg/kg), significantly increased cortical ACh release. CONCLUSION: Loxapine has effects on cortical and NAC DA and ACh release which are comparable to those of known atypical APDs. Ziprasidone and thioridazine have effects on cortical DA and ACh characteristic of atypical and typical APDs, respectively. It is concluded that further clinical studies of the atypical APD properties of loxapine are indicated.

Acetylcholine↗
PubMed1996

A neurochemical basis for the antipsychotic activity of loxapine: interactions with dopamine D1, D2, D4 and serotonin 5-HT2 receptor subtypes.

Loxapine is a typical neuroleptic that shows great structural and functional homology to the atypical antipsychotic clozapine. Chronic loxapine treatment is usually associated with extrapyramidal symptoms (EPS), whereas clozapine treatment is not. Conversely, loxapine does not produce the agranulocytosis that often results from protracted clozapine treatment. Earlier studies of loxapine have usually implicated D2 receptor blockade as the cause of the tardive dyskinesia that occurs with chronic treatment. More recently, loxapine's ability to potentiate serotonergic neurotransmission has also been implicated. In this study, the pharmacological affinities of loxapine for the dopamine D1, D2, D4, as well as serotonin-2 (5-HT2) and NMDA receptor subtypes, were investigated through direct radioreceptor assays. The findings indicate that loxapine displays an extremely strong binding affinity for dopamine D4 and serotonin 5-HT2 receptors, which suggests that both serotonergic and dopaminergic mechanisms contribute to the antipsychotic drug action and EPS associated with loxapine in the treatment of schizophrenia.

Antipsychotic Agents↗
PubMed2000

Loxapine for schizophrenia.

BACKGROUND: Loxapine is a drug with D2/D3 receptor antagonist activity and a higher affinity for D3 than D2. Some authors have suggested that loxapine is more effective than typical antipsychotics in reducing the negative symptoms of schizophrenia, that extrapyramidal side-effects are not usually seen at clinically effective antipsychotic doses and that it should therefore be classed as atypical. OBJECTIVES: To determine the effects of loxapine compared with placebo, typical and other atypical antipsychotic drugs for schizophrenia and related psychoses. SEARCH STRATEGY: Electronic searches of Biological Abstracts (1980-1999), The Cochrane Library (Issue 1, 1999), The Cochrane Schizophrenia Group's Register (January 1999), EMBASE (1980-1999), MEDLINE (1966-1999), LILACS (1982-1996), PSYNDEX (1977-1995) and PsycLIT (1974-1999) were undertaken. In addition, pharmaceutical databases on the Dialog Corporation Datastar and Dialog services were searched. References of all identified studies were searched for further trials. Pharmaceutical companies and authors of trials were contacted. SELECTION CRITERIA: All randomised controlled clinical trials relevant to the care of schizophrenia that compared loxapine to other treatments. DATA COLLECTION AND ANALYSIS: Citations and, where possible, abstracts were independently inspected by reviewers, papers ordered, re-inspected and quality assessed. Data were independently extracted but excluded if loss to follow up was greater than 50%. For homogeneous dichotomous data the risk ratio (RR), 95% confidence interval (CI) and, where appropriate, the number needed to treat (NNT) were calculated on an intention-to-treat basis. For continuous data, weighted mean differences were calculated (WMD). All data were inspected for heterogeneity. MAIN RESULTS: Compared to placebo, loxapine is antipsychotic (Global effect - not improved at 6 weeks, n=66, RR 0.6 CI 0.4-0.9 NNT 4 CI 2-62) with similar adverse effect profile to typical drugs. Is as effective as typical drugs in the short term (4-12 weeks) (Global effect - not improved, n=411, RR 0.89 CI 0.7-1.2). Very limited heterogeneous data suggest that, given intramuscularly (IM), loxapine may be at least as sedating as IM haloperidol and thiothixene. REVIEWER'S CONCLUSIONS: Loxapine is antipsychotic but its effects are under researched. It is not clearly different from typical drugs in either its positive or adverse effects.

Antipsychotic Agents↗
PubMedDate not supplied

Interspecies variability and drug interactions of loxapine metabolism in liver microsomes.

Loxapine is a dibenzoxazepine neuroleptic that is metabolized by the liver in humans. In the present study, we investigated first in vitro loxapine metabolism in liver microsomes from various species including rats, mice, guinea pigs, dogs, rabbits, monkeys and humans. This enables us to choose between species to further validate drug-drug interaction studies. We observed the formation of desmethyl- and hydroxy- metabolites of loxapine after incubation of the different species liver microsomes. Hydroxylation pathway was major in all species. Wide interspecies variability of loxapine metabolism was observed. Loxapine metabolism was similar in human, guinea pig and dog microsomes. We screened in vitro effects of 67 molecules, representative of 8 therapeutic classes, on loxapine metabolism. Loxapine (100 microM) was incubated with guinea pig liver microsomes (1 mg/ml) 30 min at 37 degrees C with and without the presence of interacting drug. We found that most of psychotropics (alimemazine, cyamemazine and levomepromazine), antifungal (ketoconazole), anticancer drugs (daunorubicin, pirarubicin) and analgesic (nefopam) inhibited more than 50% of hydroxyloxapine formation in vitro. Complementary clinical and pharmacokinetic studies should be performed to confirm these results.

Animals↗
PubMed2005

Contrasting loxapine to its isomer isoloxapine--the critical role of in vivo D2 blockade in determining atypicality.

BACKGROUND: Loxapine is a typical antipsychotic while isoloxapine, its 8Cl-isomer, shows atypicality in some animal models. The basis for this difference is not well understood. The purpose of this study was to systematically compare the two drugs in in vitro and in vivo animal models, and to understand mechanisms underlying their differential typical/atypical profiles. METHODS: The in vitro and in vivo receptor profiles as well as the action of loxapine and isoloxapine on rat conditioned avoidance response (CAR), catalepsy (CAT), striatal FOS expression and prolactin levels were determined. To understand loxapine's typical profile, we added MDL100,907, to provide loxapine+MDL the same in vivo 5-HT2/D2 ratio as isoloxapine, while holding its D2 component constant. RESULTS: Isoloxapine behaved as an "atypical" antipsychotic demonstrating CAR inhibition, low CAT, no significant prolactin elevation, and minimal FOS expression in the dorsolateral striatum. Loxapine behaved like a typical antipsychotic, showing unexpectedly high in vivo D2 occupancy. Addition of MDL100,907, which resulted in a very high 5-HT2/D2 in vivo ratio, did not alter loxapine + MDL's typical profile. CONCLUSIONS: Loxapine's behaviour as a typical antipsychotic is most likely due to its disproportionately high D2 occupancy. Appropriate action at D2 receptors in vivo, rather than the high 5-HT2/D2 ratio, seems to be critical in determining why isoloxapine behaves like an atypical antipsychotic.

Animals↗
PubMed2000

Loxapine intoxication: case report and literature review.

Loxapine is a dibenzoxazepine tricyclic compound used to treat schizophrenia in the United States since 1976. Metabolism includes demethylation to its primary metabolite, amoxapine. There are few documented reports of the disposition of loxapine in deaths due to overdose. This report discusses the overdose suicide of a 69-year-old white female found dead in her home by her husband. A prescription for loxapine (50-mg capsules) was found near the body. An autopsy was performed and heart blood, bile, vitreous humor, and gastric contents were submitted for toxicological analysis. The blood specimen was subjected to comprehensive testing that included volatile analysis by headspace gas chromatography (GC); acidic/neutral and basic drug screening by GC; benzodiazepine screening by high-performance liquid chromatography; opiate screening by modified immunoassay; and acetaminophen, salicylate, and ethchlorvynol screening by colorimetry. Loxapine and amoxapine were detected in the basic drug screen. No other drugs were detected in the case specimens. The respective concentrations of loxapine and amoxapine in each specimen were as follows: heart blood, 9.5 and 0.6 mg/L; bile, 28.8 and 4.7 mg/L; gastric, 278 mg/L and negative; and vitreous, 1.5 mg/L and negative. A review of the literature showed that the heart blood concentration of loxapine measured in this case was the highest reported to date. Based on the autopsy findings, patient history, and toxicology results, the cause of death was determined to be acute intoxication of loxapine and the manner, suicide.

Aged↗
PubMedDate not supplied

GLC/MS assay for loxapine in human biofluids and tissues with deuterium labeled analog as an internal standard.

A quantitative gas liquid chromatographic-mass spectrometric (GLC/MS) assay was developed for the determination of loxapine in human blofluids and tissues. The assay utilizes selected ion monitoring in a GLC effluent of the molecular ion of loxapine generated by electron-impact ionization (EI). Loxapine-d3 was used as the internal standard. The assay can measure 2 ng/mL of loxapine with about 6% precision. The curve relating the amounts of loxapine added in control plasma versus the ion intensity ratio (m/e 327/330) over a large range of loxapine concentrations was linear with essentially zero intercept. The method was used for the analysis of loxapine in human urine, plasma, brain, liver, lung and spleen.

Brain Chemistry↗
PubMed1983

Loxapine in the treatment of psychotic-depressive disorders: Measurement of antidepressant metabolites.

Psychotic patients who also have endogenous depressive symptoms often require treatment with several drugs (usually a neuroleptic-antidepressant combination) or electroconvulsive therapy. Loxapine is a neuroleptic of the dibenzoxazepine class; it is metabolized in vivo to desmethylloxapine (amoxapine) and 8-hydroxyamoxapine, two compounds with antidepressant activity. We traced the serum levels of total amoxapine (amoxapine plus 8-hydroxyamoxapine) in two treatment-resistant patients with psychotic-depression syndromes. One patient was treated with loxapine alone and the other with a loxapine-amoxapine combination. We also determined the total loxapine and amoxapine serum levels of ten patients treated at various dosages of loxapine alone. The results demonstrate that many patients treated with loxapine attain substantial serum levels of total amoxapine, some in concentrations thought to be therapeutic for nonpsychotic endogenous depression. We recommend further studies to determine the efficacy of loxapine in the management of treatment-resistant patients with psychotic-depression syndromes.

Adult↗
PubMed1993

Potential interaction between carbamazepine and loxapine: case report and retrospective review.

OBJECTIVE: To report a potential interaction between carbamazepine (CBZ), an anticonvulsant medication, and loxapine, an antipsychotic. CBZ is being increasingly used to treat a variety of psychiatric disorders. Because of this, the potential for multiple-drug therapy and subsequent drug interactions is increased. METHODS: We prospectively monitored plasma CBZ and carbamazepine epoxide (CBZE) concentrations in a single patient during and after withdrawal of loxapine comedication. Additionally, we retrospectively evaluated four patients who had received concomitant therapy with CBZ and loxapine. RESULTS: Plasma CBZE/CBZ ratios decreased from 0.76 to 0.18 following discontinuation of loxapine. Absolute CBZE plasma concentrations also decreased from 1.7 to 0.6 micrograms/mL after loxapine therapy was stopped. Retrospectively screened patients who were receiving concomitant loxapine-CBZ therapy all had unusually elevated CBZE/CBZ plasma concentration ratios (0.75-1.91). CONCLUSIONS: These cases suggest that an interaction occurs between loxapine and CBZ. Possible mechanisms include either induction of CBZ metabolism to its epoxide metabolite, or inhibition of the enzymatic metabolism of CBZE (epoxide hydrolase).

Adult↗
PubMed1979

Determination of loxapine in human plasma and urine and identification of three urinary metabolites.

1. A g.l.c. method for quantitative determination of loxapine (2-chloro-11-(4-methyl-1-piperazinyl)dibenz(b,f)(1,4)oxazepine), in human plasma and urine is described. 2. Preliminary pharmacokinetic data on plasma concn of loxapine over 12 h from five psychiatric patients who received a total average dose of 80 mg of loxapine succinate per day orally for twelve weeks are presented. 3. In addition to unchanged loxapine, three urinary metabolic products, namely aromatic ring-hydroxy loxapine, desmethyl loxapine and loxapine-N-oxide, were identified using g.l.c.--mass spectrometry.

Adult↗
PubMed1977

Efficacy of loxapine in the treatment of paranoid schizophrenia.

A combined analysis of data from 11 controlled studies of loxapine versus either chlorpromazine or trifluoperazine in acute schizophrenia (5 studies) and chronic schizophrenia (6 studies) showed statistically significant superiority of loxapine on several items and factors of standardized psychiatric rating scales. Upon review of these findings, it was observed that the rating scale symptoms for which loxapine appeared superior to the reference compounds could, in the main, be considered a broad paranoid "cluster". The data were then reanalyzed to detect possible differences in efficacy of loxapine versus the reference compounds in those patients with a clinical diagnosis of schizophrenia, paranoid type and in those patients of any diagnostic subtype other than paranoid. Results of these analyses demonstrated clear superiority of loxapine in paranoid schizophrenic patients; nonparanoid patients responded at least equally as well to loxapine as to the reference compounds. Findings could not be attributed to inadequate dosages of the references compounds or inequality of treatment groups at baseline.

Adult↗
PubMed1978

Loxapine versus perphenazine in psychotic patients. A double-blind, randomized, multicentre trial.

A double-blind, randomized, multicentre trial was carried out in 47 psychotic patients to evaluate the efficacy of oral treatment with loxapine compared with perphenazine. In total, 22 patients were included in diagnostic Group I (cases of acute schizophrenia and psychogenic (reactive) psychoses). The average maximum daily dose was 60.0 mg in the loxapine group and 36.8 mg in the perphenazine group. After 3-weeks' treatment, no significant differences were found between the two treatment groups according to the Brief Psychiatric Rating Scale (BPRS), Clinical Global Impression (CGI) Scale or side-effect records. Twenty-five patients were included in diagnostic Group II (cases of chronic schizophrenia). The average daily dosage was 81.1 mg in the loxapine group and 90.1 mg in the perphenazine group. After 10 to 12-weeks' treatment, no significant differences between the two treatment groups could be found according to BPRS, CGI scale, Nurses' Observation Scale for In-patient Evaluation (NOSIE) or side-effect records. The diastolic blood pressure (lying and standing) tended to increase slightly in both treatment groups. In conclusion, it was found that loxapine and perphenazine seemed to be equally effective and, based on experience with parenteral loxapine treatment, it is suggested that further investigation of oral loxapine should be carried out in psychotic patients in whom agitation is a feature.

Acute Disease↗
PubMed1978

Clinical and plasma level characteristics of intramuscular and oral loxapine.

The intramuscular and oral forms of loxapine succinate were compared in their clinical, side effect, and blood level characteristics in ten hospitalized chronic schizophrenic patients. The first phase of the study determined the single dose that produced moderate sedation (i.e., the sedation threshold), and this dose was essentially the same for the two forms. Continuous administration of the two forms using the individualized sedation threshold dosage also failed to indicate any clinical or side effect differences in the two forms. The blood level characteristics, however, did differ between the two forms. The kinetic studies indicated that there was a larger are under the loxapine curve with the intramuscular form than with the oral form, while the 8-OH loxapine area was larger with the oral form. The steady-state studies also showed that the i.m. form had higher loxapine levels than the oral form. The significance of these findings, both clinically and in terms of the relative activity of loxapine and its metabolites, is discussed.

Administration, Oral↗
PubMed1982

Ligand binding and platelet uptake studies of loxapine, amoxapine and their 8-hydroxylated derivatives.

Loxapine, amoxapine and their 8-hydroxylated derivatives were studied by means of [3H]imipramine binding to rat cortical membranes, [3H]spiperone binding to rat striatal membranes, and the inhibition of serotonin uptake by human platelets. As inhibitors of [3H]imipramine binding: amoxapine greater than hydroxyamoxapine greater than loxapine = hydroxyloxapine; as inhibitors of platelet serotonin uptake: hydroxyamoxapine greater than amoxapine greater than hydroxyloxapine greater than loxapine; and as inhibitors of [3H]spiperone binding: loxapine greater than amoxapine greater than hydroxyamoxapine greater than hydroxyloxapine. The antipsychotic properties of loxapine and amoxapine were supported by the binding results, which also indicated the probable antipsychotic activities of the metabolites. All 4 compounds may possess dual action of antidepressant effect as well as antipsychotic effect.

Amoxapine↗
PubMed1999

Comparative oxidation of loxapine and clozapine by human neutrophils.

The clozapine-induced agranulocytosis could be due to the formation of a reactive intermediate formed in polymorphonuclear neutrophils and granulocyte precursors with the myeloperoxidase-hydrogen peroxide system. On the contrary, no case of agranulocytosis has been described for loxapine, an other neuroleptic drug with a very close structural analogy. We have compared the clozapine and loxapine interaction with the oxidative burst and particularly with this enzymatic complex. On the one hand, the assay of the oxidative species demonstrated a different impact for the two neuroleptics. The 50% inhibitory concentration was 92 microM for hydrogen peroxide and 40 microM for hypochlorous acid for loxapine. The loxapine target is located before the myeloperoxidase-hydrogen peroxide system in the oxidative stream, whereas clozapine diverts the chlorination pathway of the enzyme. On the other hand, the in vitro metabolism of drugs by the myeloperoxidase-hydrogen peroxide system has been investigated by mass spectrometry. Loxapine remains inert but clozapine undergoes the oxidation. The glutathione or ascorbate addition in the medium leads to a removal of the oxidation. Glutathione is able to trap the toxic intermediate and could avoid its formation.

Antioxidants↗
PubMed1997

PET evidence that loxapine is an equipotent blocker of 5-HT2 and D2 receptors: implications for the therapeutics of schizophrenia.

OBJECTIVE: Loxapine, a dibenzoxazepine antipsychotic, is closely related to clozapine and shares clozapine's high affinity for binding to serotonin 5-HT2 and dopamine D4 receptors. The purpose of this study was to document loxapine's 5-HT2 and D2 receptor occupancy in vivo in patients with psychoses. METHOD: Ten patients who were taking loxapine (10-100 mg/day) had their D2 and 5-HT2 receptors assessed by means of positron emission tomography with [11C]raclopride and [18F]setoperone, respectively. RESULTS: The D2 receptor occupancy ranged from 43% to 90%; 5-HT2 occupancy varied from 27% to near saturation. Statistical comparison of the results showed that loxapine was equipotent in blocking 5-HT2 and D2 receptors. CONCLUSIONS: Loxapine differs from typical neuroleptics in demonstrating a high degree of 5-HT2 receptor occupancy. However, it is not "atypical" like clozapine and risperidone, since its 5-HT2 occupancy is not higher than its D2 occupancy. The results demonstrate that a high level of 5-HT2 occupancy is not a sufficient condition for atypicality. If atypical antipsychotic action is predicated on a combination of 5-HT2 and D2 effects, then it requires > 80% 5-HT2 occupancy in conjunction with < 80% D2 occupancy.

Adult↗