Direct microtitre plate radioimmunoassay of savoxepine in unextracted plasma.

An original solid phase method for direct radioimmunoassay of the antipsychotic savoxepine (CGP 19,486 A) in plasma has been developed which does not require the extraction of the parent drug with organic solvents. The assay showed good reproducibility over the working concentration range 1.9-30.6 nmol/l with intra- and inter-assay coefficients of variation < or = 16%. The procedure, which requires only small volumes of plasma (10 microliters), is simple to handle and well suited for routine analysis. The method allowed to investigate the pharmacokinetics of savoxepine in schizophrenic patients given low oral doses of the drug.

Effect of inhaled aerosol of 1-chloroacetophenone (CN) and Dibenz (b,f)-1,4 oxazepine (CR) on lung mechanics and pulmonary surfactants in rats.

Inhalation toxicity following exposure to 1-Chloroacetophenone (CN) and Dibenz(b,f)-1,4 oxazepine (CR) aerosols for 60 min at sublethal concentrations were studied in rats. The dynamic surface tension (gamma max and stability ratio) of lung homogenate increased significantly on CN exposure. The lung mechanics studies revealed a significant increase in compliance in CN exposed rats. CR, on the other hand did not influence any of the above variables except for a decrease in compliance. Total lung phospholipids and sphingomyelin contents decreased significantly following exposure to CN, while CR exposure produced an increase in sphingomyelin, reduction in phosphatidylcholine and ethanolamine, with no change in total phospholipid contents. Histomorphological observations indicated cellular degeneration in the epithelium of the bronchiole and alveolar septal-wall thickening due to the presence of an increased number of mononuclear cells in CN exposed rats. However, CR induced inflammatory reaction and enlargement of respiratory air spaces. It is concluded that of the two sensory irritants (tear gases) examined, CN is potentially more toxic compared to CR in rats.

Antinociceptive effect of spinally delivered prostaglandin E receptor antagonists in the formalin test on the rat.

The antinociceptive effect of spinally administered prostaglandin E2 receptor antagonists, SC-51089 and SC-51234A, which are selective for EP1 receptors, was examined in rats using the formalin test. Intrathecal injection of SC-51089 (30-300 micrograms) or SC-51234A (30-300 micrograms) resulted in a significant, dose-dependent, suppression of the second phase (10-60 min), but not the first phase (0-9 min), flinching behavior evoked by formalin injection into the paw. ED25 values and 95% confidence intervals for the second phase were 120 (70-200) micrograms for SC-51089 and 80 (50-140) micrograms for SC-51234A. These data demonstrate that specific nociceptive behaviors are attenuated by spinal prostaglandin E2 receptor antagonists and suggest that prostaglandin E2 is involved in facilitated processing at the spinal level.

In vitro extended-release properties of drug-loaded poly(DL-lactic acid) nanoparticles produced by a salting-out procedure.

Savoxepine-loaded poly(DL-lactic acid) (PLA) nanoparticles were prepared using an emulsion technique involving a salting-out process which avoids surfactants and chlorinated solvents. After their formation, the nanoparticles were purified by cross-flow microfiltration and subsequently freeze-dried. The drug loading and the drug entrapment efficacy were improved by using savoxepine base rather than the methanesulfonate salt and by modifying the pH of the aqueous phase. A drug entrapment efficacy as high as 95% was obtained with a 9% drug loading. The overall yield of the procedure can rise up to 93%. In vitro release studies have demonstrated that by varying the mean size of the nanoparticles and their drug loading, the release of the drug from the nanoparticles can be modulated to last from several hours to more than 30 days, thus allowing the preparation of an injectable extended-release dosage form.

Time dependent histomorphological assessment of lung damage induced by inhaled dibenz(b,f)-1-4-oxazepine (CR) and 1-chloroacetophenone (CN) in rats.

Lung damage caused by inhalation (single exposure for 60 min) of sublethal concentration of pure aerosols of dibenz(b,f)-1,4-oxazepine (CR) and 1-chloroacetophenone (CN) have been examined at different time intervals in rats. The damage was not severe with CR (2830 mg.m-3) but in the case of CN (60.26 mg.m-3) it was evident up to 30th day post exposure. Necrobiosis, attenuation of bronchiolar epithelium, edema in the air ways and also in the lumen of alveoli leading to substantial changes in the histoarchitecture of the lung were observed during CN exposure. On the other hand CR caused degenerative changes which disappeared on 30th day.

Use of neuroleptics after an episode of neuroleptic malignant syndrome.

The authors report a case of unequivocal Neuroleptic Malignant Syndrome, in which the patient was successfully rechallenged with a different potent neuroleptic in substantial dosage during the recovery phase. The Neuroleptic Malignant Syndrome did not recur and the patient's psychosis cleared. Reference is made to the relevant world literature.

The combined effects of dopamine (DA) and the DA antagonists EGYT-2509, chlorpromazine and haloperidol on the kidney function.

In anaesthetized dogs renal function was investigated in four successive 20-min periods in four experimental series. (1) In the first series following the first period (serving as control) 2.5 micrograms/kg/min of dopamine (DA) dissolved in 0.5 ml/min of Ringer's solution was infused into the left renal artery (period 2), than during periods 3 and 4. It was found that first (period 2) and second (period 3) doses of DA induced a significant decrease of about 20-30% in renal vascular resistance, and an increase of about 15-25% in renal blood flow. At the same time, systemic arterial blood pressure fell by 10%. The other investigated parameters of the left kidney (Cinulin, CPAH, sodium, potassium and water excretion) did not differ from the respective parameters of the intact right kidney. (2) In the second experimental series following the first period (prior to period 2) 1.0 mg/kg of the DA antagonist EGYT 2509 was administered intravenously. Prior to the period 3 again 1.0 mg/kg of EGYT 2509 and prior to period 4 2.0 mg/kg of EGYT 2509 was given intravenously. During periods 2 through 4 2.5 micrograms/kg/min of DA was infused into the left renal artery. It could be ascertained that EGYT 2509 abolished the renal effects of DA while not inducing any decrease in arterial blood pressure. (3) In the third experimental series, following the control period, prior to periods 2,3 and 4, 1.0 mg/kg, 1.0 mg/kg and 2.0 mg/kg chlorpromazine respectively, was administered i.v. followed by the infusion of DA into the left renal artery. After the administration of chlorpromazine arterial blood pressure and renal vascular resistance fell concomitantly and DA failed to induce any further changes in these parameters. According to our experiments chlorpromazine abolishes the effect of DA on kidney function. (4) In the fourth series, prior to DA infusion the dogs were given 0.5 mg/kg (period 2) then again 0.5 mg/kg and finally 1.0 mg/kg of haloperidol intravenously. Haloperidol decreased arterial blood pressure as well as renal vascular resistance, thus renal blood flow did not change. Renal blood flow could then be increased by DA infused into the left renal artery. It seems that haloperidol could not abolish the vascular effects of DA in the kidney. Our experiments indicate that substance EGYT 2509 possesses the most marked dopaminergic antagonistic effect, chlorpromazine had also been effective, while haloperidol had proved to be practically ineffective.

Neuroleptic profile of cipazoxapine (Savoxepine), a new tetracyclic dopamine antagonist: clinical validation of the hippocampus versus striatum ratio model of dopamine receptors in animals. A preliminary report.

Cipazoxapine is a new tetracyclic dopamine antagonist which we tested to validate an animal model for neuroleptics. This model was based on drug affinity to dopamine receptors in hippocampus versus striatum. For haloperidol the ratio was 0.67, for cipazoxapine 0.06. In this preliminary trial on eight schizophrenic patients we found that cipazoxapine in doses between 0.40 and 2 mg had an antipsychotic effect (measured by the BPRS) without extrapyramidal side-effects (measured by the Simpson-Angus-Scale). Our preliminary results thus support the animal findings.

Rapid tranquilization: a comparison of thiothixene with loxapine.

This 6-day study evaluated the efficacy of equivalent doses of loxapine and thiothixene for rapid tranquilization of acutely disturbed, psychotic patients. After initial tranquilization with intramuscular injections for 24 hours, 58 patients were treated for 5 days with oral medication. With both drugs, intramuscular treatment demonstrated clinically significant improvement from baseline on Clinical Global Impressions and Brief Psychiatric Rating scales; this improvement continued during the oral phase. Median time to tranquilization was significantly less with loxapine (60 minutes) than with thiothixene (95 minutes); during the oral phase, there were no significant differences between the two treatment groups. Side effects were minimal during the intramuscular phase; dystonia was most common during the oral phase.

A repeated dose study of the toxicity of technical grade dibenz-(b.f.)-1,4 oxazepine in mice and hamsters.

The repeated dose inhalation toxicology of technical grade dibenz-(b.f.)-1,4 oxazepine (CR) was studied in mice and hamsters. The animals were exposed 5 days/week for 18 weeks and retained until 1 year after the start of exposure. CR, at high doses, affected survival of both species, nevertheless the material produced little specific organ-directed toxicity.

Systematic studies with amoxapine, a new antidepressant.

Amoxapine, a tricyclic dibenzoxazepine is an antidepressant which in the dosage range of 150-300 mg/day is notable for its rapid onset of action. Because of the rather long, approximately 30-hour, half-life of 8-hydroxyamoxapine, the active metabolite of amoxapine, the possibility was raised that amoxapine therapy may be carried out with single daily dosages. Such a dosage schedule may improve compliance and, if appropriately timed, decrease perception of some of the unwanted effects of the drug. To test the hypothesis that there may be no disadvantages and perhaps even advantages of a once-a-day regimen as compared to a divided dosage schedule, a 6-week double-blind clinical trial was carried out in 35 hospitalized patients with major (18 patients) and minor (17 patients) depressive disorders. While no statistically significant difference was found in overall therapeutic and adverse effects between the groups treated with single or divided daily doses, onset of therapeutic effect appeared a bit faster in the group treated with single daily doses. Of particular relevance for drugs which can be given in single daily doses is their effect on psychomotor performance tests. In view of the findings that a once-a-day dosage regimen with amoxapine may have advantages over divided daily doses, a second study was carried out in which the effects of amoxapine (50 and 100 mg) were compared to an inactive placebo and amitriptyline (50 mg) with and without ethanol in 8 normal male volunteers. The study was double-blind and followed a latin square design. Since the effects of amoxapine on motor reflex, visual-motor coordination and depth perception did not differ significantly from placebo, the results suggest that the effects of amoxapine on the performances measured are clinically insignificant. No significant interaction with ethanol was noted.

Very high dose loxapine in refractory schizophrenic patients.

The authors report on three chronic, treatment-refractory schizophrenic patients who dramatically improved when placed on very high doses of loxapine (300-500 mg/day). Numbness transiently appeared in two patients at very high doses of loxapine; it may be a frequently occurring but unreported side effect. The relative lack of serious side effects to very high dose loxapine suggests that this may be a useful intervention in carefully selected refractory patients. The authors recommend that controlled studies be done to elucidate the benefit to risk ratio.

Amoxapine: once versus divided daily doses in neurotic and endogenous depression.

In a six-week, double-blind clinical study of 35 hospitalized patients with the diagnoses of endogenous depression (18 patients) and depressive neuroses (17 patients), two dosage schedules of amoxapine were compared. While no statistically significant difference in overall therapeutic and adverse effects between the groups treated with single daily doses and divided daily doses were found by the end of the six weeks investigational period, onset of therapeutic effect was faster in the group treated with single daily doses. There was a significantly greater improvement in Anxiety-Somatization and Sleep Disturbance (HAM-D factors) in the group with depressive neurosis than in the group with endogenous depression.

Effects of neuroleptic adjustment on clinical condition and tardive dyskinesia in schizophrenic patients.

The authors decreased neuroleptic medication in 21 chronic schizophrenic patients in an attempt to minimize the risks of tardive dyskinesia. Level of psychopathology and severity of dyskinetic symptoms were monitored while the neuroleptic was gradually decreased over 3 months and then discontinued. Only 1 patient relapsed during drug decrease; however, 15 patients relapsed within 6 months after drug withdrawal. After relapse, medication was gradually increased. The doses needed to induce recovery were higher than those which had been sufficient to prevent relapse during gradual drug reduction. Dyskinetic symptoms were not significantly modified during drug reduction but increased significantly after drug discontinuation.

Parenteral loxapine in severely disturbed schizophrenic patients.

Loxapine is a tricyclic antipsychotic drug of the dibenzoxapine class. An uncontrolled open trial of this compound has been performed by intramuscular route in 28 patients previously refractory to other neuroleptic drugs. These patients received 50 to 200 mg loxapine daily by intramuscular route. Clinical evaluation, BPRS, NOISE and biological evaluation were performed before and at the 8th day of the treatment. Global clinical evaluation and statistical analysis of BPRS showed the high efficacy of loxapine with a sedative effect during the initial phase and a disinhibiting and "hallucinolytic" character at a later stage. Tolerance to the preparation appeared good both locally and systematically with the possible exception of transient effects upon body temperature.

Evaluation of loxapine hydrochloride oral concentrate (loxitane C) in acute schizophrenia.

In an open study of 4-weeks duration, both an oral liquid concentrate formulation of loxapine hydrochloride (LOXITANE C) and capsules of loxapine succinate (LOXITANE) were administered to 11 acutely disturbed schizophrenic patients. Optimal dosage levels achieved with the concentrate proved satisfactory with the capsules. Efficacy evaluation with the Brief Psychiatric Rating Scale (BPRS), Systematic Nurses' Observation of Psychopathology (SNOOP), and Clinical Global Impressions (CGI) indicated rapid improvement with concentrate administration and continued improvement with capsule administration. All but two side effects were extrapyramidal or sedative, all but one were mild or moderate in severity, and the frequency was similar with the two formulations. Cardiovascular and clinical laboratory findings remained essentially unchanged with both formulations.

The acute mammalian toxicology of dibenz(b,f)-1,4-oxazepine.

Dibenz(b,f)-1,4-oxazepine (CR), a potent peripheral sensory irritant material, has been shown to have a very low acute lethal and sub-lethal toxicity by intravenous, intraperitoneal, oral, percutaneous and inhalation routes to several species of laboratory mammal. There was no organ-specific pathology. Comparison of the acute toxicity of CR with that of two other peripheral sensory irritants, 1-chloroacetophenone (CN) and 2-chlorobenzyl-lidene malononitrile (CS), shows CR to be significantly less toxic than either of them. Pyrotechnically generated CR smoke was more toxic than pure (thermally generated) aerosols of CR; this was due to the presence of pyrotechnic decomposition products in the atmosphere from the burning of the smoke generating composition. However, the median lethal toxicity of pyrotechnically generated CR smoke was very significantly less than that of either pyrotechnically generated CN or CS smokes. Short-term cumulative toxicity did not occur following multiple oral dosing with CR. The acute toxicology of three ether intermediates encountered in the synthesis of CR from 1-chloro-2-nitrobenzene and sodium phenoxide (2-nitrodiphenyl ether, 2-aminodiphenyl ether and 2-formamidodiphenyl ether) was investigated; all three ethers were found to be less acutely toxic than CR itself.