NEW METHODOLOGY FOR DEVELOPMENT OF ORODISPERSIBLE TABLETS USING HIGH-SHEAR GRANULATION PROCESS.

Development of orodispersible delivery system of high mechanical properties and low disintegration time is a big challenge. The aim of the current work was to assess and optimize the high shear granulation process as a new methodology for development of orodispersible tablets of high quality attributes using design of experiment approach. A two factor, three levels (32), full factorial design was carried out to investigate the main and interaction effects of independent variables, water amount (XI) and granulation time (X2) on the characteristics of granules and final product, tablet. The produced granules were analyzed for their granule size, density and flowability. Furthermore, the produced tablets were tested for: weight variation, breaking force/ crushing strength, friability, disintegration time and drug dissolution. Regression analysis results of multiple linear models showed a high correlation between the adjusted R-squared and predicted R-squared for all granules and tablets characteristics, the difference is less than 0.2. All dependent responses of granules and tablets were found to be impacted significantly (p < 0.05) by the two independent variables. However, water amount demonstrated the most dominant effect for all granules and tablet characteristics as shown by higher its coefficient estimate for all selected responses. Numerical optimization using desirability function was performed to optimize the variables under study to provide orodispersible system within the USP limit with respect of mechanical properties and disintegration time. It was found that the higher desirability (0.915) could be attained at the low level pf water (180 g) and short granulation time (1.65 min). Eventually, this study provides the formulator with helpful information in selecting the proper level of water and granulation time to provide an orodispersible system of high crushing strength and very low disintegration time, when high shear granulation methodology was used as a method of manufacture.

Multiple mechanisms of hERG liability: K+ current inhibition, disruption of protein trafficking, and apoptosis induced by amoxapine.

The antidepressant amoxapine has been linked to cases of QT prolongation, acute heart failure, and sudden death. Inhibition of cardiac hERG (Kv11.1) potassium channels causes prolonged repolarization and is implicated in apoptosis. Apoptosis in association with amoxapine has not yet been reported. This study was designed to investigate amoxapine effects on hERG currents, hERG protein trafficking, and hERG-associated apoptosis in order to elucidate molecular mechanisms underlying cardiac side effects of the drug. hERG channels were expressed in Xenopus laevis oocytes and HEK 293 cells, and potassium currents were recorded using patch clamp and two-electrode voltage clamp electrophysiology. Protein trafficking was evaluated in HEK 293 cells by Western blot analysis, and cell viability was assessed in HEK cells by immunocytochemistry and colorimetric MTT assay. Amoxapine caused acute hERG blockade in oocytes (IC(50) = 21.6 microM) and in HEK 293 cells (IC(50) = 5.1 microM). Mutation of residues Y652 and F656 attenuated hERG blockade, suggesting drug binding to a receptor inside the channel pore. Channels were mainly blocked in open and inactivated states, and voltage dependence was observed with reduced inhibition at positive potentials. Amoxapine block was reverse frequency-dependent and caused accelerated and leftward-shifted inactivation. Furthermore, amoxapine application resulted in chronic reduction of hERG trafficking into the cell surface membrane (IC(50) = 15.3 microM). Finally, the antidepressant drug triggered apoptosis in cells expressing hERG channels. We provide evidence for triple mechanisms of hERG liability associated with amoxapine: (1) direct hERG current inhibition, (2) disruption of hERG protein trafficking, and (3) induction of apoptosis. Further experiments are required to validate a specific pro-apoptotic effect mediated through blockade of hERG channels.

Determination of tricyclic antidepressants in human plasma using pipette tip solid-phase extraction and gas chromatography-mass spectrometry.

A method for the simultaneous extraction of four tricyclic antidepressants from human plasma samples using pipette tip SPE with MonoTip C(18) tips is presented. Human plasma (0.1 mL) containing four tricyclic antidepressants (amitriptyline, amoxapine, imipramine, and trimipramine) and an internal standard (IS), protriptyline, was mixed with 0.4 mL of distilled water and 100 microL 1 M NaOH solution. After centrifugation of the mixture, the supernatant was extracted to the C(18) phase of the tip by 20 repeated aspirating/dispensing cycles using a manual micropipettor. The analytes retained in the tip were eluted with methanol by five repeated aspirating/dispensing cycles. Without evaporation and reconstitution, the eluate was directly injected into a gas chromatograph injector and detected by a mass spectrometer with SIM in the positive-ion electron impact mode. Recovery of the four antidepressants and IS spiked into human plasma was 80.2-92.1%. The regression equations for the four antidepressants showed excellent linearity in the range of 0.2-40 ng/0.1 mL. LODs and LOQs for the four drugs were 0.05-0.2 ng/0.1 mL and 0.2-0.5 ng/0.1 mL, respectively. Intra- and interday CVs for the four drugs in plasma were no greater than 9.5%.

Detection and treatment of akathisia in advanced cancer patients during adjuvant analgesic therapy with tricyclic antidepressants: case reports and review of the literature.

OBJECTIVE: There is substantial evidence that tricyclic antidepressants are effective in the management of chronic pain, including cancer pain. In oncological settings, these agents are used as adjuvant analgesic drugs. However, cases of akathisia due to tricyclic antidepressants used as adjuvant analgesic therapy have not previously been reported. CASE REPORTS: Two cancer patients experiencing chronic pain who were refractory to nonsteroidal anti-inflammatory drugs and opioids were prescribed amoxapine as an adjuvant analgesic therapy for neuropathic pain. These patients developed inner restlessness and restless physical movements after amoxapine was prescribed. Although symptoms were atypical, akathisia was suspected and discontinuation of amoxapine resolved the symptoms. RESULTS AND SIGNIFICANCE OF RESULTS: Akathisia should be considered in patients receiving adjuvant analgesic therapy with tricyclic antidepressants. Early detection and appropriate treatment will relieve this distressing symptom. Restless movements involving parts of the body other than the legs may be the clue to the diagnosis.

[Case of prolonged recovery from serotonin syndrome caused by paroxetine].

We report a case of serotonin syndrome in a patient being treated with paroxetine for depression. Despite prompt discontinuation of medication, his serotonin syndrome continued for 10 days before full consciousness was restored. The patient was a 48-year-old male with chief complaints of hypobulia and suicidal thoughts. He consulted as a psychiatric outpatient, and oral paroxetine 20 mg/day, etizolam 1.0 mg/day, and brotizolam 0.25 mg/day were immediately started. Upsurge of feeling and disinhibition state were noted the following day, then on treatment day 6 his condition deteriorated to substupor state and he was admitted for further treatment. On admission, change of mental condition (consciousness disturbance), perspiration, hyperreflexia, myoclonus and tremor were seen, and serotonin syndrome caused by paroxetine was suspected. Paroxetine was thus discontinued, and under intravenous drip his condition gradually improved. However, it was not until the 10th hospital day that he became fully alert. In examinations, no infectious, metabolic or organic diseases were detected. The patient's condition often improves with in 24 hours of discontinuation of the causative medication in serotonin syndrome. Symptoms continued for 10 days in this patient, however, perhaps because paroxetine was administered for 6 days before discontinuation. In addition, interaction with other medications may have occurred. Therefore, when serotonin syndrome is suspected, prompt discontinuation of the suspected causative medication, followed by close monitoring of the pharmacokinetics is warranted.

[Successful treatment using high-dose amoxapine for a depressive patient].

We present a case of successful treatment of a patient with depression who showed remarkable improvement with a high-dose treatment of amoxapine. The case involved a 59-year old in-patient male who suffered severe depression. While a variety of medications, including anti-depressants, mood stabilizers, and anti-psychotics, were tried, none were successful. However, after starting amoxapine and increasing the dose to 375 mg/day, symptoms significantly improved. The patient underwent continued therapy with same dose, and no relapse was seen until it occurred about the same time poor compliance was observed. The case suggests that, while the patient seemed "treatment-resistant" at first, a higher dose and/or elongation of medication, led to improvement. It also suggests that anti-depressant treatment with a sufficient dose and period, should be continued for patients with treatment-resistant depression.

ECT in genetically confirmed Huntington's disease.

The authors report successful ECT treatment of a severely depressed man with genetically confirmed Huntington's disease. He responded well to treatment and showed no abnormal movements or worsening in his cognitive status.

Response of psychotic depression subtypes to pharmacotherapy.

Patients with psychotic depression respond well when treated with a combination of an antidepressant and antipsychotic medication. We previously reported that they will respond in a similar fashion when treated with amoxapine monotherapy. There are few prospective studies on the pharmacologic treatment response of psychotic depression subtypes. We treated 37 inpatients, 21 with mood congruent (MC) psychotic depression and 16 with mood incongruent (MI) psychotic depression, in a randomized double-blind fashion with either the combination of amitriptyline and perphenazine or with amoxapine for 4 weeks. Depression and psychosis ratings improved in a similar manner in both the MC or MI patients irrespective of medication treatment group. Global response rates were similar in the MI patients and MC patients. The data suggest that classifying psychotic depression into MC versus MI subtypes may have limited acute prognostic value in pharmacotherapy response rates.

A comparison of the effects of single doses of amoxapine and amitriptyline on autonomic functions in healthy volunteers.

We have studied the effects of single oral doses of amoxapine (100 mg and 200 mg), amitriptyline (50 mg and 100 mg), and placebo on some autonomic functions in ten healthy volunteers, using a balanced double-blind crossover design. Amitriptyline significantly reduced salivation and it significantly attenuated both miosis evoked by locally applied pilocarpine and sweat secretion evoked by locally applied carbachol. Amoxapine did not significantly alter any of these measures. Neither treatment significantly altered the pupillary light reflex (latency, amplitude, or 75% recovery time). Resting pupil diameter was significantly reduced by the higher dose of amoxapine but was not affected by the other treatments. The higher dose of amoxapine significantly increased supine systolic blood pressure, but did not affect heart rate or diastolic blood pressure; amitriptyline had no effect on any of these cardiovascular measures. These results confirm the antimuscarinic effects of amitriptyline in man, but provide no evidence for antimuscarinic effects of amoxapine.

[Preclinical pharmacology of amoxapine and amitriptyline. Implications of serotoninergic and opiodergic systems in their central effect in rats]. / Pharmacologie préclinique de l'amoxapine et de l'amitriptyline. Implications des systèmes sérotoninergiques et opioïdergiques dans leurs effets centraux chez le rat.

The effects of two antidepressant drugs, amoxapine and amitriptyline, that belong to distinct chemical classes, have been examined on various biochemical parameters related to serotoninergic and opioidergic neurotransmission in the rat brain and spinal cord. In vitro binding studies showed that both amoxapine and amitriptyline interact in the nanomolar range with 5-HT2 receptors labelled by [3H]ketanserin in cortical membranes. By contrast, neither amoxapine nor amitriptyline can be considered as possible ligands of 5-HT1A and 5-HT1B receptors because their affinities for these sites are in the micromolar range (or even worse). Interestingly, amoxapine binds with a good affinity (IC50 = 0.30 microM) to 5-HT3 receptors labelled by [3H]zacopride in cortical membranes. Complementary experiments using the 5-HT3-dependent Bezold-Jarisch reflex confirmed that amoxapine really acts in vivo as a 5-HT3 antagonist (IC50 = 50 micrograms/kg i.v.), whereas amitriptyline is essentially inactive on 5-HT3 receptors. The second part of this study consisted of looking for possible changes in central 5-HT receptors 24 h after either a single or a repeated (for 14 days) treatment with amoxapine (10 mg/kg i.p. each day) or amitriptyline (10 mg/kg i.p.). A marked decrease in the density of 5-HT2 receptors was found in the cerebral cortex in both treatment groups. By contrast, neither 5-HT1A nor 5-HT1B receptors were significantly affected in any brain region studied. Finally we explored whether acute and/or chronic administration of amoxapine or amitriptyline affected the levels of opioid peptides and the mu and delta classes of opioid receptors in various regions of the brain and the spinal cord.(ABSTRACT TRUNCATED AT 250 WORDS)

Amoxapine versus amitriptyline for continuation therapy of depression.

The efficacy of continuation therapy with tricyclic antidepressants has been established in a number of controlled trials. This study investigated the efficacy of continuation therapy with a relatively new antidepressant, amoxapine, using a double-blind controlled comparison with amitriptyline. Subjects met DSM-III criteria for major depressive disorder and were randomized to treatment with either amoxapine 400 mg (N = 47) or amitriptyline 300 mg (N = 45). The acute phase lasted up to 8 weeks. Responders were continued on the same drug at the same dose for a 16-week continuation phase. Some measures found more rapid onset for amitriptyline, which is inconsistent with findings from some prior studies. Amitriptyline was more effective in inducing full recovery. There was a trend for higher relapse rates on amoxapine, perhaps related to the fact that there were more partial responders entering continuation therapy from this group. Side effect rates were equivalent in the two drugs. However, physicians rated amoxapine's side effects as more frequently interfering with its therapeutic effect. These data suggest that amoxapine does not offer any clear advantage over amitriptyline for continuation therapy in patients who have major depressive disorder. Of potential clinical relevance is the finding that achieving full recovery in the acute phase may reduce the likelihood of relapse in the continuation phase, regardless of the type of antidepressant medication prescribed.

Valoración clínica multicéntrica de la eficacia y seguridad de la amoxapina en pacientes adultos, ambulatorios, con diversos tipos de depresión / A multicentric clinical evaluation of the efficacy and safety of Amoxapine in adult out patients with various types of depression

Con el objetivo de valorar la eficacia, tolerancia y seguridad de amoxapina en pacientes adultos ambulatorios con diferentes tipos de depresión, de acuerdo a los criterios del DSM III, se llevó a cabo un estudio clínico multicéntrico, abierto, no comparativo , prospectivo, que incluyó 91 pacientes que recibieron tratamiento con amoxapina durante ocho semanas. Se realizaron seis valoraciones clínicas, 60% correspondientes al sexo femenino, y el 40% restante al masculino. La edad promedio del grupo fué de 36+-12.8 años con edades mínimas y máximas de 19 y 75 años respectivamente. Diecisite por ciento de los pacientes no presentaban episodios previos de depresión, en tanto que el resto presentaba un episodio previo de 22%; dos episodios en 21% y tres o más episodios con 40%. La duración del episodio actual fué de una semana a un mes en 9%, de uno a tres meses en 32% de tres meses a 1 años en 30% y de 1 año o más en 30% restante. Los principales diagnósticos fueron: depresión neurótica en 33%, depresión mayor recurrente en 25%, transtorno distímico en 17% y depresión mayor, primer episodio en 10%. En lo referente a resultados, se concluyeron el síndrome depresivo, en general la dosis inicial de 100-150 mg/día produjo resultados positivos con buena tolerancia, observándose un franco efecto terapéutico en el curso de las dos primeras semanas de tratamiento con mejoría significativa de todos los parámetros estudiados incluyendo escala de Hamilton, escala de Zung, impresión clínica global y escala visual analógica de psicopatología global. Se informaron efectos colaterales en 66% de los pacientes, principalmente de tipo anticolinérgico, de naturaleza benigna e intersidad de leve a moderada. En ningún caso se requirió descontinuación del tratamiento. Los signos vitales no sufrieron alteraciones significativas durante el estudio

Electrophysiological effects of amoxapine in untreated and in amoxapine-pretreated rat atria.

The effects of amoxapine (10(-7)-10(-4) M) have been studied in rat atrial fibres obtained from untreated animals and animals pretreated for 28 days with amoxapine (10 mg kg-1, i.p.). In untreated atria amoxapine reduced atrial rate, contractile force and df/dtmax, prolonged the sinus node recovery time and decreased atrial excitability. Amoxapine also decreased amplitude and Vmax of the upstroke, prolonged the duration of the action potential (APD) and effective refractory period (ERP) and reduced the resting membrane potential. During the treatment with amoxapine behavioural and cardiovascular adverse effects, including hypotension, tachycardia and prolongation of the Q-Tc, were observed. However, with the exception of the ERP which was significantly prolonged in pretreated atria, pretreatment with amoxapine did not modify the control values of the measured parameters compared to those obtained in untreated atria. Further addition of amoxapine produced similar changes in both pretreated and untreated atria. However, in contrast to untreated atria, in pretreated atria the prolongation of the ERP produced by amoxapine exceeded the prolongation of the APD and thus, the ERP/APD ratio increased. The decrease in atrial excitability was also more marked in pretreated than in untreated atria. Amoxapine inhibited the slow action potentials and contractions induced by isoprenaline in K-depolarized atria. It is concluded that the electrophysiological effects of amoxapine on rat atrial fibres are similar to those described for other tricyclic antidepressants. Possible explanations for the lower cardiodepressant activity of amoxapine are discussed.

Pancreatitis following overdose with amoxapine and procyclidine.

A case is described in which a patient developed acute pancreatitis following an overdose of amoxapine and procyclidine. Pancreatitis is not at this time a recognized complication of the use or abuse of these two drugs. Other drugs were used in the medical management of the complications of the overdose, but none of these are drugs known to be associated with pancreatitis. Amoxapine is probably, but not certainly the cause of the pancreatitis. Possible mechanisms for this unusual and serious complication are described.

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.