Levocabastine: an effective topical treatment of allergic rhinoconjunctivitis.

The new H1-receptor antagonist levocabastine is the most potent antihistamine available, as shown in classical animal tests for antihistamine activity. Its effects also are very specific, with doses as high as 40,000 times the effective antihistamine dose not displaying other pharmacological effects. In nasal and ocular provocation tests, levocabastine nasal spray and eye drops protected against allergen-induced nasal and ocular symptoms. Twenty-three clinical trials have been performed with levocabastine nasal spray in 1363 patients with allergic rhinitis. At a dose of two sprays per nostril twice daily (if necessary to be increased up to four times daily), levocabastine was significantly better than placebo and as good as or slightly better than cromoglycate in alleviating nasal symptoms. Good to excellent results were reported in about 60% of patients on levocabastine, compared with 37% with placebo and 47% with cromoglycate. Levocabastine eye drops were studied in 21 clinical trials including 1218 patients with allergic conjunctivitis. One drop per eye twice daily (up to four times daily) provided significantly better symptom control than placebo and similar effects as those observed with cromoglycate. Response rates were 71-80% with levocabastine, 55% with placebo and 76% with cromoglycate. Levocabastine has a fast onset of action, with 94% of patients experiencing symptom relief within 15 min after the first instillation of levocabastine eye drops. Three long-term studies (10-16 weeks' duration) showed absence of tachyphylaxis during prolonged treatment with levocabastine. The incidence of adverse experiences was similar for levocabastine, cromoglycate and placebo, for nasal spray as well as eye drops.(ABSTRACT TRUNCATED AT 250 WORDS)

Pilot clinical investigation of risperidone in the treatment of psychotic patients.

Sixty-one adult psychotic patients were treated for four weeks in an open dose-finding study with the new combined serotonin-dopamine antagonist risperidone (R 64 766). Risperidone had a rapid onset of action; a highly significant decrease in the total score on the Brief Psychiatric Rating Scale (BPRS) was already noticed after the first week of treatment. There was also a significant decrease in score for individual BPRS items related to positive, negative, and affective symptoms. In spite of the withdrawal of antiparkinson medication at selection, a significant decrease in extra-pyramidal symptoms (EPS) was observed, as assessed on the Simpson and Angus Scale. The Clinical Global Impression of therapeutic effect was consistent with the BPRS scores, showing a constant improvement throughout the study. The mean daily dose of risperidone at the end of the study was 3.7 mg. Tolerance was excellent and only mild side-effects were reported. Vital signs, ECG-parameters, and laboratory values remained within normal limits. This study demonstrates that risperidone has great potential as an effective and well-tolerated alternative for the treatment of chronically psychotic patients. It has potent antipsychotic effects, a low EPS-inducing profile, and, at the same time, it improves the negative and affective symptoms of schizophrenia.

El desarrollo de nuevas drogas antipsicoticas / Development of new antipsychotic drugs

Se da por sentado que en la esquizofrenia, los efectos terapéuticos de los neurolépticos se basan en el bloqueo de los receptores de dopamina situados en el cerebro. Sin embargo, también se admite que los neurolépticos "clásicos" presentan algunos incovenientes importantes: su relativa falta de efectos sobre los síntomas negativos y su capacidad de inducción de síntomas extrapoiramidales (SEP). Experiencias clínicas llevadas a cabo con pipamperona mostraron que un antagonista combinado de serotinina 5-HT2 y dopamina D2 presentaba ventajas en el tratamiento de la esquizofrenia. Esto se hizo patente a través de los efectos antiautísticos observados, de la regulación de los ritmos de sueño y de vigilia perturbados y de la baja tendencia a la inducción de SEP. Los estudios realizados con setoperona, compuesto de perfil farmacológico comparable, confirmaron estas observaciones. No se pudo explorar la exacta implicación del antagnista 5-HT2 en los tratamientos psicofarmacológicos de la esquizofrenia hasta no haberse realizado la síntesis del receptor antagonista selectivo y específico: la ritanserina. En efecto las pruebas de doble ciego efectuadas demostraron una majoría sensible de los síntomas negativos y extrapiramidales. Puesto que las ventajas de la monoterapia en el tratamiento de la esquizofrenia son innegables, lo lógico era pasar a la selección de un compuesto con un antagonismo central comparable al de... (AU)

El desarrollo de nuevas drogas antipsicoticas / Development of new antipsychotic drugs

Se da por sentado que en la esquizofrenia, los efectos terapéuticos de los neurolépticos se basan en el bloqueo de los receptores de dopamina situados en el cerebro. Sin embargo, también se admite que los neurolépticos "clásicos" presentan algunos incovenientes importantes: su relativa falta de efectos sobre los síntomas negativos y su capacidad de inducción de síntomas extrapoiramidales (SEP). Experiencias clínicas llevadas a cabo con pipamperona mostraron que un antagonista combinado de serotinina 5-HT2 y dopamina D2 presentaba ventajas en el tratamiento de la esquizofrenia. Esto se hizo patente a través de los efectos antiautísticos observados, de la regulación de los ritmos de sueño y de vigilia perturbados y de la baja tendencia a la inducción de SEP. Los estudios realizados con setoperona, compuesto de perfil farmacológico comparable, confirmaron estas observaciones. No se pudo explorar la exacta implicación del antagnista 5-HT2 en los tratamientos psicofarmacológicos de la esquizofrenia hasta no haberse realizado la síntesis del receptor antagonista selectivo y específico: la ritanserina. En efecto las pruebas de doble ciego efectuadas demostraron una majoría sensible de los síntomas negativos y extrapiramidales. Puesto que las ventajas de la monoterapia en el tratamiento de la esquizofrenia son innegables, lo lógico era pasar a la selección de un compuesto con un antagonismo central comparable al de...

R 75251, a new inhibitor of steroid biosynthesis.

R 75251, a new imidazole derivative, inhibited the conversion of androgens to estrogens, of progestins to androstenedione and testosterone, and of 11-deoxycorticosterone to corticosterone in human placenta microsomes, subcellular fraction of rat testis, bovine adrenocortical mitochondria, in cultured rat granulosa, testicular and adrenal cells, respectively. In vitro, no effect on cholesterol synthesis and cholesterol side-chain cleavage was found at concentrations up to 10 microM. In rat granulosa cells, no effect on progesterone production was detected. In vitro, no effect on steroid radioligand binding was observed. In male volunteers, a single dose of 300 mg of R 75251 significantly lowered plasma testosterone and estradiol for 24 hours and increased plasma concentration of 17 alpha-hydroxyprogesterone and progesterone. As compared with ketoconazole high dose (600 mg b.i.d), R 75251 (300 mg b.i.d) was at least as efficacious as inhibitor of testosterone synthesis when studied during ACTH stimulation. In contrast to ketoconazole, R 75251 did not significantly affect circulating adrenal androgen levels in male volunteers. Precursors of gluco- and mineralocorticoids such as 11-deoxycortisol and 11-deoxycorticosterone accumulated more than after ketoconazole administration. The data show that the cytochrome P450-dependent aromatase, 17-hydroxylase/17,20-lyase, and 11-hydroxylase are the target enzymes for R 75251.

[Development of new antipsychotic drugs]. / El desarrollo de nuevas drogas antipsicóticas.

As far as schizophrenia is concerned, therapeutical effects of neuroleptics based on brain-located dopamine receptor blockers are taken for granted. It is also admitted, however, that classical neuroleptics have inconveniences, namely: Their relative lack of effect on negative symptoms, and their liability to induce extrapyramidal symptoms (EPS). Pipamperone-based clinical studies evidenced that an antagonist combining serotonin 5-HT2, and dopamine D2 was successful in the treatment of schizophrenia--which could be clearly observed in (a) anti-autistic effects, (b) regulating disrupted sleep-wake rhythms, and (c) a lesser tendency to EPS. Setoperone-based studies--a compound with a comparable pharmacological profile--confirmed the above observations. Until, however, the synthesis of ritanserin--a specific, and selective antagonistic receptor--was not achieved, no exact implication of 5-HT2 antagonist in psychopharmacological treatments of schizophrenia could be explored further. Indeed, double-blind trials evidenced a remarkable improvement in negative as well as extrapyramidal symptoms. Since a monotherapy appeared as undeniably called for in the treatment of schizophrenia, the next logical step to be taken was selecting a compound with a central antagonism comparable to ritanserin's, and a central D2 antagonism comparable to haloperidol's. Among a chemical range of benzisoxazole derivatives, risperidone was thus selected. The first double-blind trials on chronic schizophrenic patients seem indeed to confirm that this substance is likely to get over the above mentioned inconveniences, so typical of classical neuroleptics.

El desarrollo de nuevas drogas antipsicóticas. / [Development of new antipsychotic drugs]

As far as schizophrenia is concerned, therapeutical effects of neuroleptics based on brain-located dopamine receptor blockers are taken for granted. It is also admitted, however, that classical neuroleptics have inconveniences, namely: Their relative lack of effect on negative symptoms, and their liability to induce extrapyramidal symptoms (EPS). Pipamperone-based clinical studies evidenced that an antagonist combining serotonin 5-HT2, and dopamine D2 was successful in the treatment of schizophrenia--which could be clearly observed in (a) anti-autistic effects, (b) regulating disrupted sleep-wake rhythms, and (c) a lesser tendency to EPS. Setoperone-based studies--a compound with a comparable pharmacological profile--confirmed the above observations. Until, however, the synthesis of ritanserin--a specific, and selective antagonistic receptor--was not achieved, no exact implication of 5-HT2 antagonist in psychopharmacological treatments of schizophrenia could be explored further. Indeed, double-blind trials evidenced a remarkable improvement in negative as well as extrapyramidal symptoms. Since a monotherapy appeared as undeniably called for in the treatment of schizophrenia, the next logical step to be taken was selecting a compound with a central antagonism comparable to ritanserins, and a central D2 antagonism comparable to haloperidols. Among a chemical range of benzisoxazole derivatives, risperidone was thus selected. The first double-blind trials on chronic schizophrenic patients seem indeed to confirm that this substance is likely to get over the above mentioned inconveniences, so typical of classical neuroleptics.

Epidural sufentanil for cancer pain control in outpatients.

Fifteen patients with cancer pain refractory to other methods of pain control were treated with epidural sufentanil. They all suffered from very severe or unbearable pain but had expressed the wish to spend the last period of their lives at home. On the first day of hospitalization, an epidural catheter and a portal catheter were implanted under local anesthesia. Sufentanil was delivered by a portable infusion pump into the portal catheter. The patients remained a further 2-3 days in hospital to titrate the infusion rate to their specific needs and to monitor pain relief and possible side effects. In the home situation, the patients were supervised by their general practitioners. Nine patients had epidural sufentanil as their sole analgesic till they died; six patients needed adjunctive nonepidural medications. There were no epidural- or portal-catheter related infections or cases of respiratory depression. After 1651 patient treatment days, we have found continuous epidural sufentanil infusion to be a safe and effective method for cancer pain control in outpatients.

Suppression of colds in human volunteers challenged with rhinovirus by a new synthetic drug (R61837).

This report describes double-blind placebo-controlled trials of a new synthetic antirhinovirus drug, R61837, which showed it to be effective in suppressing colds in human volunteers challenged with rhinovirus type 9. In one trial, R61837 was given by intranasal spray six times a day, commencing 28 h before virus challenge; treatment continued for 4 days and one dose (total dose, 25 mg). This regimen suppressed symptoms until 48 h after medication ceased, at which time colds developed. In another trial, medication with R61837 commenced at 4 h before virus challenge and continued for a total of 6 days (total dose, 36 mg). The drug produced substantial reductions in both the mean daily clinical score and the mean daily nasal secretion weight compared with patients given the placebo. These differences reached statistical significance for 2 and 4 days, respectively. In a further trial, intranasal R61837 was not effective in treating colds even when given shortly after the onset of symptoms and in doses of up to 15 mg/day.

Alfentanil pharmacokinetics and metabolism in humans.

The metabolism of alfentanil was studied in three healthy subjects after a 1-h infusion of 2.5 mg alfentanil-3H. One of the subjects was a poor hydroxylator of debrisoquine. Pharmacokinetic parameters were similar in the three subjects and were in the same range as those reported for volunteers. The majority of the administered radioactivity was excreted in the urine (90% of the dose), but unchanged alfentanil represented only 0.16-0.47% of the dose. Alfentanil and metabolites were characterized by HPLC co-chromatography with reference compounds and/or by mass spectrometry and quantified by GLC and radio-HPLC. The main metabolic pathway was N-dealkylation at the piperidine nitrogen, with formation of noralfentanil (30% of the dose). Other Phase I pathways were aromatic hydroxylation, N-dealkylation of the piperidine ring from the phenylpropanamide nitrogen, O-demethylation, and amide hydrolysis followed by N-acetylation. Glucuronic acid conjugation of aromatic or aliphatic hydroxyl functions was the main Phase II pathway. The second major metabolite was the glucuronide of N-(4-hydroxyphenyl) propanamide (14% of the dose). The metabolite pattern in these subjects was qualitatively very similar to that described previously in rats and dogs. Differences in the mass balance of urinary metabolites between the three subjects were very small, and there was no qualitative or quantitative evidence for a deficiency in the metabolism of alfentanil in the subject who was a poor metabolizer of debrisoquine.

Intranasal sufentanil for pre-operative sedation.

Sufentanil, a short-acting and potent narcotic agent, was studied as a premedicant administered by the nasal route. A total dose of 5 micrograms appeared to be too low, while either 10 or 20 micrograms was very effective in producing sedation. Side effects were minor. There appeared to be no differences between nose drops and spray. In a further study, sufentanil nose drops were compared with saline 0.9% in a double-blind fashion. Sedation of rapid onset but of limited duration was observed in the majority of patients who received sufentanil.

ECG studies with astemizole.

1 Six healthy volunteers took part in a 2-week haemodynamic safety study of astemizole. 2 They were given 30 mg daily (3 X 10 mg tablets) for the first 3 days and 10 mg daily for the next 12 consecutive days. 3 Heart rate, blood pressure, ECG and systolic time intervals at rest were measured before the start and five times during the day. 4 No changes were observed in any of the parameters measured. The configuration of the ECG was not influenced. 5 Serum concentrations of astemizole plus hydroxylated metabolites measured at the end of the study were 16 times lower than those detected in a patient overdosing on 200 mg astemizole.

Clinical profile of astemizole. A survey of 50 double-blind trials.

From clinical-pharmacologic and clinical data involving over 2,800 patients, astemizole appears to be a very effective and well-tolerated antihistamine. It is superior to placebo and commonly used antihistamines for the relief of rhinitis, particularly rhinorrhea and sneezing. It has a pronounced effect on ocular itching and lacrimation in conjunctivitis and on pruritus and wheals in urticaria. This superiority is due to a very specific, almost complete and sustained histamine H1-blockade. The clinical data confirm the experimental data in relation to its lack of sedative effects.

The pharmacokinetic basis of alfentanil infusion.

Owing to the rapid blood:brain equilibration and the short duration of action, alfentanil is well suited for use in infusion techniques. A pharmacokinetic basis is given for alfentanil infusion schemes in patients undergoing routine surgery. Practical schemes can be worked out according to the general principle of a loading dose followed by a maintenance infusion. The loading dose of 100 micrograms kg-1 may be given as a short infusion, as two incremental doses, or as a combination of a single dose and short infusion. The maintenance infusion rate of approximately 1 microgram kg-1 min-1 results in steady-state plasma levels in the therapeutic range in most patients. Application of small extra doses, in addition to the maintenance infusion and modification of the infusion rate, might result in an appropriate and safe anaesthetic technique in most patients and surgical situations.

Practical aspects of alfentanil infusion.

The administration of alfentanil by infusion appears to present advantages for the induction and maintenance of anaesthesia during general surgery lasting over 1 h. The following dosage scheme is proposed: a loading dose of 100 micrograms kg-1, given either in one or two doses, or as a fast infusion administered over 10 min, followed by a maintenance infusion at a rate of 1 microgram kg-1 min-1. During maintenance anaesthesia, the infusion rate should be the lowest possible compatible with adequate analgesic effect, and should be further decreased 15-20 min before the projected end of surgery. Fine control of the opioid effect can be achieved with small increments of 7-15 micrograms kg-1 or by alterations of the alfentanil infusion rate. Breathing should be carefully monitored during the post-operative phase. Dedicated syringe pumps have been designed to avoid laborious calculations of the infusion rates and allow simple, rapid changes of the infusion rate.

Potential of interaction between the H1-antagonist astemizole and other drugs.

Astemizole is a potent H1-antagonist devoid of sedative effects, which was found at single oral daily doses to be very effective in the treatment of allergic rhinitis, allergic conjunctivitis, and urticaria. Its interaction potential on other drugs was studied in various ways. Studies on salivary antipyrine clearance, the 6-beta-hydrocortisol excretion, the elimination rate of ethanol and the indocyanine-green clearance are presented. No changes were observed. Astemizole also was given in combination with diazepam or alcohol. Psychomotor performance failed to show any effects. In none of these studies was there any evidence of interaction of astemizole on other drugs. This review summarizes the data available thus far.

Plasma concentrations of astemizole in patients with terminal renal insufficiency, before, during and after hemodialysis.

Four patients undergoing hemodialysis because of terminal renal insufficiency have taken 10 mg of astemizole on two consecutive days. The elimination was followed for 7 days and was found not to be delayed. During dialysis no decrease of the plasma levels of astemizole and its hydroxylated metabolites were observed. On the contrary, a small nonsignificant increase was found which can be explained by the thickening of the blood after ultrafiltration. It can be concluded that astemizole cannot be eliminated by dialysis because of its high protein binding capacity.

Epidural sufentanil for postoperative pain relief.

An open pilot study was undertaken to evaluate the analgesic properties of epidurally administered sufentanil in the early postoperative period. After orthopaedic surgery of the lower extremity, four different groups of five adult patients each received either 15 micrograms (group 1), 30 micrograms (group 2), 50 micrograms (group 3) or 75 micrograms (group 4) sufentanil via an epidural catheter previously used for the surgical procedure. Results were satisfactory in groups 3 and 4 with very good relief of pain and a mean duration of action of 372 and 307 minutes respectively. Dosage above 50 micrograms did not seem to improve the quality or duration of pain relief, although the onset of action was faster with 75 micrograms. Sedation was always present in patients with effective analgesia. In the present study respiratory depression was not evident, but three patients complained of itching and two of urinary retention.

[Total review of all results collected worldwide with astemizole (Hismanal)]. / Gesamtübersicht über alle weltweit gewonnenen Ergebnisse mit Astemizol (Hismanal).

From the start of the Astemizole clinical investigations, until now the results of 39 trials including more than 2300 patients are available. These results show that Astemizole is an effective and safe Histamine-H1-antagonist for the therapy of hayfever, chronic allergic rhinitis, allergic conjunctivitis, chronic urticaria and allergic bronchitis in adults and children. Astemizole was superior to placebo and the classical antihistamines like Clemastine, Terfenadine, Ketotifen, Mequitazine, pheniramine and Chlorphenamine.