A randomised,placebo-controlled study comparing two formulations of dimenhydrinate with respect to efficacy in motion sickness and sedation

It is known that sedation by H1 antihistaminic drugs can be reduced or avoided if slow release formulations are used for their administration, probably because of a slower increase of the drug concentration in plasma and brain. The aim of this study was to compare two different formulations of dimenhydrinate (CAS 523-87-5), a single fast release tablet with three chewing gums (divided dose principle), with regard to their efficacy in a motion sickness model and their detrimental effect on vigilance and central nervous system (CNS) performance. Caloric stimulation of the eardrum (air at 44 degrees C) was used to induce the symptoms of motion sickness in 24 symptomatic volunteers in a three-way cross-over design comparing three chewing gums (Superpep forte, chewed for 30 min each) containing 20 mg dimenthydrinate each with a 50 mg dimenhydrinate tablet and placebo. During caloric stimulation the following parameters were measured in order to compare efficacy: Quantitative analysis of sodium excretion by sweat (main target parameter), subjective well being (vertigo) by visual analogue scales (VAS) and frequency of binocular nystagmus by computer nystagmography. Unwanted effects on vigilance and CNS performance were measured by means of the N1-P2 peak to peak amplitudes of auditory evoked potentials (AEPs) as an objective, quantitative parameter of vigilance and the latency to correct responses and the number of correct responses (complex choice reaction task) in the oculodynamic test (ODT) as parameters of complex choice reaction ability. As a main efficacy result sodium excretion by sweat was markedly reduced by the chewing gums and by the tablet. The differences to placebo were highly significant (chewing gums vs. placebo p < 0.0001, tablet vs. placebo p < 0.0001). There was no relevant and no significant difference between both medications (p = 0.308). The secondary efficacy parameters, frequency of binocular nystagm and the VAS vertigo were markedly reduced by both medications in comparison to placebo, i.e. both medications were markedly effective. In both cases, however, this result failed statistical significance. The unwanted depressing effects on vigilance and CNS performance of the chewing gums were less pronounced than that of tablets. The N1/P2 peak-to-peak amplitudes of the AEPs were significantly reduced by both the chewing gums and the tablets. The effect of the tablets was, however, larger than that of the chewing gums. This highly significant (tablet vs. chewing gums, p = 0.0003) difference shows that the tablet had a larger depressing effect on vigilance (greater sedation). In line with this result, the number of correct responses in the ODT was markedly and significantly reduced by the tablet (p = 0.0027) but not significantly by the chewing gums (p = 0.8140). The difference between the tablet and the chewing gums was highly significant (p = 0.0052). The complex choice reaction time was markedly and nearly significantly (p = 0.0558) prolonged by the tablet whereas the chewing gums produced only a very small and insignificant prolongation. That the objective measurements of vigilance and CNS performance showed significantly larger detrimental effects of the tablet than of the chewing gums is probably a consequence of a faster increase of the dimenhydrinate concentration in the CNS after administration of the tablet in comparison to the divided dose principle of the chewing gums.     

Microcapsule-gel formulation of promethazine HCl for controlled nasal delivery: a motion sickness medication

The current method of choice for astronauts to treat space motion sickness is an intra-muscular injection of promethazine hydrochloride (PMZ HCl) which is invasive and causes considerable local irritation and discomfort at the site of injection. Intra-nasal delivery is considered a feasible alternative route for administration of medications to treat space motion sickness. The purpose of this research is to develop a PMZ HCl formulation that can be administered intra-nasally without irritation (i.e. leukocyte infiltration) in the nasal epithelium when dosed at PMZ HCl concentrations greater than the cytotoxic limit. The biocompatibility of PMZ HCl was tested in vitro and was shown to be cytotoxic at concentrations greater than 10(-5) molar regardless of pH. A controlled-release microencapsulated dosage formulation was developed using spinning disk atomization and release rates for the PMZ HCl microcapsules were determined in phosphate buffered saline. An animal study was conducted to determine the irritation response of rat nasal mucosa when dosed with encapsulated and non-encapsulated PMZ HCl.     

Decongestant activity of a new formulation of xylometazoline nasal spray: a double-blind,randomized versus placebo and reference drugs controlled,dose-effect study

Xylometazoline hydrochloride is an imidazoline derivative commonly used in topical application to relieve nasal congestion associated with acute or chronic rhinitis, common cold, sinusitis and hay fever or other allergies. To reduce the negative effects on the mucosal defensive mechanism, a new formulation of xylometazoline (Rhinostop) with inactive preservatives and hyaluronic acid (HA) was studied. The most appropriate concentration of xylometazoline and its decongestant activity in the new formulation were investigated in a double-blind, dose-effect study. The new formulation at three different concentrations of xylometazoline (0.025%, 0.05% and 0.1%) was compared with a placebo formulation, three equivalent aqueous solutions containing xylometazoline (without HA) and a reference formulation, containing benzalkonium chloride as preservative. The drugs' efficacy in reducing airflow resistance was also evaluated. The effects of xylometazoline on inspiratory and expiratory nasal resistance were found to be concentration-dependent. Indeed, the new formulation at a concentration of 0.05% was more effective than the new formulation at a concentration of 0.025%, but was statistically equivalent to the new formulation at a concentration of 0.1%; therefore, the 0.05% concentration of xylometazoline seemed to achieve maximal decongestant activity. These findings were confirmed by the observation that the efficacy of the new formulation at a concentration of 0.05% was also statistically comparable to that of the reference formulation and the aqueous solution of xylometazoline 0.1%. HA seems to act as an enhancer/carrier of the active principle, xylometazoline, as already demonstrated for other drugs. The new formulation at a concentration of 0.05% was therefore selected for further clinical development.     

Alcoholism and depression: a placebo controlled study with viloxazine

Depressive disorders are frequently associated with alcohol abuse. Though many studies have been carried out to clarify the role of antidepressant drugs in the management of alcoholic patients, the data are controversial. The present placebo-controlled study was planned to assess the antidepressant and attenuating drinking-behaviour efficacy of viloxazine (400 mg per os daily) versus a placebo in 30 dysthymic patients affected by alcohol dependence. The results significantly favour viloxazine treatment in alleviating depression and in reducing alcohol abuse. All patients showed baseline haematochemical evidence of liver dysfunction that did not change significantly during the treatment.     

A replicate study design for testing bioequivalence: a case study on two desmopressin nasal spray preparations

Objective The present study was carried out to test bioequivalence between two different desmopressin nasal spray preparations. Due to the high variability of plasma pharmacokinetics of intranasally administered peptides like desmopressin, appropriate study designs are required to assess bioequivalence. Therefore, a single-dose, replicate study design was used to evaluate bioequivalence of two desmopressin nasal sprays.Subjects and methods Thirty-two healthy male volunteers were enrolled in the study and were randomly assigned to receive the test- and reference drug on two occasions in a 4-period 2-sequence crossover study design. Subjects received a single dose of 20 µg (10 µg per nostril) of desmopressin-acetate per study day separated by wash-out periods of at least 1 week. Desmopressin blood concentrations were measured serially over a 14-h period using a validated radioimmunoassay method. Statistical analysis was initially performed using a complicated mixed-analysis model testing for individual bioequivalence according to recommendations by the Food and Drug Administration. This approach, however, failed to converge with all defined main PK parameters and, thus, a traditional mixed analysis of variance analysis based on population averages was definitely used for testing bioequivalence between study drugs. The procedure of selecting an appropriate statistical analysis for a replicate study design was predefined in the study protocol.Results The 90% confidence intervals (CI) were calculated for the area under the time–concentration curve (AUC), maximum concentration (C_max) and the time to reach C_max (t_max) of test/reference drug ratios for a bioequivalence range from 0.80–1.25. The mean test/reference drug ratios were completely within the 90% CIs with values of 1.041 (CI: 0.892–1.216), 1.021 (CI: 0.913–1.140) and 1.068 (CI: 0.914–1.249) for AUC_{0–14 h}, C_max and t_max, respectively.Conclusion The rate and the extent of intranasal desmopressin absorption are identical for both study preparations. Thus, the desmopressin test preparation met all equivalence criteria and thereby was proven bioequivalent with a marketed reference nasal desmopressin spray.Further details on authors can be obtained at     

Comparative study on the bioequivalence of two formulations of pravastatin. Data from a crossover, randomised, open-label bioequivalence study in healthy volunteers

An open-label, randomised, crossover single-dose study, using two periods, two sequences, with a minimum washout period of 7 days, was conducted in order to assess the comparative bioavailability of a pravastatin (CAS 81131-70-6) 40 mg formulation and that of a reference formulation. Blood samples were collected up to +14 h post dosing, the plasma was separated and pravastatin concentrations were determined by high-performance liquid chromatographic method with tandem mass spectrometry detection (HPLC-MS/MS), with a lower limit of quantification of 0.40 ng/mL. Bioequivalence analyses were conducted using two models. The main analysis was done according to a general linear model (model I) using formulation, period and sequence as fixed model effects, and subject(sequence) and residual as random effects; gender-related differences were investigated using ANOVA (model II), including formulation, period, sequence, gender, sequence-by-gender interaction and gender-by-formulation interaction as fixed model effects and subject within sequence-by-gender interaction and residual as random effect. Mean values of the individual Cmax were 126.73 +/- 61.99 ng/mL and 123.52 +/- 52.78 ng/mL for the test and reference, spectively. Mean +/- SD total area under the curve up to the last measurable concentration (AUClast) was 224.26 +/- 104.74 ng x h/mL for the test formulation and 216.55 +/- 80.30 ng x h/mL for the reference formulation. Mean +/- SD total area under the curve (AUCinf) was 226.72 +/- 104.69 ng x h/mL for the test formulation and 218.81 +/- 79.95 ng x h/mL for the reference. Terminal elimination half-life was 2.15 +/- 0.85 h for test and 1.97 +/- 0.54 h for the reference. Ninety percent confidence intervals were comprised within the bioequivalence acceptance criteria (80-125 %) for all of the parameters analysed, both using model I and model II. Model II returned a statistically significant gender effect (p < 0.05) for Cmax, AUClast and AUCinf but the effect became non-significant (p > 0.05) when the dose was adjusted per body weight for all three parameters. The comparison between male and female mean body weight showed a significant difference: p = 0.03, 95 % confidence intervals 68.27-76.93 kg (men), 56.84-60.61 kg (women). These results suggest that the effect of gender in the bioequivalence analysis in model I could be due to a difference in body weight between males and females. Both formulations were shown to be bioequivalent in terms of rate and extent of absorption, irrespectively of the model used.     

Beta-adrenoceptor blockade and hypoglycaemia. A randomised, double-blind, placebo controlled comparison of metoprolol CR, atenolol and propranolol LA in normal subjects.

1. The effect of 1 week of treatment with propranolol LA (160 mg), atenolol (100 mg) and metoprolol CR (100 mg) on awareness of and the physiological responses to moderate hypoglycaemia were compared with placebo using a randomised, cross-over design in 12 healthy volunteers. 2. All three beta-adrenoceptor antagonists reduced resting heart rate, systolic blood pressure and heart rate responses to submaximal exercise compared with placebo. 3. Under hyperinsulinaemic (60 mu m-2 min-1) clamp conditions, at a blood glucose of 2.5 mmol l-1, atenolol prevented the rise in systolic and atenolol and metoprolol CR prevented the fall in diastolic blood pressure usually associated with hypoglycaemia. At this level of hypoglycaemia, the expected increase in heart rate was inhibited by atenolol but not metoprolol CR. Pre-treatment with propranolol LA resulted in a significant pressor response and a bradycardia during hypoglycaemia. In addition the normal increase in finger tremor was abolished by propranolol LA. 4. During hypoglycaemia all three beta-adrenoceptor blockers augmented sweating compared with placebo but hypoglycaemic symptoms, awareness and slowing of reaction time were the same with drugs and placebo. 5. The rise in plasma adrenaline and other counter-regulatory hormones during hypoglycaemia was enhanced by beta-adrenoceptor blockade. 6. We conclude that beta-adrenoceptor antagonists modify the physiological and hormonal responses to, but do not adversely affect awareness of, moderate hypoglycaemia in healthy volunteers.     

Piracetam in alcoholic organic mental disorder: a placebo controlled study comparing two dosages

The following paper presents an investigation of the efficacy of piracetam in alcoholic organic mental disorder. A double-blind placebo-controlled study design was used to compare 2 dosages of the substance (2 X 3 g vs. 2 X 12 g). Cognitive function was assessed on days 0, 7, 14, 28, 42. Analysis of the results from 24 patients showed a clear-cut amelioration of cognitive functions in all 3 treatment groups. No difference could be demonstrated between the administration of placebo and the lower dose of piracetam. Patients on the higher dose showed an earlier improvement on one of the tests, but the final scores were similar in all three treatment groups.     

Speed of onset, efficacy and tolerability of zolmitriptan nasal spray in the acute treatment of migraine: a randomised, double-blind, placebo-controlled study

INTRODUCTION: Migraine is a common, disabling condition that has a significant impact on patients and relatives, and is a considerable economic burden on society. Migraine patients want fast-acting treatments with high efficacy. Previous studies have demonstrated that orally administered formulations of zolmitriptan are rapidly and highly effective in the acute treatment of migraine. The objective of this study was to assess the efficacy, speed of onset and tolerability of the nasal spray formulation of zolmitriptan in migraine treatment. METHODS: This multicentre, randomised, double-blind study recruited 2122 patients (aged 18-65 years) who had an established diagnosis of migraine (according to International Headache Society criteria), with or without aura. Patients were randomised to receive zolmitriptan 5mg nasal spray or placebo to treat up to two migraine attacks within 15 minutes of headache pain becoming moderate or severe. The primary endpoint was headache response (reduction in migraine pain from severe/moderate to mild/none) at 2 hours, 1 hour, 30 minutes and 15 minutes post-dose (analysed using a step-down approach). Secondary endpoints included headache response at 4 hours, pain-free rates at 30 minutes and 1, 2 and 4 hours, and sustained headache response and pain-free status at 24 hours post-dose. RESULTS: The headache response rate at 2 hours post-dose was 66.2% for the zolmitriptan group, compared with 35.0% for the placebo group (p < 0.001). Zolmitriptan nasal spray also produced significantly higher headache response rates than placebo at all earlier timepoints assessed, starting as early as 15 minutes post-dose (p < 0.001). Similar results were obtained for the analysis of the first attack. Significantly higher pain-free rates were obtained with zolmitriptan nasal spray, compared with placebo, from 15 minutes post-dose onward (p < 0.005). Zolmitriptan nasal spray was also significantly superior to placebo for headache response at 4 hours, sustained headache response at 24 hours and sustained pain-free rate at 24 hours.Zolmitriptan nasal spray was well tolerated, with most adverse events being of short duration and mild or moderate intensity. CONCLUSIONS: Zolmitriptan nasal spray is highly effective in the acute treatment of migraine and has a very fast onset of action, producing significant headache response and pain-free rates as early as 15 minutes post-dose (the earliest assessment in this study). In addition to the very fast onset of action, zolmitriptan nasal spray produced significantly higher sustained headache response and pain-free rates at 24 hours post-dose compared with placebo. These desirable efficacy outcomes were combined with good tolerability.     

A double-blind crossover comparison of lidamidine, loperamide and placebo for the control of chronic diarrhoea

Fourteen patients with chronic diarrhoea, but no evidence of active organic disease, completed a double-blind crossover comparison of the anti-diarrhoeal effects of loperamide, placebo and the clonidine analogue, lidamidine. Failure of diarrhoea control led to early withdrawals from seven placebo- and six lidamidine-treatment periods, but there was only one early withdrawal during treatment with loperamide. Loperamide was found to be superior to lidamidine or placebo for the control of stool consistency in patients with chronic diarrhoea.     

Terfenadine and placebo compared in the treatment of chronic idiopathic urticaria: a randomised double-blind study.

Terfenadine, a potent and non-sedative antihistamine, was shown to be effective in chronic idiopathic urticaria in a double-blind crossover placebo controlled trial. An oral twice daily 60 mg dose of terfenadine was given and itch and wheal parameters were assessed daily. Despite the overall effectiveness of terfenadine, a variable response was noted which was similar to that shown in previous studies with other antihistamines.     

Recurrent oral ulceration treated with Mysteclin: a controlled study.

Twenty patients with recurrent oral ulceration participated in a placebo-controlled, double-blind trail of Mysteclin syrup (tetracycline hydrochloride and amphotericin) used as a mouthwash. Though a small, consistent improvement occurred with placebo, there was a significant reduction in mean pair scores and numbers of new ulcers recorded daily during the active-treatment periods, the effect lasting for at least four weeks after treatment was stopped. In contrast to topical steroid preparations, Mysteclin syrup is efficacious when begun at any stage of the disorder and is not associated with adverse systemic effects.