Development of antimigraine transdermal delivery systems of pizotifen malate.

The aim of this study was to develop and evaluate a transdermal delivery system of pizotifen malate. Pizotifen is frequently used in the preventive treatment of migraine, but is also indicated in eating disorders. In the course of the project, the effects of chemical enhancers such as ethanol, 1,8-cineole, limonene, azone and different fatty acids (decanoic, decenoic, dodecanoic, linoleic and oleic acids) were determined, first using a pizotifen solution. Steady state flux, diffusion and partition parameters were estimated by fitting the Scheuplein equation to the data obtained. Among the chemical enhancers studied, decenoic acid showed the highest enhancement activity, which seemed to be due to the length of its alkyl chain and unsaturation at the 9th carbon. The influence of iontophoresis and the involvement of electrotransport in said process was determined. The absorption profile obtained with iontophoresis was similar to that obtained with fatty acids and terpenes, though skin deposition of the drug was lower with the former. Transdermal delivery systems (TDS) of pizotifen were manufactured by including chemical enhancers, decenoic acid or oleic acid, and were subsequently characterized. When the results obtained with solutions were compared with those obtained with the TDS, a positive enhancement effect was observed with the latter with respect to the partitioning and diffusion of the drug across the skin. Our findings endorse the suitability of our TDS for delivering therapeutic amounts of pizotifen malate.

HPLC-UV analytical method for determination of pizotifen after in vitro transdermal diffusion studies.

Pizotifen malate is an antihistamine and serotonin inhibitor used in the preventive treatment of migraine and eating disorders. A simple, rapid, accurate and precise high-performance liquid chromatography (HPLC) method involving ultraviolet detection was validated for the quantitative analysis of pizotifen malate in samples from in vitro transdermal diffusion studies. The method was validated for specificity, linearity, accuracy, precision, limit of detection, limit of quantification and robustness. Drug stability in the solution was also determined under different conditions. Separation was carried out using a 250 × 4.0 mm Kromasil(®) C(18) column at room temperature. The detector response, fitted at 254 nm, was found to be linear in a concentration range between 0.24 and 24.0 µg/mL. The limit of detection was 0.02 µg/mL and the limit of quantification was 0.07 µg/mL. Finally, in vitro transdermal diffusion of pizotifen malate was characterized using the validated HPLC method.

Pizotifen Activates ERK and Provides Neuroprotection in vitro and in vivo in Models of Huntington's Disease.

BACKGROUND: Huntington's disease (HD) is a dominantly inherited neurodegenerative condition characterized by dysfunction in striatal and cortical neurons. There are currently no approved drugs known to slow the progression of HD. OBJECTIVE: To facilitate the development of therapies for HD, we identified approved drugs that can ameliorate mutant huntingtin-induced toxicity in experimental models of HD. METHODS: A chemical screen was performed in a mouse Hdh(Q111/Q111) striatal cell model of HD. This screen identified a set of structurally related approved drugs (pizotifen, cyproheptadine, and loxapine) that rescued cell death in this model. Pizotifen was subsequently evaluated in the R6/2 HD mouse model. RESULTS: We found that in striatal Hdh(Q111/Q111) cells, pizotifen treatment caused transient ERK activation and inhibition of ERK activation prevented rescue of cell death in this model. In the R6/2 HD mouse model, treatment with pizotifen activated ERK in the striatum, reduced neurodegeneration and significantly enhanced motor performance. CONCLUSIONS: These results suggest that pizotifen and related approved drugs may provide a basis for developing disease modifying therapeutic interventions for HD.

P3MC: a double blind parallel group randomised placebo controlled trial of Propranolol and Pizotifen in preventing migraine in children.

BACKGROUND: A recent Cochrane Review demonstrated the remarkable lack of reliable clinical trials of migraine treatments for children, especially for the two most prescribed preventative treatments in the UK, Propranolol and Pizotifen.Migraine trials in both children and adults have high placebo responder rates, e.g. of 23%, but for a trial's results to be generalisable "placebo responders" should not be excluded and for a drug to be worthwhile it should be clearly superior, both clinically and statistically, to placebo. METHODS/DESIGN: Two multicentre, two arm double blind parallel group randomised controlled trials, with allocation ratio of 2:1 for each comparison, Propranolol versus placebo and Pizotifen versus placebo. The trial is designed to test whether Propranolol is superior to placebo and whether Pizotifen is superior to placebo for the prevention of migraine attacks in children aged 5-16 years referred to secondary care out-patient settings with frequent migraine (2-6/4 weeks). The primary outcome measure is the number of migraine attacks during trial weeks 11 to 14. DISCUSSION: A strength of this trial is the participation of clinically well defined migraine patients who will also be approached to help with future longer-term follow-up studies. TRIAL REGISTRATION: ISRCTN97360154.

Weight gain with pizotifen therapy.

OBJECTIVE: To describe the characteristics of weight gain occurring in children treated for migranous conditions with pizotifen DESIGN: Retrospective case note review SETTING: West Suffolk Hospital between 1999 and 2003 PATIENTS: 405 clinic attendances of 121 children receiving pizotifen treatment MAIN OUTCOME MEASURES: Rates of change in weight for age z score between successive outpatient appointments were used to detect excessive weight gain. RESULTS: The mean rate of weight z score increase for 105 patients receiving a constant dosage in 181 intervals between appointments was 0.79 standard deviations per year compared with 0.11 standard deviations per year for height z score increases. The rate of weight z score increase was not correlated with pizotifen dose per kg (r = -0.08), per m(2) (r = -0.05) or initial body mass index (r = -0.04). Mean rates of z score increase were similar in patients with a satisfactory and unsatisfactory therapeutic responses. CONCLUSIONS: Excess weight gain in pizotifen therapy is not predicted by drug dosage or therapeutic response within the range of doses used in clinical practice.

Síndrome confusional por pizotifeno / No disponible

No disponible

Weight variations in the prophylactic therapy of primary headaches: 6-month follow-up.

We conducted a study on 367 patients (86% female, 14% male; mean age 37+/-15 years) suffering from migraine with and without aura and chronic tension-type headache to evaluate the incidence of weight gain, an undesirable side effect observed during prophylactic therapy in primary headaches. Patients treated with amitriptyline (20 and 40 mg), pizotifen (1 mg), propranolol (80-160 mg), atenolol (50-100 mg), verapamil (160-240 mg), valproate (600 mg) and gabapentin (900-1200 mg) were evaluated after a period of 3 and 6 months. In particular, 89 patients were assessed (78% female, 22% male) at 6 months, of whom 10 were in treatment with amitriptyline 20 mg, 19 with amitriptyline 40 mg, 7 with pizotifen (1 mg), 13 with propranolol (80-160 mg), 4 with verapamil (160 mg), 10 with valproate (600 mg), 15 with atenolol (50 mg) and 11 with gabapentin (900-1200 mg). The control group consisted of 97 patients with migraine (79% female, 21% male; mean age 35+/-16 years) without indication for prophylactic therapy. Weight variations >or=1 kg were considered. After 6 months of therapy, the percentage of patients with weight gain was 86% with pizotifen (6/7; mean weight increase 4.4+/-2.5 kg), 60% with amitriptyline 20 mg (6/10; 3.1+/-1.6), 47% with amitriptyline 40 mg (9/19; 5.4+/-2.7), 25% with valproate 600 mg (2/8, 3.0+/-2.8 kg), 25% with verapamil (1/4, 2.5 kg), 20% with atenolol (3/15, 1.7+/-0.6 kg), 9% with gabapentin (1/11, 1.5 kg) and 8% with propranolol (1/13; 6 kg). We conclude that propranolol, gabapentin, atenolol, verapamil and valproate affect body weight in a modest percentage of patients at 6 months. A greater mean weight gain at 6 months was found in patients treated with pizotifen, amitriptyline, and, in one patient out of 13, with propranolol.

[Current views on migraine and anti-migraine preparations]. / Sovremennye predstavleniia o migreni i mekhanizmakh deistviia sredstv dlia ee lecheniia i profilaktiki.

On the basis of comprehensive experimental and clinical research the authors defined a variety of migraine-related mechanisms and schemes of migraine-correction by drugs, which should be both of the vascular- and general-actions to ensure an effective medication.

[Effectiveness of tolfenamic acid in the prevention of migraine]. / Tolfenamines rugsties veiksmingumas migrenos profilaktikai.

The migraine prophylactic effect of tolfenamic acid 300 mg versus pizotifen 1.5 was evaluated in a prospective, randomized, double-blind, parallel group study. 192 patients were included with a frequency of 4-8 moderate to severe migraine attacks monthly, with or without aura, fulfilling the diagnostic criteria for migraine as defined by the International Headache Society. A four-week baseline period without medication was followed by 12 weeks of treatment with tolfenamic acid 300 mg or pizotifen 1.5 mg. In both periods patients were allowed to take escape medication (paracetamol and codeine) if the treatment was inefficient. All the patients had a headache diary before and during treatment. The primary criterion of efficacy was reduction in attack frequency per 4 weeks. Also reduction in intensity or duration of migraine attacks in hours at the end of 12 weeks treatment compared to the baseline period was measured. Both groups exhibited significant reduction in attack frequency (p < 0.001). Tolfenamic acid significantly reduced severity compared to the run-in period (p = 0.009). Patients treated with pizotifen needed more escape medication when compared to the run-in period (p < 0.01). Tolerance, especially weight gain, was a major drawback with pizotifen. Because of its high efficacy, excellent tolerability and low cost, tolfenamic acid is an interesting option for migraine prophylaxis.

Cyclic vomiting syndrome in Thai children.

Cyclic vomiting syndrome (CVS) is a severe childhood vomiting disorder of unknown etiology and pathogenesis. Clinical manifestations and prophylactic therapy of vomiting have been described in the literature. The data were limited in Asian children. The aim of this study was to study the clinical manifestation, to evaluate using antimigraine prophylactic drugs and response in Thai children with CVS. The medical records of children with a diagnosis of CVS in the Department of Pediatrics, Siriraj Hospital, Mahidol University from 1994 to 2001 were retrospectively reviewed. Demographic data, clinical manifestations, investigations, treatment and outcome were collected and analyzed. Twenty five patients were enrolled in this study including 13 females and 12 males. Their ages ranged from 2.3 years to 14 years (7.8 +/- 3.4 years). The age of onset was 5.2 +/- 3.2 years. They had 14.7 +/- 6.5 episodes per year with a duration of each attack 4 +/- 1.8 days. There were 8 mild, 10 moderate and 7 severe cases. There were only 6 patients (24%) who had headache and 50 per cent of these had a family history of migraine. Eight patients received pizotifen which had 3 good, 1 fair, and 4 poor responses. Of this group, in 3 patients pizotifen was changed to amitriptyline. Eighteen patients received amitriptyline and the result of treatments were 11 good, 4 fair, and 3 poor. The other 2 patients were on propranolol with one good and one poor responses. The efficacy of amitriptyline and pizotifen were compared (83.3% vs 50%) which revealed no statistical significance (p = 0.14). There was no side effect from any of the medication in this study. In conclusion, the present report showed similar data of clinical features, prophylactic treatment and outcome as previous reports, except for fewer migraine headaches in patients and their families. Amitriptyline and pizotifen were effective in prophylactic therapy of vomiting episodes.

Noncompliance may render migraine prophylaxis useless, but once-daily regimens are better.

Medicines work better if taken, which must be true of migraine prophylaxis. There is evidence that compliance with regular medication can be badly deficient. To assess how serious the problem might be in routine migraine management, we undertook a covert observational 2-month survey in a specialist headache clinic using objective measures of compliance. Subjects were 38 patients needing prophylaxis with medication prescribed once (od), twice (bd), or three times daily (tds). Medication was dispensed, unknown to them, in Medication Event Monitoring Systems (MEMS) to record openings in real time. Number, timing, and pattern of actual openings were compared with what was expected. Compliance rates averaged 66%, although returned pill counts indicated 91%. A substantial and significant difference was shown between od and bd or tds regimens. Measures of dosing interval--used-on-schedule rate and therapeutic coverage--averaged between 44% and 71%. Once-daily treatment was associated with a used-on-schedule rate more than double those of multiple daily dosing, but still only 66%. We conclude that routine use of drug prophylaxis in migraine may be so seriously undermined by poor compliance that it has little chance of efficacy. Returned-pill counting is inadequate for compliance assessment.

Monotherapy or polytherapy in migraine.

The majority of current therapeutic papers concerns the prophylactic therapy of migraine using only one drug, very few advocating the simultaneous use of two drugs. The theoretical usefulness of polytherapy in migraine is examined with examples from personal experience, and found justified.

Flunarizine-pizotifen single-dose double-blind cross-over trial in migraine prophylaxis.

The results of a double-blind cross-over clinical trial involving 27 patients with classical or common migraine are described to compare the prophylactic effect of the calcium entry blocker flunarizine with that of pizotifen. Duration of the treatment was two months, with an evening single-dose administration of both drugs. For most parameters, there was no definite difference between flunarizine and pizotifen in migraine prophylaxis. It has been demonstrated previously that pizotifen is an effective drug in migraine prophylaxis, and these results suggest that flunarizine is effective, too. Weight gain as a side effect was less frequent and less severe with flunarizine than with pizotifen; other side effects showed the same incidence with both drugs.

Metoprolol and pizotifen in the prophylactic treatment of classical and common migraine. A double-blind investigation.

The prophylactic anti-migraine effect of the serotonin antagonist pizotifen and the beta 1-selective beta-adrenoceptor antagonist metoprolol was compared in a double-blind cross-over study. The dosage of pizotifen was 0.5 mg t.i.d. and that of metoprolol 50 mg b.i.d. Thirty-five patients with classical or common migraine were included in the investigation. Five patients withdrew during the course of the study; four because of side effects (three on pizotifen, one on metoprolol) and one because of unassociated illness. The results show that there was no statistically significant difference in efficacy between metoprolol and pizotifen. The tolerance, especially regarding weight gain, was the major drawback with pizotifen, while metoprolol was generally well tolerated.

Pizotifen once daily in the prophylaxis of migraine: results of a multi-centre general practice study.

In an open, multi-centre, general practice study, 834 patients were entered to determine the efficacy and tolerance of pizotifen in a dose of 1.5 mg at night in the prophylaxis of migraine. Patients took pizotifen for 2 months after a run-in period of 1 month on previous prophylactic therapy. The results from the 307 patients who fully completed daily diary cards showed that pizotifen significantly reduced the mean number of migraine attacks per month and, on general questioning, the majority of patients said that they found pizotifen beneficial. The most frequent side-effects reported were drowsiness, although in one-third of affected patients this was transient, and weight gain, where the average increase was 0.7 kg (1.5 lb) over 2 months.

Effects of chronic treatment with antidepressants on aggressiveness induced by clonidine in mice.

It has previously been found that a number of typical and atypical antidepressants, given chronically, intensify clonidine-induced aggressiveness in mice. Further experiments now show that chronic, but not acute, administration of nisoxetine, a selective inhibitor of noradrenaline uptake, potentiates clonidine-induced aggressiveness. Citalopram and fluvoxamine, two selective inhibitors of serotonin uptake, have no such action. Of the two isomers of flupenthixol, only the trans-form potentiates clonidine-induced aggressiveness of chronic experiments. The cis-form induces an inhibiting effect. Clonidine-induced aggressiveness is also intensified by chronic, but not by acute, administration of pizotifen, an antagonist fo serotonin and noradrenaline. The results seem to support the previous hypothesis that potentiation of clonidine-induced aggressiveness is mediated by an alpha 1-adrenergic mechanism.