Ability of hydroxypropyl chitosan nail lacquer to protect against dermatophyte nail infection.

The development of a topical agent that would strengthen the nail, improve the natural barrier, and provide better drug penetration to the nail bed is needed. In this study, we examined the effects of a hydroxypropyl chitosan (HPCH)-based nail solution using a bovine hoof model. Following application of the nail solution, changes in the hardness of the hoof samples were measured using the Vickers method. Tensile and flexural strengths were tested by stretching or punching the samples, respectively. The ultrastructure was examined using scanning electron microscopy (SEM), and samples stained with periodic acid-Schiff (PAS) stain were used to determine the fungal penetration depth. The comparators included 40% urea and 70% isopropyl alcohol solutions. The HPCH nail solution increased hoof sample hardness in comparison to the untreated control sample (mean, 22.3 versus 19.4 Vickers pyramid number [HV]). Similarly, the HPCH solution increased the tensile strength (mean, 33.07 versus 28.42 MPa) and flexural strength (mean, 183.79 versus 181.20 MPa) compared to the untreated control. In contrast, the comparators had adverse effects on hardness and strength. SEM showed that the HPCH solution reduced the area of sample crumbling following abrasion compared to the untreated control (7,418 versus 17,843 pixels), and the PAS-stained images showed that the HPCH solution reduced penetration of the dermatophyte hyphae (e.g., penetration by Trichophyton mentagrophytes was <25 µm at day 9 versus 275 µm in the untreated control). Unlike chemicals normally used in cosmetic treatments, repeated application of the HPCH nail solution may help prevent the establishment of new or recurring fungal nail infection.

Validation of bovine hoof slices as a model for infected human toenails: in vitro ciclopirox transungual permeation.

BACKGROUND: Topical therapy has recently been proposed for treating onychomycosis and other nail disturbances. However, the clinical outcome may be limited by the difficulty of active ingredients effectively penetrating the nail plate. Bovine hoof membranes have been widely used to predict in vitro efficacy of drug products in nail diseases. Many studies have compared bovine hooves with human healthy nails, considering the difference between healthy and unhealthy nails to be negligible. OBJECTIVES: To validate bovine hoof slices as a model for human unhealthy nails by investigating the transungual permeation/retention of ciclopirox (CPX) through bovine hoof slices and excised infected human toenails after application of a new film-forming formulation (P-3051). To investigate the ability of CPX to achieve fungicidal concentrations in and through infected toenails. METHODS: A new experimental technique based on a permeation unit allowed analysis by high-performance liquid chromatography of the amounts of CPX permeating through and retained in the membranes. The efficacy index was evaluated as follows: amount of permeated CPX/Trichophyton rubrum minimum inhibiting concentration. RESULTS: Extrapolated CPX flux through bovine hoof slices was about 14-fold higher than through infected human toenails, the difference being mainly due to the fourfold higher thickness of the toenails. In toenails, the CPX efficacy index for T. rubrum was positive (>1·0) soon after P-3051 application. CONCLUSIONS: This study confirms the validity of bovine hoof slices as a model for infected human nails, and suggests a substantial equivalence between the two models. Following P-3051 application, CPX reaches fungicidal concentrations in and through human infected toenails.

Hydrosoluble medicated nail lacquers: in vitro drug permeation and corresponding antimycotic activity.

BACKGROUND: Two nail lacquers, containing ciclopirox (CPX) or amorolfine (MRF), based on water-insoluble polymers are currently considered mainstays of topical treatment of onychomycosis. The present study aimed at evaluating the antimycotic activity of a new water-soluble nail lacquer containing CPX (CPX/sol), easily removable by washing with water and applicable to periungual skin. OBJECTIVES: To compare transungual permeation of CPX with that of MRF in the same hydroxypropyl chitosan-based nail lacquer (MRF/sol) and with a nonwater-soluble reference (Loceryl); Galderma International, La Défense, France), and to evaluate the antimycotic activity of CPX/sol and Loceryl against the most common fungal strains that cause onychomycosis. Methods In vitro drug permeation experiments with CPX/sol, MRF/sol and Loceryl were carried out through bovine hoof slices. Experimental permeates from CPX/sol and Loceryl underwent in vitro susceptibility testing against clinical isolates of dermatophytes, moulds and yeast. Results MRF transungual flux from MRF/sol lacquer was significantly higher when compared with Loceryl. CPX was able to permeate hoof membranes more easily compared with MRF. CPX and MRF concentrations in the subungual fluids collected after application of CPX/sol or Loceryl were sufficient to inhibit fungal growth, with the exception of Candida parapsilosis. Smaller amounts of fluid containing CPX were required for complete inhibition of fungal growth. Efficacy index values were significantly higher for CPX/sol. Conclusions Application of the CPX/sol nail lacquer allows rapid nail penetration of CPX, providing CPX levels sufficient to inhibit fungal growth for a prolonged period of time (30 h) after application of lacquer dose. CPX/sol nail lacquer appeared superior to the market reference Loceryl in terms of both vehicle (hydroxypropyl chitosan) and active ingredient (CPX) as witnessed by its higher efficacy on all nail pathogens.

In vitro transungual permeation of ciclopirox from a hydroxypropyl chitosan-based, water-soluble nail lacquer.

Commercial antimycotic nail lacquers are commonly based on water-insoluble resins. The present study was aimed at evaluating a novel, experimental nail lacquer (P-3051, Polichem SA, Lugano, Switzerland) based on the water-soluble film-forming agent hydroxypropyl chitosan (HPCH). The in vitro permeation of ciclopirox (CPX) from P-3051 and from a commercial, water-insoluble lacquer based on a vinyl resin (Penlac, Aventis Pharma), was investigated using thin membranes obtained from bovine hooves, an accepted model for human nails. Similar CPX permeation fluxes at steady state through the membranes, but significantly different lag times were observed for P-3051 and Penlac, when these were tested as dry films. The formulations thus appeared to influence only the time required by CPX to saturate the membrane, and not the final drug concentration gradient in the membrane. Permeation experiments performed on the same membranes and on hairless mouse skin with P-3051 and with a similar, HPCH-free vehicle (ERV), both tested in liquid form, disproved the possibility that HPCH might act as a permeation enhancer for CPX in either substrate. The possible reasons for the greater efficiency of the HPCH vehicle in terms of CPX transfer from the vehicle itself to the keratin membrane are discussed. This effect might be tentatively attributed to a particular affinity of HPCH for the membrane, resulting in intimate contact and strong adhesion of the HPCH lacquer to the keratin substrate.

Alpha-dihydroergocryptine and predictive factors in migraine prophylaxis.

OBJECTIVE: A double-blind, crossover study was carried out to compare the efficacy of alpha-dihydroergocryptine mesylate (10 mg twice daily) vs propranolol (40 mg twice daily) in the prophylaxis of migraine without aura, and to identify possible predictors of therapeutic response by evaluating the symptomatological profile of individual migraine attacks and the autonomic cardiovascular response to noradrenergic and dopaminergic (cold pressor, bromocriptine) tests. PATIENTS AND METHODS: Forty migraineurs (10 males, 30 females) were randomized according to a two-period (3-month), two-treatment, crossover design. Efficacy was assessed using quantitative data recorded in the patient's headache diary. Data were evaluated using the Wallenstein's method. RESULTS: Both drugs showed a significant reduction in all the efficacy variables (headache attacks, days with headache, analgesic consumption) with no difference between treatments. Neither a bromocriptine test, nor a cold pressor test nor the symptomatological profile of individual migraine attacks differed between the two groups of migraine patients. Ten patients experienced at least one adverse drug reaction during the first period of the crossover design, 5 being treated with alpha-dihydroergocryptine and 5 with propranolol. CONCLUSIONS: It is concluded that alpha-dihydroergocryptine is an effective medication for migraine prophylaxis. The biochemical tests and the type of psychological profile cannot be used to predict drug response.

Alpha-dihydroergocryptine in the treatment of de novo parkinsonian patients: results of a multicentre, randomized, double-blind, placebo-controlled study.

INTRODUCTION: A multicentre, randomized, double-blind, placebo-controlled, parallel group study was carried out in 123 patients suffering from never treated (de novo) idiopathic Parkinson's disease (PD). The aim of the study was to confirm the efficiency and safety of alpha-dihydroergocryptine (alpha-DHEC) given as monotherapy in the symptomatic treatment of PD. The total score of the Unified Parkinson's Disease Rating Scale (UPDRS) was identified as the efficacy target variable. PATIENTS AND METHODS: Sixty-two patients (32 males, 30 females, mean age +/- SD 64 +/- 10) were randomized to alpha-dihydroergocryptine and 61 (30 males, 31 females, mean age 63.8 +/- 9.1) to placebo. According to the experimental design, a 18-month double-blind phase vs placebo was followed. Two interim analyses were planned both at the 3rd and 12th month of treatment, in order to avoid continuation on placebo, if clear differences between groups were found (stopping criterium: nominal significance level equal to 0.022 in the analysis of the target variable). Analysis of variance was performed both on the per protocol (PP) and intent-to-treat (ITT) sample. RESULTS: The results on the first interim analysis showed significant differences between treatment groups of the UPDRS total score both in the ITT (115 patients, alpha-DHEC: No. 56; placebo: No. 59; P=0.019) and PP (96 patients, alpha-DHEC: No. 46; placebo: No. 50; P=0.001) sample, why the trial was stopped. At the time of stopping the trial, 73 patients (alpha-DHEC: No. 37; placebo: No. 36) had reached the 6-month observation visit; the analysis carried out on this subset of patients confirmed the efficacy of alpha-dihydroergocryptine in early PD and the correctness of the decision to stop. The incidence of adverse drug reactions (ADR) did not differ between alpha-dihydroergocryptine and placebo recipients, gastrointestinal complaints being the most frequent. CONCLUSION: The results indicate that alpha-dihydroergocryptine is safe and effective in improving symptoms of de novo parkinsonian patients.

Alpha-dihydroergocryptine in the prophylaxis of migraine: a multicenter double-blind study versus flunarizine.

This multicenter, double-blind, clinical study was designed to compare the efficacy and safety of alpha-dihydroergocryptine and flunarizine in the prophylaxis of migraine without aura. One hundred thirty-five patients fulfilling the diagnostic criteria of the International Headache Society were enrolled at five neurologic centers. The study design included a 1-month pretreatment phase with placebo; a 6-month, double-blind, double-dummy treatment phase with alpha-dihydroergocryptine (10 mg twice daily) or flunarizine (5 mg once daily); a further 3-month follow-up phase without treatment. Efficacy was assessed using the patient's diary. Laboratory tests, vital signs, and adverse events were monitored. Analysis of covariance for repeated measures was performed on the intent-to-treat sample. Both treatments led to a significant reduction in the frequency of migraine, days with headache, and use of relief medication. Overall, 51% of those treated with alpha-dihydroergocryptine and 49% of those treated with flunarizine were responders (50% or greater reduction in attack frequency), the average percentage of reduction being 64% with alpha-dihydroergocryptine and 51% with flunarizine. There was no significant difference between the two groups in terms of incidence of adverse events; dizziness and weight gain were the most frequent observed adverse events with alpha-dihydroergocryptine and flunarizine, respectively. Based on the overall improvement in migraine parameters, alpha-dihydroergocryptine can be recommended for use in migraine prophylaxis.

Toxicological evaluation of pidotimod.

This paper reports the toxicological evaluation of pidotimod ((R)-3-[(S)-(5-oxo-2-pyrrolidinyl) carbonyl]-thiazolidine-4-carboxylic acid, PGT/1A, CAS 121808-62-6). Its acute toxicity in mice, rats and dogs was very low after oral, i.v., i.m. and i.p. administration. The repeated administration studies in rats were performed for 4 months via the i.p. route and for 12 months via the oral route. Pidotimod did not show toxic effects at dosages up to 200 mg/kg i.p. and 800 mg/kg p.o. These dosages correspond to 32.5 times the maximum dosage intended for clinical use. The repeated administration studies in dogs were performed for 26 weeks via the i.m. route and for 52 weeks via the oral route. Pidotimod did not show toxic effects at dosages up to 300 mg/kg i.m. and 600 mg/kg p.o.. It did not affect male or female rat fertility at dosages up to 600 mg/kg by oral and 500 mg/kg by i.v. route. The compound was not teratogenic in rats (600 mg/kg p.o. and 1000 mg/kg i.v.), with no effects on subsequent embryofoetal development at dosages up to 1000 mg/kg/day, and in rabbits (300 mg/kg p.o. and 500 mg/kg. i.v.). There were no peri- and postnatal toxic effects in rats (600 mg/kg p.o. and 500 mg/kg i.v.). Local tolerability of pidotimod after i.m. administration was very good. In conclusion pidotimod is characterized by a high safety margin in all animal species.

Genotoxicity testing of pidotimod in vitro and in vivo.

The mutagenic potential of pidotimod ((R)-3-[(S)-(5-oxo-2- pyrrolidinyl)carbonyl]-thiazolidine-4-carboxylic acid, PGT/1A, CAS 121808-62-6) was assessed in a series of five assays designed to measure gene mutation, chromosomal damage and primary DNA damage. All tests were carried out in accordance with appropriate EEC and OECD Guidelines. No indications of mutagenic potential were observed in any of the assays.

Pharmacokinetics and oral bioavailability of pidotimod in humans.

Pidotimod ((R)-3-[(S)-(5-oxo-2-pyrrolidinyl) carbonyl]-thiazolidine-4-carboxylic acid, PGT/1A, CAS 121808-62-6), a new biological response modifier, was investigated in 3 different pharmacokinetic experiments in healthy volunteers. A first trial was carried out with a cross-over design in 12 subjects, given the drug in single administration by intravenous route (200 mg in bolus) and by oral route at 3 dose levels: 200, 400 and 800 mg (tablets). The second experiment was performed in 36 subjects, by intramuscular route at 50, 100 and 200 mg (12 volunteers/group) twice a day for 15 days. Blood samples were drawn and urine collected at different times after the first and the last administration (29th) of the compound. The third experiment was done in 12 subjects given the product at the same single oral dose (800 mg) in different galenic formulations: sachets, vials and tablets, to assess the relative bioavailability, with a cross-over design. Pidotimod plasma and urinary levels were measured by HPLC. The plasma levels after parenteral administration followed a second-order pharmacokinetic, while after oral administration they were processed by a first order input-output model.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of pidotimod in elderly volunteers and in renal failure patients.

The pharmacokinetics of pidotimod ((R)-3-[(S)-(5-oxo-2-pyrrolidinyl) carbonyl]-thiazolidine-4-carboxylic acid, PGT/1A, CAS 121808-62-6) in elderly volunteers and in patients with renal failures were investigated. No differences in absorption, excretion and pharmacokinetic parameters was evident between old volunteers and the youngs of a previous work. Patients with impaired renal function showed different pharmacokinetic parameters of pidotimod in relation to different grade of kidney function. There were linear relationships between elimination half-lives and plasma levels of creatinine and urea; longer half-lives correspond to higher levels of creatinine and urea. As the half-life of the compound did never exceed 8-9 h, the data do not support any change of pidotimod administration schedule (every 24-12 h).

Evaluation of the mutagenicity of a-dihydroergocryptine in vitro and in vivo.

The mutagenic potential of the ergot alkaloid a-dihydroergocryptine (a-DEC, CAS 14271-05-7) was assessed in a series of 5 assays designed to measure gene mutation, chromosomal damage and primary DNA damage. All tests were carried out in accordance with appropriate EEC and OECD Guidelines. No indications of mutagenic potential were observed in any of the assays.

Effect of dihydroergocryptine on serum prolactin levels and milk secretion in puerperal women.

The aim of the present study was to evaluate the efficacy and tolerability of the dopamine agonist drug dihydroergocryptine in the suppression of puerperal lactation. A single blind and placebo-controlled study was performed. A total of 90 postpartum women was acutely or repeatedly treated with dihydroergocryptine at different doses in order to investigate the efficacy of this drug in the suppression of puerperal lactation and to find the optimum dose for therapy. Prolactin levels, mammary symptomatology and rebound effects were monitored during the repeated treatment and also 1 and 8 days after drug discontinuation. With acute administration, dihydroergocryptine significantly reduced prolactin levels only at the dose of 10 mg and not at 5 mg. With repeated administration, a daily dose of 15 mg was more effective than 10 mg in reducing prolactin levels and in suppressing puerperal lactation. No side-effects occurred during the treatment. These results suggest that dihydroergocryptine might be considered an effective drug in the suppression of puerperal lactation.

[The pharmacokinetics of dihydroergocristine in free-will subjects after oral administration of three formulations]. / Untersuchungen zur Pharmakokinetik von Dihydroergocristin bei freiwilligen Probanden nach oraler Verabreichung von drei Formulierungen.

This paper reports the pharmacokinetics of three dihydroergocristine (DHEC, CAS 17479-19-5) oral formulations in six volunteers. In a randomized crossover trial the volunteers received 6 mg of the drug (1 tablet of 6 mg; 3 ml of drops containing 2 mg/ml; 1 single-dose bottle containing 6 mg); radioimmunoassay was used for the determination of the unchanged drug plasma levels. DHEC shows a plasma profile according to a 3-compartment pharmacokinetic model with a long half-life and high distribution volume. The analysis of AUC0-infinity, Cmax, tmax, and other pharmacokinetic parameters shows that the three formulations investigated are practically bioequivalent.

[The effect of dihydroergocristine on cognitive functions and sleep in elderly subjects]. / Wirkung von Dihydroergocristin auf kognitive Funktionen und Schlaf bei älteren Probanden.

The aim of this study was to assess the effect induced by the dopamine agonist dihydroergocristine (DHEC, CAS 17479-19-5), whose memory-improving activity is well-known, on sleep pattern and cognitive function, and the possible relationship between them. Ten elderly volunteers were included in the study. Selected subjects had to be neither demented nor depressed, according to neuropsychodiagnostic criteria (SCAG < 30, Hachinski dementia score < or = 15, Hachinski ischemic score < 6, HRSD < or = 22). All subjects underwent a nightly polysomnographic evaluation during placebo, after single and long-term once-daily 6 mg DHEC administration. Cognitive function and attention were also assessed by the Randt memory test and WAIS digit-symbol subtest. DHEC caused a marked and significant increase in the acquisition subitem, and memory improvement was documented during DHEC treatment. A significant direct relationship between the effect of DHEC on REM sleep and memory test was also evidenced. Our results confirmed the role of REM sleep in the restoration of cognitive function.

Dihydroergokryptine versus dihydroergotamine in migraine prophylaxis: a double-blind clinical trial.

Dihydroergokryptine has been evaluated in the prophylaxis of headache attacks in patients with migraine without aura. The study was controlled vs dihydroergotamine with a double-blind crossover design. After a 1-month run-in period, 30 patients were randomized into two groups and submitted to 4 months treatment with dihydroergokryptine 10 mg b.i.d. or dihydroergotamine (controlled release) 5 mg b.i.d. The treatment was repeated in crossover after 2 months washout. The clinical patients' evaluation was determined by monthly Pain Total Index recording, headache days/month and analgesic consumption. The patients were considered responsible when Pain Total Index decreased by 50% or more in 1 or more months of each treatment period; otherwise the patients were considered unresponsive. The response rate to dihydroergokryptine was 66% while 48% of cases were responsive to dihydroergotamine. The response rate to both treatments was 41%, while 26% did not respond to either treatment. Seven cases unresponsive to dihydroergotamine responded positively to dihydroergokryptine while two cases only, resistant to dihydroergokryptine, responded positively to dihydroergotamine. Three cases dropped out during treatment with dihydroergotamine due to gastric pain and nausea, while they did not show any side effects during dihydroergokryptine therapy. During treatment with dihydroergokryptine there was one case of skin rash which disappeared after drug withdrawal. In conclusion, dihydroergokryptine appears to be an effective drug for the prophylaxis of migraine attacks.

Pharmacokinetics of alpha-dihydroergocryptine in rats after intravenous and oral administration.

The pharmacokinetic properties of alpha-dihydroergocryptine methanesulphonate (alpha-DHEK, CAS 19467-62-0) were investigated in rat using a radioimmunoassay technique for nonmetabolized drug. alpha-DHEK, intravenously administered at the dose of 6 mg/kg, showed a plasma profile according to an open 3-compartment pharmacokinetic model with a long half-life (about 7.56 h). The kinetics of alpha-DHEK after oral administration (6 mg/kg) showed two peaks; the second peak at 8 h was probably due to an enterohepatic cycle. The disposition of alpha-DHEK consisted in a fast absorption and a slow elimination (t1/2el about 6.78 h). The alpha-DHEK was largely metabolized as results from the complex metabolite profile in body fluids and from very low urinary elimination of unchanged drug.

Pharmacokinetics of alpha-dihydroergokryptine in monkeys after oral administration.

The pharmacokinetic profile of a single dose (6 mg/kg) of alpha-dihydroergokryptine (alpha-DHEK) was established after oral administration in monkeys using a radio-immunoassay technique for non-metabolized drug. alpha-DHEK showed a plasma profile according to an open three-compartment pharmacokinetic model with a long half-life (mean = 5.787 h). The disposition of alpha-DHEK involves a fast absorption, a slow distribution phase and a slow elimination phase. alpha-DHEK showed an high total clearance and distribution volume; the drug is largely metabolized, as concluded from the very low urinary excretion.

Comparison of a vasodilating beta-blocker and a cardioselective beta-blocker in long-term treatment of hypertension: a European multicentre study.

The therapeutic effectiveness and safety of indenolol, a vasodilating beta-blocker with beta 2-agonism, was compared with that of atenolol, a cardioselective beta-blocker, in a 1-year double-blind trial. A total of 143 hypertensive patients (diastolic blood pressure 95-115 mmHg after 1 month of placebo) were randomly allocated to either atenolol, 50 mg/day, or indenolol, 60 mg/day. If the target diastolic blood pressure (less than or equal to 90 mmHg) was not reached after 1 month, the beta-blocker was doubled. If the target was still not reached, a diuretic was added after 2 months and doubled after 4 months. There was a higher overall responsiveness and monotherapy was more effective in the atenolol group, but at the lower dose indenolol was more effective than atenolol; however, no differences between drugs were significant. Although the drop-out rate was higher with indenolol, withdrawals due to side effects were similar in both groups. Indenolol was as effective and safe as atenolol in long-term antihypertensive therapy.