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.

Dihydroergocriptine in management of microprolactinomas.

The effects of dihydroergocriptine (DHECP), a dihydrogenated ergot alkaloid with dopaminergic agonistic and alpha-adrenergic antagonistic properties, were studied in 22 women with PRL-secreting microprolactinomas and compared with those recorded in 36 previously studied patients treated with bromocriptine (BRC). After acute administration of 5 mg DHECP, orally, serum PRL decreased by 61 +/- 18% (+/- SD); only 1 patient was unresponsive. The nadir was reached at 300 min. Long term treatment with increasing DHECP doses caused a progressive PRL fall from 125 +/- 142 (+/- SD) to 81 +/- 159 micrograms/L after 1 week of a 3 mg twice daily regimen, to 64 +/- 88 micrograms/L after 1 week of 5 mg twice daily, 46 +/- 57 micrograms/L after 1 week of 10 mg twice daily, and 28 +/- 34 to 33 +/- 45 micrograms/L throughout 9 months of treatment with 10 mg DHECP 3 times daily. Seventy-seven percent of patients had normal serum PRL levels during chronic treatment. All women, including those with supranormal serum PRL levels, resumed regular menses, and 16 had ovulatory cycles; 1 woman became pregnant. Galactorrhea disappeared in all. During treatment the PRL response to TRH, initially absent in all patients, became positive in 10. In 7 patients, after DHECP treatment for 9 months, high definition computed tomographic scan no longer showed the focal lesions initially seen. After drug withdrawal, serum PRL increased again in all except 1 patient. Two patients had regular menses for 6 months, and 3 still had no adenoma imaged by high definition computed tomography. In BRC-treated patients the serum PRL changes and clinical results were very similar to those in the DHECP-treated patients, except for the persistence of normal serum PRL levels in 4 patients after drug withdrawal. On the other hand, side-effects were negligible during DHECP treatment, but remarkable during BRC. Systolic and diastolic blood pressures decreased by only 5.4 and 3.0 mm Hg, respectively, after acute 5 mg DHECP administration, but decreased by 12.8 and 14 mm Hg after acute 2.5 mg BRC administration. Orthostatic hypotension and peripheral vasomotor phenomena occurred in the long term DHECP treated patients except one, but they occurred in 9 and 3 of those treated with BRC, respectively. Gastric discomfort or mild nausea occurred in 12 DHECP-treated patients, while mild or severe nausea or vomiting were observed in 18, 11, and 2 of those taking BRC, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)

Indenolol in hypertension.

After a complete washout 14 hypertensive inpatients were given placebo for 3 days. Undistinguishable 30- or 60-mg indenolol tablets were then given twice daily for 14 days in a double-blind, randomized manner. Supine and standing arterial pressure and heart rate were measured at rest three times a day. Indenolol decreased systolic and diastolic arterial pressure as well as heart rate in subjects in supine and standing positions. Placebo had no effect. The effect of indenolol on systolic arterial pressure was dose and time related, but independent of the intensity of hypertension. No dose-effect relationship was found on diastolic arterial pressure. Decrease of heart rate was dose and time related, although bradycardia was never noted. Indenolol was well tolerated.

Indenolol pharmacokinetics and pharmacodynamics after single and repeated daily doses.

The relationship between indenolol (an investigational agent) plasma levels and the drug's effect on blood pressure and heart rate was investigated after single and repeated once daily administration at two dosage levels (60 mg and 120 mg) in two different groups of patients with first or second stage hypertension, according to the World Health Organization classification. The pharmacokinetic data were indicative of a first order absorption-elimination curve; time of maximum plasma levels was 1.5 to two hours, and elimination half-life was four hours. The drug did not accumulate in the central compartment after repeated administrations. A long-lasting decrease of both resting and isometric exercise systolic pressure values was recorded after acute indenolol administration. Diastolic pressure was affected only by repeated administrations. The lower dose (60 mg daily) of indenolol did not affect heart rate, whereas the higher dose (120 mg daily) decreased this parameter. A steady state of pressure values and heart rate was reached after 14 days of once daily treatment.

The effects of amineptine on the mood and nocturnal sleep of depressed patients.

The effect of amineptine, a new tricyclic antidepressant, was studied on the sleep of 12 depressed patients. A single blind comparative trial vs placebo was carried out and changes in depression symptoms were recorded using Hamilton Rating Scale for Depression (HRSD). The sleep was evaluated according to the Rechtschaffen and Kales criteria to determine various parameters. Amineptine treatment induced statistically significant reduction of HRSD total score after 14 days of treatment. Polysomnographic analysis revealed significant differences between depressed patients and healthy volunteers.

Amineptine in the management of the depressive syndromes.

The antidepressant activity of amineptine was evaluated in 34 patients in a double-blind study vs clomipramine. Clinical results, assessed using the Hamilton rating scale for depression, failed to show any significant difference in the activity of the two drugs. Amineptine was however much better tolerated than clomipramine. The antidepressant activity of amineptine was further investigated in an open multicenter study carried out in 351 depressed patients. The significant reductions in the scores of the Hamilton rating scale for depression and the final clinical evaluations (87% favorable results, 69% of which excellent or good) confirmed the therapeutic efficacy of amineptine. Tolerance was excellent also in elderly, at risk patients.

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.

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.

Indenolol kinetics versus pharmacodynamics in hypertension.

A kinetic model has been employed to compare the duration of the antihypertensive activity of indenolol to its plasma half-life both after single administration and at steady-state. After a 14 day run-in period with placebo, 60 or 120 mg indenolol were given to hypertensive patients I or II grade, according to W.H.O. guidelines, once a day for 14 days. Blood samples were drawn and blood pressure recorded at intervals after the first dose, during treatment and after the last dose of the compound. Both plasma concentration and mean arterial pressure difference curves were fitted by a first order input-output model, where plasma half-life was 4 h, while pharmacological half-life was 24 h for both dose-levels tested. Therefore, with once-a-day dose regimen an accumulation of the antihypertensive effect of indenolol was demonstrated, with 99% steady-state of blood pressure reached after 7 days, while the drug did not accumulate in the central compartment.

Measuring the inhibition of TRH-stimulated prolactin by dihydroergocristine (DEC) in man: an indirect assessment of bioavailability.

An indirect method to assess bioavailability of dihydroergocristine-methansulfonate (DEC) is described. The method uses the inhibitory effect of DEC on TRH stimulated prolactin production. By means of this method it was possible to investigate the relative bioavailability of DEC tablets versus Diertina liquid. The results show that the relative bioavailability is complete.

[Nutrition of the very low birth weight newborn infant (less than 1500 g). Experience with a formula for the premature infant]. / La nutrizione del bambino di peso neonatale molto basso (less than 1500 g). Esperienza con una formula per prematuri.

After a short review on the topic of nutrition of very low-birth-weight infants, particularly the very small preterms, results are reported on a trial with an adapted milk for prematures. Subjects involved had a gestational age of 28-34 weeks and weighed less than 1500 g thus representing a sample of very low birth weight babies. By using levels of MCT in the milk, a protein quota of 3, 15 g/Kg/day with 40/60 casein whey-protein ratio, an electrolyte content slightly higher than in most adapted formulas (for fullterm babies) and low osmolarity, good results were obtained for body weight growth, length, head circumference and subcutaneous fat. Growth indices were similar to those typical of the terminal months of intrauterine development as well as a satisfactory overall portrayal of biochemical indices of the nutritional status of VLBW babies.

Effect of indenolol treatment on beta-adrenergic receptors of polymorphonucleates in essential hypertension.

Indenolol is a new antihypertensive agent, whose beta 1-adrenoceptor antagonist properties combined with beta 2-adrenoceptor agonist properties have been shown by experimental studies in animals. Our previous work reported that in vivo beta-adrenoceptor blocking drugs markedly increase the beta-adrenoceptor (BAR) number, without increasing BAR affinity. The aim of this study was to evaluate BAR density and affinity before and after indenolol therapy in membranes of polymorphonucleates (PMN) of patients with essential hypertension. Polymorphonuclear binding parameters were studied in 12 hypertensives (WHO stages I and II) after 14 days of placebo and after 21 days of indenolol therapy (120 mg once daily orally). Indenolol did not increase BAR number but significantly decreased (P less than 0.01) BAR affinity. On the basis of these data it is concluded that indenolol does not induce the same changes in PMN's BAR as previously observed with oxprenolol, propranolol and labetalol. This phenomenon may account for the absence of rebound effect after withdrawal of indenolol in hypertensives.

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.

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.

[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.

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)

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.