Oral terbinafine in the treatment of toenail onychomycosis: North American multicenter trial.

BACKGROUND: Onychomycosis is an increasing problem with limited therapeutic options. OBJECTIVE: We evaluated the safety and efficacy, of oral terbinafine, a new fungicidal antimycotic, in patients with toenail onychomycosis. METHODS: A North American multicenter, double-blind, placebo-controlled study evaluated the mycologic and clinical efficacy of oral terbinafine 250 mg/day for 12 or 24 weeks in 358 patients with toenail onychomycosis. RESULTS: A total of 74% of patients treated with 12 or 24 weeks of terbinafine achieved a successful clinical outcome. Approximately 11% of terbinafine responders showed evidence of relapse 18 of 21 months after cessation of treatment. Terbinafine was well tolerated; most adverse events were transient and mild to moderate in severity. CONCLUSION: The results of this study confirm that oral terbinafine is a safe and effective therapy for the treatment of onychomycosis.

Cyclosporine as maintenance therapy in patients with severe psoriasis.

BACKGROUND: Low-dose cyclosporine therapy for severe plaque psoriasis is effective. Most side effects can be controlled by patient monitoring, with appropriate dose adjustment or pharmacologic intervention, or both, if indicated. Prevention or reversibility of laboratory and chemical abnormalities may be achieved by discontinuation of therapy after the induction of clearing. However, relapse occurs rapidly on discontinuation. Maintenance therapy with cyclosporine after induction has not been fully evaluated. OBJECTIVE: Our purpose was to compare a regimen of 3.0 mg/kg per day of oral cyclosporine with placebo in maintaining remission or improvement in patients with psoriasis. METHODS: After a 16-week unblinded induction phase in which 181 patients received cyclosporine, 5.0 mg/kg per day (an increase up to 6.0 mg/kg per day and a decrease to 3.0 mg/kg per day were allowed, if required, to achieve efficacy or tolerability, respectively), those patients showing a 70% decrease or more in involved body surface area (BSA) entered the 24-week maintenance phase and were randomly assigned to either placebo, cyclosporine, 1.5 mg/kg per day, or cyclosporine, 3.0 mg/kg per day. Patients were considered to have had a relapse when BSA returned to 50% or more of the prestudy baseline value. Clinical efficacy, adverse effects, and laboratory values were monitored regularly throughout both study phases. RESULTS: During induction, cyclosporine at approximately 5.0 mg/kg per day produced a reduction in BSA of 70% or more in 86% of the patients. During maintenance, the median time to relapse was 6 weeks in both the placebo and cyclosporine 1.5 mg/kg per day groups, but was longer than the 24-week maintenance period in the 3.0 mg/kg per day group (p < 0.001 vs placebo). By the end of the maintenance period, 42% of the patients in the 3.0 mg/kg per day cyclosporine group had a relapse compared with 84% in the placebo group. Changes in laboratory values associated with the higher induction dosage generally exhibited partial or complete return toward mean prestudy baseline values during the maintenance phase, with the greatest degree of normalization in the placebo group. CONCLUSION: Cyclosporine, 3.0 mg/kg per day, adequately and safely maintained 58% of patients with psoriasis for a 6-month period after clearing of their psoriasis with doses of approximately 5.0 mg/kg per day.

Efficacy of a 1-week, twice-daily regimen of terbinafine 1% cream in the treatment of interdigital tinea pedis. Results of placebo-controlled, double-blind, multicenter trials.

BACKGROUND: Patients with tinea pedis often discontinue treatment before eradication of the fungus when their symptoms improve. The result is an incomplete cure/recurrence. OBJECTIVE: Terbinafine, a topical fungicidal agent, was evaluated in double-blind, placebo-controlled trials (159 patients) for its ability to achieve cure and relief of symptoms in the same time frame, that is, before compliance wanes. METHODS: Mycologic characteristics (with potassium hydroxide examination and culture) and clinical signs and symptoms were assessed at baseline, at the end of a 1-week, twice-daily treatment and at 1, 3, and 5 weeks after the completion of therapy. RESULTS: Both terbinafine and vehicle provided early relief of symptoms. However, only terbinafine gave progressive mycologic improvement such that at 5 weeks after treatment, 88% of the patients receiving terbinafine had converted from positive to negative mycology compared with 23% of the patients treated with vehicle. CONCLUSION: The rapid and potent fungicidal action of terbinafine results in a high cure rate in interdigital tinea pedis with 1 week of treatment and may avoid failures caused by non-compliance.

Intralesional cyclosporine for psoriasis. Relationship of dose, tissue levels, and efficacy.

UNLABELLED: BACKGROUND AND DESIGN--To avoid systemic side effects, topical and intralesional administration of cyclosporine has been used; however, only intralesional administration has been successful. To understand more about the dosing requirements and resultant tissue levels of intralesional cyclosporine, we injected psoriasis plaques in a double-blind fashion with three different concentrations of cyclosporine (17 mg/mL in seven patients, 10 mg/mL in 13 patients, and 2.5 mg/mL in 11 patients) or matching vehicle three times weekly for 4 weeks. RESULTS--Statistically significant improvement was observed in plaques treated with 17 mg/mL (P = .003) compared with vehicle-treated plaques; the improvements in plaques treated with 10 mg/mL (P = .078) and 2.5 mg/mL (P = .054) achieved marginal statistical significance compared with vehicle treatment. Four weeks after discontinuation of therapy, the change from pretherapy in plaques that had received 17 mg/mL of cyclosporine was statistically significantly better (P less than .0001) than that with vehicle treatment. A similar finding but of marginal statistical significance (P = .059) occurred in the plaques that had received 10 mg/mL of cyclosporine. Throughout the study, untreated psoriasis plaques did not improve. Transient pain was the most common side effect noted with both cyclosporine and vehicle injections. Tissue levels of cyclosporine tended to be highest in plaques receiving the 17-mg/mL concentration; blood levels of cyclosporine were low throughout the study. CONCLUSIONS: --Intralesional cyclosporine requires a sufficient dosage to improve psoriasis, apparently by a local mechanism of action. Improvement may persist for 4 weeks or longer.

Pharmacology of the allylamines.

The allylamines are a new class of antifungal drugs that inhibit ergosterol synthesis at the level of squalene epoxidase. These agents are highly selective for the fungal enzyme and have a minimal effect on mammalian cholesterol synthesis. Naftifine, the original member of the allylamine series, possesses only topical activity, whereas the naftifine analog terbinafine is active both topically and orally. In vitro, terbinafine is exceptionally active against dermatophytes, molds, and dimorphic fungi in which it exerts a fungicidal action. This in vitro profile is reflected by the clinical effectiveness of this allylamine in the treatment of dermatophyte infections. When given orally, terbinafine is well absorbed and rapidly and extensively distributed to the skin and sebum in concentrations that exceed the minimum inhibitory concentrations of these organisms by several orders of magnitude.

Retinoic acid induces cyclic changes in epidermal thickness and dermal collagen and glycosaminoglycan biosynthesis rates.

The effects of daily topical application onto guinea pig ears of a therapeutic concentration of all trans-retinoic acid (RA) on epidermal thickness and dermal collagen and glycosaminoglycan (GAG) biosynthesis rates were studied during a 40-day period. Clinically, the RA-treated skin became erythematous and scaly beginning at 5-6 days, conditions which persisted throughout the experiment. The epidermis became thickened and hyperplastic with marked psoriasi-form histologic features, and the phenomenon was dependent on RA concentration. The initial hyperplasia resulted from a transient 4-fold increase in epidermal basal cell replication during the first 3-4 days, as shown by the rise and fall of [3H]thymidine labeling index which preceded the hyperplasia. The extent of epidermal hyperplasia as measured by epidermal thickness was not constant throughout the 40-day treatment period, but exhibited maxima on days 11, 25, and 36. These maxima were followed by periods of decreased thickness, although the minima were always greater than the untreated controls. Retinoic acid induced similar temporal cycles in GAG and collagen biosynthesis rates, but the collagen cycles occurred at different times with maxima on days 6, 20, and 34. After 8 weeks' treatment, the blood flow rates in the ear microcirculation (laser Doppler photometry) were increased 81% above that of the water-treated controls. The demonstration of these RA-induced cyclic changes in epidermal hyperplasia and dermal fibroblast biosynthetic activities have revealed the presence of control mechanisms in these tissues which normally operate to maintain tissue homeostasis.

Electrical field stimulation of isolated primate sweat glands.

An in vitro method is described for inducing secretion in isolated monkey eccrine sweat glands by means of electrical field stimulation (EFS). Ultrastructural analyses of these glands revealed unmyelinated nerve fibres surrounding the secretory coils. Numerous small clear vesicles, characteristic of cholinergic nerve terminals, were observed, along with a few which were large and dense-cored. EFS elicited an immediate secretory response which ceased abruptly upon termination of the current. The response was inhibited in a dose-dependent manner by atropine (IC50 1.5 X 10(-9) mol/l). Although most glands were completely inhibited by atropine, a minor atropine insensitive component was operative in some preparations. Physostigmine (10(-6) mol/l) potentiated the response to subthreshold EFS. Lidocaine (3 X 10(-4) mol/l) completely and reversibly blocked EFS but had no effect on methacholine (10(-6) mol/l) induced secretion. These results confirm that eccrine sweat gland activation is predominantly via cholinergic pathways and that EFS of isolated glands may be a useful model to study the control of secretory function in normal and diseased states.

CL 115,347 (DHV-PGE2 ME): a new orally and topically active prostaglandin antihypertensive agent.

CL 115,347 orally (0.25-10 mg/kg) and topically (0.03 and 0.1 mg/kg) lowered blood pressure in a dose-dependent manner in conscious spontaneously hypertensive rats (SHR). Duration of action of the oral dose range was from 1 to more than 8 h and of the topical dose range, from more than 6 to more than 24 h. CL 115,347 was 100-200 times more potent orally and greater than 250 times more potent topically than l-prostaglandin (PG) E2. When 3 mg/kg was administered orally, CL 115,347 was also active in Dahl "S" salt-sensitive hypertensive rats, deoxycorticosterone acetate-salt hypertensive rats, aorta-coarcted renin-dependent hypertensive rats, normotensive rats, bilaterally nephrectomized SHR, and bilaterally ureteral-ligated SHR. CL 115,347 was also orally active at 0.1 mg/kg in normotensive rhesus monkeys and in renal hypertensive dogs at 1 mg/kg. CL 115,347 was as active as l-PGE2 in relaxing the rabbit ear arterial smooth muscle in vitro. In anesthetized dogs, CL 115,347 injected intra-arterially (0.5-10 micrograms) into the vascular bed being studied increased blood flow to femoral, carotid, coronary, superior mesenteric, and renal vascular beds. CL 115,347 decreased vasopressor responses induced by electrical stimulation of the spinal cord at T7-T9 but did not decrease the tachycardia induced by stimulation of the cardioaccelerator segments (C7-T1) in pithed SHR. CL 115,347 has a broad spectrum of antihypertensive activity in various animal models and probably exerts its major antihypertensive effects through relaxation of blood vessels.

Cutaneous erythema and blood pressure lowering effects of topically applied 16-vinylprostaglandins.

Topically applied 16-vinylprostaglandins demonstrate the property of rapid transit through the skin and a profound effect on the cutaneous vasculature. At low concentrations in the guinea pig and rabbit. 15-deoxy-16-hydroxy-16-vinyl-PGE2 (DHV-PGE2) and its methyl ester (DHV-PGE2Me) elicit a distinct and persistent erythema which is restricted to the area of application and is not associated with a wheal. Skin temperatures are elevated for several hours following application. Accordingly, these compounds may have therapeutic utility in conditions where local blood flow is compromised or where an enhanced blood flow is desired . In the spontaneously hypertensive rat, topically applied DHV-PGE2 and DHV-PGE2Me produce a dramatic and persistent lowering of blood pressure. The maximal effects are comparable to those obtained wit equal oral or intravenous doses and are maintained for a longer period of time. Moreover, with the topical route, there is no prolongation in the time required for onset of action (3-5 minutes). It appears that while the skin presents only a minimal diffusion barrier to these compounds, a sufficient depot is maintained to give sustained release and prolonged duration. Transdermal delivery of 16-vinyl prostaglandins may offer a convenient means of achieving a clinical antihypertensive effect without the characteristic side effects generally associated with oral or intravascular prostaglandins.

A new prostaglandin E1 analogue (CL-115,574) II. Effects on gastric acid secretion in the dog.

The efficacy of CL-115,574, a prostaglandin E1 analogue, as an acid antisecretory agent was evaluated in dogs. CL-115,574 inhibited acid secretion maximally at an oral dose of 20 micrograms/kg causing 100% inhibition of acid secretion up to one hour after administration, with significant inhibition of secretion (30%) still present nearly four hours after drug administration. The wide disparity between the maximally effective antisecretory dose 20 micrograms/kg and the dose at which reproducible side effects occurred (1 mg/kg) suggests that this compound may be developed as an antisecretory compound for use in man.

A new prostaglandin E1 analogue (CL115,574). I. antisecretory and cytoprotective effects in the rat.

The effects of a new analogue of PGE1 (CL115,574) on gastric acid secretion, mucus secretion and protection against stress and indomethacin-induced ulcers were studied in the rat. CL115,574 was more potent than PGE1 and cimetidine in inhibiting acid secretion. CL115,574 protected against the development of stress and indomethacin-induced ulcers and prevented the indomethacin-induced decrease in hematocrit at an ED50 (3 micrograms/kg) far below the antisecretory ED50 (1 microgram/kg). While inhibiting acid secretion, CL115,574 increased the volume of gastric secretion indicating a stimulation of nonparietal cell secretion by the rat stomach. In addition the compound stimulated the secretion of mucus into the gastric juice. On the basis of its potency as an inhibitor of acid secretion and these additional effects which are indicative of cytoprotective activity, CL115,574 should be further studied as a possible anti-ulcer agent in man.

Nasal vasoconstrictor activity of a novel PGE2 analog.

A novel PGE2 analog (CL 116,069) was shown to be effective in dogs as a nasal decongestant. Threshold doses were approximately 0.1 microgram/kg with intravenous administration and between 0.08 and 4 microgram with topical administration. CL 116,069 was compared to 17-phenyltrinor PGE2 (CL 116,147), a compound recently studied in humans, and xylometazoline, a well-known nasal decongestant. When given i.v., efficacious doses of xylometazoline tended to raise blood pressure and be shorter acting than the PGs, which did not affect blood pressure. When given topically, all three were long-acting. CL 116,069 usually had the lowest threshold and CL 116,147 usually induced the smallest response. All three agents were more effective than PGE1 or PGE2. A 30-day (b.i.d., topical) toxicity test with CL 116,069 produced no inflammation or nasal pathology and no loss in tissue sensitivity. In vitro examination of xylometazoline and CL 116,069 for vasoconstrictor activity on dog isolated mucosa revealed a response profile similar to that observed with these agents in vivo; i.e., the magnitude of response was comparable for both agents but the t 1/2 was only 74 minutes for xylometazoline and greater than 6.5 hours for CL 116,069. The data suggest that CL 116,069 may provide a therapeutic alternative in which constriction of the nasal blood vessels need not be associated with a generalized vasoconstrictor liability.

Studies on type II collagen-induced polyarthritis in rats. Effect of antiinflammatory and antirheumatic agents.

The effect of a variety of antiinflammatory and antirheumatic agents on both developing and established lesions of type II collagen induced polyarthritis in rats was examined. Administration of the nonsteroidal antiinflammatory agents indomethacin or phenylbutazone suppressed the paw inflammation associated with the disease without affecting type II collagen antibody titers. Radiographic analysis of the joints showed suppression of several parameters related to joint destruction. This was most probably related to the antiinflammatory properties of the two drugs. Administration of prednisolone, a steroidal antiinflammatory agent, suppressed paw inflammation; type II collagen antibody titers were significantly decreased in the developing lesion, but the drug had no effect on antibody titers in the established lesion. Radiographic analysis of the joints showed decreases in several parameters of joint destruction. Cyclophosphamide, an immunosuppressive agent, completely suppressed the inflammation associated with the developing lesion but had only minimal effect against the established disease. Collagen antibody titers were decreased and an improvement in only one radiologic parameter (periostitis) was detected. Treatment with antirheumatic agents such as gold thioglucose or levamisole enhanced severity of inflammation in the established lesion and caused increases in collagen antibody titers. Radiographic analysis of the joints indicated that while gold had no effect, levamisole enhanced joint destruction. Treatment with D-penicillamine had no effect on paw inflammation, despite increases in collagen antibody titers. Radiographic analysis of the joints indicated an improvement in all parameters related to joint destruction in animals treated with penicillamine.

Bronchodilator activity of a PGE2 analog in animals and in man.

A C-11 substituted PGE2 analog, DHET-PGE2 [alpha-11-deoxy-11 alpha-(2-hydroxyethylthio)-PGE2 methyl ester], was demonstrated to exert potent bronchodilator activity in three in vivo models of augmented airway resistance: (1) acute bronchospasms, induced by 5-hydroxytryptamine, histamine and acetylcholine in the anesthetized guinea pig, (2) acute bronchospasm, induced by pilocarpine, in the anesthetized dog, and (3) chronic bronchospasm, induced by SO2 exposure, in the unanesthetized dog. In acute and 30-day toxicological studies in the dog, no cardiovascular, respiratory or gastrointestinal side effects were observed at aerosol doses at least 1,000 times those required for efficacy. In vitro, DHET-PGE2 effectively relaxed isolated preparations of dog bronchus that had been contracted with carbachol. In clinical studies, human asthmatics and bronchitics responded consistently to beta-agonist bronchodilators but variably to DHET-PGE2. Overall, increases in pulmonary resistance or decreases in FEV1 were observed with DHET-PGE2. Subsequent evaluation in isolated carbachol-contracted human bronchus revealed that, in contrast to the bronchodilator activity of PGE1 and beta-agonists, DHET-PGE2 and PGE2 induced contraction. Considered along with results from previous clinical studies on other PGs, these data underscore the difficulties in making extrapolations on this class of compounds from animal models to humans and suggest that human bronchial tissue may provide the only appropriate preclinical test system for predicting the clinical efficacy of PG bronchodilators.