Comparative efficacy of once-daily flurandrenolide tape versus twice-daily diflorasone diacetate ointment in the treatment of psoriasis.

BACKGROUND: Flurandrenolide tape has recently been listed as a group I topical corticosteroid. There are no studies that compare this product to group I ointments in the treatment of steroid-responsive dermatoses. OBJECTIVE: Our purpose was to determine the relative efficacy of flurandrenolide (4 microg/cm2) tape versus 0.05% diflorasone diacetate ointment in plaque psoriasis. METHODS: Thirty patients participated in an investigator-blinded, randomized, bilateral paired-comparison study of flurandrenolide tape applied to lesions of one side of the body once daily for up to 16 hours versus diflorasone diacetate ointment applied contralaterally twice daily. Lesions were assessed at baseline, then reevaluated at 2 and 4 weeks. RESULTS: Flurandrenolide tape-treated plaques showed consistently greater clearing in terms of erythema, scaling, induration, and treatment success for all plaques, as well as the subset of knee and elbow plaques, when compared with the lesions receiving diflorasone diacetate ointment. CONCLUSION: The efficacy of flurandrenolide tape in the treatment of psoriatic plaques surpasses that of diflorasone diacetate ointment.

Safety and efficacy of 0.5% podofilox gel in the treatment of anogenital warts.

OBJECTIVE: To determine the safety and efficacy of a new gel formulation of podofilox in the treatment of anogenital warts. DESIGN: Double-blind, randomized, multicenter, vehicle-controlled investigation. SETTING: Private dermatology practices, university clinics (dermatology, gynecology, and infectious diseases), and contract research organizations. PATIENTS: Three hundred twenty-six patients with anogenital warts. MAIN OUTCOME MEASURE: Number of patients with clearing of all treated warts (treatment success). RESULTS: The 0.5% podofilox gel was significantly better than vehicle gel for successfully eliminating and reducing the number and size of anogenital warts. In the intent-to-treat population, 62 (37.1%) of 167 patients treated with 0.5% podofilox gel had complete clearing of the treated areas (treatment successes) compared with 2 (2.3%) of 86 patients who had clearing of warts with the vehicle gel (P < .001) after 4 weeks. Nineteen additional patients treated with 0.5% podofilox gel and 2 patients treated with vehicle gel had clearing of warts with continued treatment up to 8 weeks. After 8 weeks, 35.9% of the baseline anogenital warts treated with 0.5% podofilox gel remained; this was significantly fewer than in the vehicle-treated group (88.4% of the baseline number) (P = .001). The 0.5% podofilox gel was generally well tolerated, with predominantly mild or moderate local adverse reactions occurring in the majority of patients. Only 7 patients (3.2%), all receiving 0.5% podofilox gel, discontinued study treatment because of drug-related local reactions. CONCLUSIONS: The results demonstrated that 0.5% podofilox gel is safe and significantly more effective than vehicle gel in the treatment of anogenital warts.

Sunscreen intolerance. Contact sensitization, photocontact sensitization, and irritancy of sunscreen agents.

Reports of contact sensitization and photocontact sensitization induced by various sunscreening agents are reviewed. Current knowledge about the most often used sunscreening agents is summarized. The problems of cross-sensitization and sensitization in photodermatoses are discussed. Strategies for patch and photopatch testing, as well as immediate-type testing, are critically evaluated.

Safety and efficacy of a broad-spectrum sunscreen in patients with discoid or subacute cutaneous lupus erythematosus.

An eight-week, open-label study was conducted to test the efficacy, safety, and cosmetic acceptability of a broad-spectrum sunscreen in patients with discoid lupus erythematosus or subacute cutaneous lupus erythematosus. The sunscreen combined the ultraviolet A absorber avobenzone (Parsol 1789, Givaudan Corp) and the ultraviolet B absorber padimate O and had a sun protection factor greater than fifteen. The overall clinical disease severity decreased from 2.7 (four point scale) at baseline to 1.7 after eight weeks (p = 0.005). Cutaneous signs and symptoms, including hyperpigmentation, papules, scaling, and erythema, were significantly less severe at the end of the study. The level of protection provided by the sunscreen was good to excellent in 54 percent of patients, and was judged to be superior or far superior to previously used sun protection factor-fifteen sunscreens in 77 percent of patients. Most patients found the sunscreen highly acceptable with respect to its cosmetic properties.

Sunscreening agent intolerance: contact and photocontact sensitization and contact urticaria.

Reports in the literature of sensitization associated with many commonly used sunscreening agents including p-aminobenzoic acid (PABA), PABA derivatives, anthranilates, salicylates, cinnamates, benzophenones, and dibenzoylmethane derivatives are reviewed. Several of these case reports involved subjects with various photodermatoses, implicating enhanced sensitivity of the patient's skin to both light and chemicals. Despite the widespread use of sunscreens, the small number of published reports of contact and photocontact sensitization to these agents suggests that either such sensitization is less than commonly perceived or is underreported. Establishment of a registry for reporting adverse effects associated with sunscreening agents would help to characterize the incidence of sensitization.

Changes in salicylate serum concentration and metabolism during chronic dosing in normal volunteers.

Steady-state serum salicylic acid (SA) concentrations and the formation rates of salicyluric acid (SU), salicylphenolic glucuronide (SPG), salicylacyl glucuronide (SAG), and gentistic acid (GA), and the excretion rate of unchanged SA were determined in three normal subjects following the administration of a single oral dose of acetylsalicylic acid (ASA) 37 mg kg-1 and during multiple dosing with ASA 56 mg kg-1 day-1. Steady-state SA concentrations fell 23 per cent during the 4-week study period (mean +/- SD: 239 +/- 35 to 183 +/- 23 micrograms ml-1; p less than 0.05). Absorption of drug did not decrease during this time. Significant increases in the Vmax for SU and SPG formation occurred between baseline and during multiple dosing. Mean Vmax SU increased from 0.93 to 1.68 mg kg-1 h-1 (p less than 0.05) and mean Vmax SPG increased from 0.09 to 0.19 mg kg-1 h-1 (p less than 0.05). First-order rate constants for the formation of SAG and GA and for the excretion of unchanged SA did not change significantly between baseline and multiple dosing. The mechanism for the decline in CpssSA with time during high-dose SA therapy is most likely due to the induction of the formation rates of the major metabolites of SA, namely SU and SPG.

Indoor and outdoor efficacy testing of a broad-spectrum sunscreen against ultraviolet A radiation in psoralen-sensitized subjects.

The efficacy of a sunscreen containing an investigational drug, butyl methoxydibenzoylmethane in combination with padimate O against the erythemogenic effect of ultraviolet A (UVA) radiation was evaluated in two double-blind studies involving subjects sensitized with topical 8-methoxypsoralen. UVA radiation was supplied from either a filtered solar simulator (indoors) or filtered sunlight (outdoors). Five formulations were tested: 3% butyl methoxydibenzoylmethane and 7% padimate O, 7% padimate O, 5% octyl salicylate, and 3% oxybenzone, 3% butyl methoxydibenzoylmethane alone, 7% padimate O alone, and vehicle. Sunscreen protection against the erythemogenic effect of UVA radiation was expressed as phototoxic protection factors. The phototoxic protection factor for each sunscreen was derived from a ratio of the minimal phototoxic dose of UVA radiation that produced delayed erythema on sunscreen-protected and unprotected skin. The combination of 3% butyl methoxydibenzoylmethane and 7% padimate O provided significantly greater protection than the other sunscreen formulations, and for each sunscreen the phototoxic protection factors determined indoors and outdoors were comparable.

Efficacy of a sunscreen containing butyl methoxydibenzoylmethane against ultraviolet A radiation in photosensitized subjects.

Topical formulations containing a new chemical entity, the ultraviolet A absorber Parsol 1789 (butyl methoxydibenzoylmethane), were evaluated as agents for protecting human skin against ultraviolet A (UVA) radiation. Healthy subjects were photosensitized to UVA radiation by ingestion of 8-methoxypsoralen (0.6 mg/kg). After 90 minutes, five formulations (vehicle, vehicle + butyl methoxydibenzoylmethane, vehicle + butyl methoxydibenzoylmethane + padimate O, vehicle + padimate O, and a marketed sunscreen containing padimate O, oxybenzone, and octyl salicylate) were applied in a randomized, double-blind manner to areas on the lower part of the back. Thirty minutes later, sites in the five treated areas and in a sixth unprotected area were exposed to graduated doses of UVA radiation. Test sites were evaluated for erythema 48 and 72 hours after UVA exposure, and for melanogenesis approximately 2 weeks later. The combination of butyl methoxydibenzoylmethane + padimate O demonstrated significantly greater protection than the combination of padimate O, oxybenzone, and octyl salicylate.

Metabolism of salsalate in normal subjects.

The metabolism of salsalate (I) was characterized in two normal volunteers. The drug was almost completely absorbed and was excreted primarily in the urine; only approximately 1% of the total dose was found in the stools. Although I is a salicylate derivative, which on hydrolysis yields two molecules of salicylic acid (II), approximately 7-10% of the dose was not hydrolyzed to salicylic acid and appeared in the urine either as unchanged drug or glucuronide conjugates. Thus, the incomplete availability of salicylate from salsalate that has been previously reported may not be due to incomplete absorption of the drug but to incomplete hydrolysis to salicylic acid.

Tiflamizole elimination from plasma in rheumatoid arthritis.

Tiflamizole is a fluorinated diarylamidazole sulfone nonsteroidal anti-inflammatory drug not metabolized or excreted in urine. Its mean (+/- SD) elimination t 1/2 from plasma was 21.6 +/- 9 days (range 11.8 to 49.5 days) in 17 subjects with rheumatoid arthritis, and appeared to be first order in most of them. Plasma elimination t 1/2 was loosely related (r = -0.67) to stool frequency in eight subjects for whom stool frequency data were available. In one, cholestyramine decreased t 1/2 to 4.1 days. In two patients, synovial fluid total tiflamizole concentrations were approximately one-third of simultaneous plasma concentrations, but elimination t 1/2s from synovial fluid were of the same order as those from plasma. Even with infrequent dosing, the longer t 1/2 may help sustain the anti-inflammatory effects of this drug.

Comparative pharmacokinetics of triethylphosphine gold (auranofin) and gold sodium thiomalate (GST).

The pharmacokinetics of gold sodium thiomalate (GST) and triethylphosphine gold (auranofin; AF) are different. Gold sodium thiomalate (GST) is completely bioavailable while only 15-25% of auranofin (AF) is absorbed. Protein binding of AF occurs to a larger extent to macroglobulins than does GST and total body retention of GST is much greater than AF at six months (30% versus approximately 1%). While terminal serum half-lives are approximately equal, total body half-lives are 250 days for GST and 69 days for AF. In addition, excretory pathways contrast markedly, with 85% of AF appearing in the feces while only 30% of GST is excreted by this route; 15% of AF gold appears in the urine and approximately 70% of GST gold is excreted via this route. With all the above differences one would expect that organ and cellular distribution of these compounds would differ. While gold from both drugs is concentrated in kidney, the percent of the dose found in the kidneys is less for AF than GST, at least in animals (0.4% vs 4.8%). Minute quantities are found in other organs but more study is needed to more clearly define organ distribution of these gold compounds, particularly in man.

Comparison of tolmetin kinetics in rheumatoid arthritis and matched healthy controls.

We could find no significant differences in the kinetics of tolmetin when comparing five rheumatoid arthritis patients with moderate disease activity with a carefully matched group of normal healthy volunteers. Further, there were no discernible clinically significant differences in the kinetics of tolmetin when comparing a single dose to one week of therapy. These results, although limited by the small number of subjects involved and the large interpatient variability, suggest that it may be possible to extrapolate pharmacokinetic data from normals to patients with moderately active disease.

Availability of salicylate from salsalate and aspirin.

Salicylate availability from salsalate (SSA) and aspirin (ASA) was examined in six rheumatoid arthritis patients in a multiple-dose double-blind crossover study. Doses contained equimolar amounts of salicylic acid. After initial ASA treatment to achieve therapeutic salicylate levels (150 to 300 micrograms/ml) the patients received equimolar doses of SSA or ASA. When steady state was achieved patients were hospitalized, and blood and urine specimens were obtained during three dosing intervals and during the washout period that followed. Thereafter, patients were placed on the alternate medication for at least a week and the in-hospital pattern was repeated. Despite insignificant differences in absorption of the formulations, as measured by urinary salicylate recovery, the plasma salicylic acid AUC was lower after SSA. Evidence indicates that this apparent lower availability of salicylate from SSA is due to incomplete hydrolysis to salicylic acid, the unhydrolyzed SSA being excreted mainly as glucuronide conjugates.

Clinical pharmacology of tolmetin: comparisons in rheumatoid arthritis patients and normal volunteers.

The pharmacokinetics of tolmetin sodium were studied in five patients with rheumatoid arthritis (RA) and five normal volunteers to determine whether data derived from normals could be applied to RA patients. In addition, prostaglandin E (PGE) levels in synovial fluid were compared with tolmetin levels in serum and synovial fluid. Both groups received 400 mg tolmetin every 6 hours for seven days. During a 24-hour washout period after the dose of tolmetin (400 mg) on day 8, blood and urine samples were obtained from all study participants, and synovial fluid samples from the RA patients only. The patients continued into a second 24-hour drug-free period, after which they received a single 400-mg dose of tolmetin. Blood and urine samples were again collected. No clinically or statistically significant differences in tolmetin kinetics between normal volunteers and RA patients were found. A comparison of multiple-dose and single-dose results in the patient group showed an 11 per cent increase in the tolmetin serum concentration after multiple dosing. Total PGE levels in synovial fluid remained significantly depressed in the patient group for 24 hours after the 400-mg test dose of tolmetin on day 8. These findings suggest that tolmetin serum kinetics may not be an appropriate indicator of the duration of biologic activity of tolmetin.

Tolmetin kinetics and synovial fluid prostaglandin E levels in rheumatoid arthritis.

Tolmetin kinetics were determined in the plasma and synovial fluid of five rheumatoid arthritis patients after they had ingested tolmetin (400 mg every 6 hr) for 7 days. Tolmetin was rapidly absorbed, with average peak levels in plasma and synovial fluid occurring at 45 min and 2 hr. The drug concentration in synovial fluid was higher than that in plasma for prolonged periods, while the rates of elimination from both plasma and synovial fluid were similar. The average half-lives of tolmetin in plasma and synovial fluid were 6.77 +/- 1.47 hr and 6.90 +/- 2.3 hr. Total prostaglandin E levels in synovial fluid of these patients were suppressed for at least 24 hr after the last dose of tolmetin, suggesting that PGE synthesis continues to be suppressed even by the very low concentrations of tolmetin remaining after 24 hr.

Relationship of serum naproxen concentration to efficacy in rheumatoid arthritis.

Twenty-four patients with rheumatoid arthritis were tested in a randomized, double-blind. Latin-square comparison of 250, 750 and 1500 mg of naproxen daily. Each received each dose for 2 wk and baseline disease activity was established during withdrawal of medication before and after the study. Nine standard measures of efficacy were tested at each evaluation. No order effect or change in baseline was found. Total and unbound naproxen concentrations were measured by high-pressure liquid chromatography and equilibrium dialysis, respectively. A linear dose-response relationship (P less than 0.05) was demonstrated between naproxen and joint count, patient's pain assessment, activities of daily living index, physician's global assessment, and grip strength. The relationship to patients' global assessment was of uncertain significance (P less than 0.07). A positive dose to serum level correlation (1, 2, and 12 hr after dose) was apparent (r greater than 0.78). When patients were defined as responders or nonresponders by a summed efficacy score, there was a serum concentration-response relationship; the percentage of responding patients increased with each serum level quartile: 25%, 31%, 59%, and 75%. Patients with a trough total serum naproxen concentration under 18 micrograms/ml did not respond, while 76% of patients with trough total serum concentrations above 50 micrograms/ml responded. No serum naproxen toxicity level relationship was established.

Formation of methyl ester of salicyluric acid during quantitation of salicyluric acid in urine by high-pressure liquid chromatography.

The formation of the methyl ester of salicyluric acid was observed during the quantitation of salicyluric acid and other salicylate metabolites in urine by high-pressure liquid chromatography. This methyl ester formation caused artificially low values for salicyluric acid and high values for salicylic acid.