The duration of response to norgestimate and ethinyl estradiol in the treatment of acne vulgaris.

OBJECTIVE: This was a postmarketing, retrospective, exploratory analysis to investigate the duration of response to a triphasic combination oral contraceptive (OC) (Ortho Tri-Cyclen; Ortho-McNeil Pharmaceutical, Raritan, NJ) [norgestimate-ethinyl estradiol]) in the treatment of moderate acne vulgaris. PROCEDURES: Healthy women with moderate acne vulgaris were enrolled in two 6-month, multicenter, randomized, double-blind, placebo-controlled clinical trials. Subjects received either 3 weeks of active OC treatment (i.e., 0.035 mg ethinyl estradiol plus increasing doses of norgestimate [0.180 mg, 0.215 mg, 0.250 mg]) and 1 week of inactive tablets, or 4 weeks of color-matched placebo tablets. RESULTS: A total of 507 subjects were enrolled in the study. Duration of response was analyzed in subjects with at least slight improvement in global progress of treatment from the earliest cycle showing response (n = 305) and in subjects with at least slight improvement at or before cycle 3 (n = 276); the duration of response was statistically significant in favor of the norgestimate-ethinyl estradiol group in both cases (P < or = .001). The variability of mean percent change in lesions was also statistically significantly greater in the placebo group than in the OC group for total lesions (P < or = .001) and inflammatory lesions (P < or = .001). CONCLUSION: A triphasic combination of norgestimate and ethinyl estradiol lengthens the time interval to recurrence of acne lesions.

Effectiveness of norgestimate and ethinyl estradiol in treating moderate acne vulgaris.

BACKGROUND: An excess of androgen is believed to contribute to development of acne in some patients. Because oral contraceptives (OCs) may reduce the active androgen level, hormonal therapy with OCs has been used successfully to treat patients with acne, although this treatment has previously not been studied in placebo-controlled trials. OBJECTIVE: Our purpose was to evaluate the efficacy of a triphasic, combination OC (ORTHO TRI-CYCLEN [Ortho-McNeil Pharmaceutical, Raritan, N.J.], norgestimate/ethinyl estradiol) compared with placebo in the treatment of moderate acne vulgaris. METHODS: Two hundred fifty-seven healthy female subjects, 15 to 49 years of age with moderate acne vulgaris, were enrolled in a multicenter, randomized, double-blind, placebo-controlled clinical trial. Each month for 6 months, subjects received either 3 consecutive weeks of the OC (i.e., tablets containing a fixed dose of ethinyl estradiol [0.035 mg] and increasing doses of norgestimate [0.180 mg, 0.215 mg, 0.250 mg]) followed by 7 days of inactive drug or placebo (color-matched tablets). Efficacy was assessed by facial acne lesion counts, an investigator's global assessment, a subject's self-assessment, and an analysis of within-cycle variation (cycle 6) in lesion counts. RESULTS: Of the 160 subjects in whom efficacy could be evaluated, the OC group showed a statistically significantly greater improvement than the placebo group for all primary efficacy measures. The mean decrease in inflammatory lesion count from baseline to cycle 6 was 11.8 (62.0%) versus 7.6 (38.6%) (p = 0.0001), and the mean decrease in total lesion count was 29.1 (53.1%) versus 14.1 (26.8%) (p = 0.0001) in the OC and placebo groups, respectively. In the investigator's global assessment, 93.7% of the active treatment group versus 65.4% of the placebo group were rated as improved at the end of the study (p < 0.001). Six of the seven secondary efficacy measures (total comedones, open comedones, closed comedones, papules, pustules, and the subject's self-assessment of study treatment) were also significantly more favorable in the OC group compared with the placebo group. CONCLUSION: An OC containing 0.035 mg of ethinyl estradiol combined with the triphasic regimen of norgestimate is a safe and effective treatment of moderate acne vulgaris in women with no known contraindication to OC therapy.

PIP: To evaluate the efficacy of a triphasic combined oral contraceptive (OC) in the treatment of moderate acne vulgaris, 231 healthy US volunteers 15-49 years of age with this dermatologic condition were enrolled in a phase III, multicenter, double-blind, placebo-controlled clinical trial. Each month for 6 months, subjects (n = 110) received either 3 consecutive weeks of Ortho Tri-Cyclen (containing a fixed dose of 0.035 mg of ethinyl estradiol and 0.180, 0.215, and 0.250 mg of norgestimate) followed by 7 days of inactive drug or placebo. The OC group showed significantly greater improvement than controls on all efficacy measures. The mean decrease in inflammatory lesion count from baseline to the sixth cycle was 11.8 (62.0%) among cases and 7.6 (38.6%) in controls, while the mean decrease in total lesion count was 29.1 (53.1%) versus 14.1 (26.8%) in the OC and placebo groups, respectively. In the investigator's global assessment, 93.7% of women in the treatment group and 65.4% of controls were rated as improved at the end of the study. Similarly, more cases than controls considered their acne "improved" at the study's end and expressed a preference for this therapy over other forms of acne treatment. These findings indicate that treatment of moderate acne vulgaris with a low-dose triphasic OC is safe and effective in women with no contraindications to OC use.

In vivo demonstration of the enhancement of MK-801 by L-glutamate.

MK-801 infused bilaterally into the nucleus accumbens of rats produced a dose-related increase in locomotor activity that was not blocked by intra-accumbens infusion of haloperidol (2.5 micrograms). Intra-accumbens infusion of L-glutamate (1.0 microgram) was without effect when administered alone, but significantly enhanced the increase in locomotor activity produced by MK-801 (5.0 micrograms). The inactive isomer of MK-801 did not produce hypermotility and L-glutamate did not enhance amphetamine(intra-accumbens)-induced hypermotility. These results extend to an in vivo model electrophysiological and radioligand binding studies demonstrating an enhancement of MK-801 activity by L-glutamate. The results also reinforce the concept that such an enhancement would occur during an escalation of excitatory amino acid levels accompanying pathological overload and, thus, would trigger a compensatory neuronal protection by MK-801.

Differential extraction of estradiol- and tamoxifen-receptor complexes from hypothalamic cell nuclei.

These experiments compared nuclear estradiol- and tamoxifen-receptor complexes from brain by measuring the ability of a series of ionic agents and DNA intercalators to release estrogen receptors from hypothalamic cell nuclei following in vivo administration of the agonist or antagonist. Over the concentration ranges tested, intercalators released 50-80% of the total estrogen receptors from hypothalamic cell nuclei in a concentration-independent fashion whereas extraction of nuclear receptors by the ionic agents was concentration dependent. In general, brain cell nuclear estrogen receptors were extracted more easily by both ionic agents and intercalators following injections of tamoxifen than of estradiol. It was also found that the polyanion heparin releases a small population of nuclear estrogen receptors that are not extracted by 0.5 M KCl, suggesting the existence of KCl-resistant chromatin acceptor sites in hypothalamic nuclei. These data support the hypothesis that estrogen agonists and antagonists promote different conformational changes when they bind neural estrogen receptors, resulting in the formation of ligand-receptor complexes with different biological activity.