Milan R. Henzl

Administration of nasal nafarelin as compared with oral danazol for endometriosis. A multicenter double-blind comparative clinical trial

Treatment with nafarelin, a gonadotropin-releasing hormone agonist, reversibly inhibits ovarian function and induces hypoestrogenemia. To determine the efficacy of such hormonal manipulation in the treatment of endometriosis, we randomly assigned 213 patients with laparoscopically confirmed endometriosis to receive, for six months, either nafarelin by nasal spray (400 or 800 micrograms per day) or oral danazol (800 mg per day). Placebo nasal spray and placebo tablets were used to double blind the study. Pretreatment and post-treatment laparoscopies were compared by means of the American Fertility Societys scoring system. More than 80 percent of the patients in each treatment group had a reduction in the extent of disease as assessed by laparoscopy. The mean laparoscopic scores decreased from 21.9 to 12.6 with 800 micrograms of nafarelin, from 20.4 to 11.7 with 400 micrograms of nafarelin, and from 18.4 to 10.5 with danazol (P = 0.0001 within each group; there were no statistically significant differences between the groups). The percentage of women with severely painful symptoms of endometriosis decreased from about 40 percent to 5 to 10 percent, whereas the percentage with no or minimal discomfort rose from 25 to 70 percent. Of the 149 patients who tried to become pregnant, 58 (39 percent) succeeded after the completion of treatment; similar rates of pregnancy applied to the three treatment groups. Danazol use decreased high-density lipoprotein levels and increased low-density lipoprotein levels. These changes were not observed in nafarelin users, but a higher percentage of them reported hot flashes and decreased libido. We conclude that nafarelin is an effective agent for treating endometriosis and has few side effects other than hypoestrogenism.

Efficacy and safety of nafarelin in the treatment of endometriosis.

The efficacy and safety of the gonadotropin-releasing hormone agonist nafarelin for treatment of endometriosis were compared with those of danazol in two large-scale, double-blind trials. Assessments of severity of symptoms, laparoscopic scores before and after therapy, and pregnancy rates showed that nafarelin, 400 and 800 micrograms administered intranasally, was as efficacious as oral danazol, 600 and 800 mg. The adverse effects seen with nafarelin, mainly hot flashes, were related to its mode of action, namely hypoestrogenemia induced by reversible inhibition of ovarian hormone production. Hypoestrogenemia was associated with a decrease of bone density in the lumbar vertebrae, but these changes were partially or completely reversible after treatment was discontinued. No significant changes in bone mass occurred in the distal radius. Danazol was associated with androgenic and metabolic adverse effects, including weight gain, negative effects on the lipid profile, and elevated liver enzyme levels. Nafarelin was found to be as effective as danazol for the management of endometriosis, with a different and more favorable safety profile.

Plasma levels and pharmacokinetics of norethindrone and ethinylestradiol administered in solution and as tablets to women

Twenty-four normal adult female volunteers were dosed orally with a solution and tablet formulation containing the contraceptive combination of norethindrone (NET, 1.0 mg) and ethinylestradiol (EE2, 0.12 mg) in a crossover bioequivalence study. Blood was sampled sequentially following single oral doses and the plasma separated for analysis of NET and EE2 by specific radioimmunoassays. Comparisons of both drugs following a dose in solution and tablets were made with respect to the following parameters: (a) plasma concentrations at each sample time; (b) maximum plasma concentration (Cpmax); (c) time to maximum plasma concentration (Tmax); (d) total area under the plasma concentration vs. time curve (AUC), and (e) plasma half-life (t1/2). It was found that the tablet and solution doses were bioequivalent with respect to EE2 absorption. However, absorption of NET from solution and tablet doses exhibited significant differences with respect to plasma levels at certain time points as well as AUC (which were higher following the tablet dose), but Cpmax, Tmax and t1/2 were not significantly different. Pharmacokinetic analysis of both drugs following the tablet dose was carried out using a two-compartment open model. The absorption rate constant (ka) and peripheral to central compartment transfer rate constant (k21) were similar for NET and EE2, but statistically significant differences were observed with respect to the distribution rate constant (alpha), the central to peripheral transfer rate constant (k12), the overall elimination rate constant (ke1), and volume of distribution (V1/F). The elimination rate constant (beta) for both drugs showed a difference of borderline statistical significance.

Anaprox in dysmenorrhea: Reduction of pain and intrauterine pressure

In a double-blind parallel trial, 24 dysmenorrheic women received a single dose of Anaprox (1,100 mg) or placebo. Over the next 2 hours, pain intensity was scored and intrauterine pressure was measured using an immobilized microballoon. At the end of 2 hours, all 11 patients given Anaprox (but only three of the 13 given placebo) experienced complete pain relief (p = 0.0004). The resting intrauterine pressure (IUP) decreased from a mean of 51.4 to 26.8 mm Hg in the Anaprox-treated group, while in the placebo group the mean resting IUP values remained essentially unchanged ( drop from 55.4 to 51.9 mm Hg was observed). This difference between the two treatment groups was statistically significant in favor of Anaprox (p = 0.03). Several patients from each group were given 0.2 mg of ergonovine by intramuscular injection following the 2 hour trial. In both groups, the resting IUP increased within 30 minutes; the corresponding increase in pain intensity was more pronounced, however, in the placebo group. These results support the premise that a decrease in resting IUP is directly linked to the pain-relieving effects of Anaprox.

Therapeutic efficacy and bone mineral density response during and following a three-month re-treatment of endometriosis with nafarelin (Synarel)☆☆☆★★★

OBJECTIVE Our goal was to determine the effects of a repeated course of the gonadotropin-releasing hormone agonist nafarelin on symptoms and signs of endometriosis and lumbar and distal radius bone mineral density. STUDY DESIGN Forty-five women previously treated for 6 months with nafarelin, who had recurrent symptoms and signs of endometriosis, received 400 mcg/day of nafarelin intranasally for 3 months. Efficacy was evaluated by changes in severity of symptoms and signs. Lumbar bone mineral density was measured by dual-energy x-ray absorptiometry and distal radius bone mineral density by single-photon absorptiometry. Bone mineral density was also measured in 10 control volunteers. RESULTS Repeated 3-month treatment significantly alleviated recurrent symptoms and signs of endometriosis. Lumbar bone mineral density decreased significantly by a mean of 2% at the end of treatment; this loss was restored within 3 to 6 months after treatment completion. No bone mineral density decline occurred in the radius. Bone mineral density changes in the control group were statistically insignificant. CONCLUSIONS A repeated 3-month course of nafarelin treatment significantly relieved recurrent endometriotic symptoms and signs without sustained loss of bone mineral density.

Gonadotropin-releasing hormone analogs: Update onnew findings

Summary Clinical trials are under way to investigate the optimal use of nafarelin. In one series of studies, the effectof nasal mucosal inflammation and the concomitant use of nasal decongestants on the nasal absorption of nafarelin was evaluated in women with perennial rhinitis. Neither rhinitis nor concomitant therapy with a long-acting nasal decongestant substantially affected the nasal absorption of nafarelin. Other clinical studies are investigating strategies for second treatment of endometriosis or to improve the safety profile of nafarelin. In one trial, a second 3-month treatment course with nafarelin in patients with recurrent symptoms of endometriosis provided substantial pain relief. In another trial, preliminary information indicates that the addition of norethindrone to nafarelin in patients with endometriosis attenuates bone density changes and menopausal symptoms associated with nafarelin treatment.

Properties of sustained-release single-dose formulations for vulvovaginal candidiasis

Vaginally applied imidazoles are the first-line treatment of vulvovaginal candidiasis (VVC). The need to develop a less messy and more patient acceptable treatment regimen led to the development of a treatment schedule from the original 3 weeks to 7 days and, then, to 3 days. Finally, it was attempted to design a single-dose treatment regimen. Currently in the US, three single-dose vaginal preparations are available: 2% butoconazole sustained release (SR) [100mg butoconazole; Gynazole-1®], 6.5% tioconazole (300mg tioconazole; Vagistat-1®), and 2% miconazole vaginal ovule (Monistat1®, combination pack providing an ovule of 1200mg of miconazole and 2% monistat cream for external use). Clotrimazole 500mg single-dose vaginal tablet was used earlier and has been withdrawn from the market.In clinical studies, treatment success is measured by the regression of signs and symptoms of VVC (clinical cure) and by the negative mycological cultures (microbiological cure). 2% butoconazole SR has been formulated in an emulsion that adheres to wet surfaces of vaginal mucosa infected with Candida albicans. After the single dose, butoconazole is gradually released from the emulsion in a sustained release fashion for 3–6 days and acts on the fungus. The results of treatment with 2% butoconazole SR were equivalent to a 7-day schedule with 2% miconazole. Adverse effects have been infrequent and usually mild. 2% butoconazole in the SR bioadhesive formulation is drug-sparing compared with treatment regimens providing a total of 300–700mg of imidazoles in 3–7 days.The second single-dose preparation, 6.5% tioconazole, for VVC provides tioconazole 300mg in a vaginal ointment. This compound has been compared with 2% miconazole in a separate and independent set of clinical trials; 2% miconazole was superior to 6.5% tioconazole in the microbiological cure rates at the first follow-up examination.The success of a single-dose antifungal treatment also depends upon the vehicle used to deliver the active drug to the target tissue. In case of 2% butoconazole SR the vehicle is formulated as a hydrophilic emulsion that adheres to the surface of the moist vaginal mucosa for 3–6 days.Representative of the orally active preparations is a single dose of fluconazole 150mg. The efficacy results of oral fluconazole are similar to the 7-day vaginal antifungal preparations; however, there is the possibility of the development of resistance and systemic adverse effects affecting the liver and kidneys.The sustained-release technology used for single dose of 2% butoconazole is an innovative approach to vaginal drug delivery.

Effects of a gonadotropin-releasing hormone agonist on the calcium-parathyroid axis and bone turnover in women with endometriosis.

OBJECTIVE Our purpose was to investigate the effects of nafarelin on bone turnover and mass (bone mineral density, in grams per square centimeter) in women with endometriosis. STUDY DESIGN We monitored 22 young women with endometriosis during and 6 months after 6 months of nafarelin treatment. We compared the bone mineral density status of these women with that of healthy controls undergoing sequential bone mineral density measurement. RESULTS Subjects had a 2.2% loss in L2-4 bone mineral density by 6 months, increasing 3 months later to 3% and returning toward baseline by 6 months after treatment. Radius bone mineral density did not change in the treatment group. Bone mineral density did not change in controls. Serum and urinary calcium levels rose during treatment. Hydroxyproline excretion increased and remained elevated 6 months after treatment. A rise in serum osteocalcin persisted 3 months after therapy but normalized by 6 months. CONCLUSIONS Bone mineral density deficits with nafarelin are reversible. Increased bone turnover persists 6 months beyond treatment, demonstrating the need for careful monitoring of women receiving prolonged or repeated treatment.

Oxymetholone: differentiation between the ovarian and endometrial effects.

Abstract Uterine bleeding was induced by oxymetholone (100 to 200 mg. per day for 3 to 7 days) in a group of women with secondary amenorrhea but sufficient endogenous estrogens. This indicated either interference with ovarian estrogen production, a direct endometrial effect, or both. In the second phase of the clinical experiment, uterine bleeding was also induced in a group of women with complete ovarian failure in whom endometrial growth was promoted by estrogen priming. The ability of oxymetholone to induce uterine bleeding in these patients suggests that this compound can exert endometrial effects directly, without necessarily interfering with the ovarian estrogens. Endometrial histology revealed minimal subnuclear vacuolization with the 100 mg. daily dose and prominent subnuclear vacuolization with the 200 mg. daily dose. The decrease of the karyopyknotic index during oxymetholone treatment was interpreted as an expression of the antiestrogenic properties of the compound.

Practical possibilities for classification of primary amenorrhea: With special reference to the use of pneumopelvigraphy

Abstract Case histories of 80 patients with primary amenorrhea were analyzed and an attempt was made to establish a classification according to pathogenesis. From the viewpoint of practical diagnosis, the importance of the following investigations have been emphasized: pneumopelvigraphy; estimation of urinary gonadotropins; and determination of nuclear chromatin pattern. By proper interpretation of these methods every individual case may be classified into one of the following main categories: (1) Gonadal dysgenesis; (2) hypogonadism; (3) adrenal disturbances; (4) polycystic ovaries; (5) damage of internal genitals by infection; (6) vaginal and uterine developmental defects; and (7) testicular feminization and rare developmental defects.