Optimizing delivery of therapeutics: percutaneous technologies.

The purpose of this communications is to 1) demonstrate the potential of percutaneous drug-delivery on the example of female reproductive steroids, 2) point out the differences between transdermal and conventional drug dosing, and 3) outline new technologies and innovations that are looming on the horizon, specifically in the area of pain control. Transdermal delivery systems are of two basic types. The first ones employ principles of passive diffusion, and they are used for hormonal replacement therapy (HRT) and contraception. Patches for HRT, designed to release estradiol (E2) only, require a simultaneous dosing with oral progestogens. Patches employing both E2 and a progestogen release the combination either continuously or sequentially. In the latter method, estrogen-only patches are applied for 14 days, followed by a 14-day application of patches releasing both hormones. Both methods successfully cope with symptoms and signs of menopause, including bone loss. Contraceptive transdermal patches deliver ethinylestradiol in combination with the progestogen norelgestromin. This system provides high contraceptive protection with predictable withdrawal bleeding and without major adverse events and weight changes. Hormones delivered by the skin avoid first-pass liver metabolism. Other advantages include rapid onset and termination of action, self-administration, and attainment of therapeutic hormone levels with low daily doses. A disadvantage is the variable intra- and inter-individual percutaneous absorption. In some patients, patches can cause skin irritation. Active systems deliver therapeutics across intact skin non-invasively by means of an electric potential (electrotransport). A system consisting of tooth-like titanium microprojections that penetrate only the keratinized epidermis facilitates painless and needle-free transport of complex molecules to the capillaries of the dermis. Other devices use low frequency ultrasound. These systems enable precise dosage, delivery of large molecules, such as growth hormone and vaccines, and dosing of analgesics "on demand". Novel transdermal technologies are profoundly changing the current methods of pain management. (Fig. 6, Ref. 47.).

Norgestimate. From the laboratory to three clinical indications.

This review of preclinical studies and clinical trials of efficacy and safety examines the relation between structure and function in the norgestimate (NGM) molecule, describes the pharmacologic characteristics of NGM and evaluates clinical experience with NGM in oral contraception (OC), treatment of hyperandrogenism in women and hormonal replacement therapy (HRT). NGM is a progestin of the 19-norsteroid series with an oxime group on C-3. In women, only low serum levels of NGM can be detected for five hours after ingestion. NGM is swiftly converted into its main metabolite, the 17-deacetylated norgestimate (norelgestromin), which carries the progestogenic properties of NGM. The metabolite reaches a mean peak concentration of 3,500 pg/mL 1.5 hours after intake and has a half-life of > 24 hours. The progestogenic potency of NGM and its main metabolite is comparable to that of progesterone. The doses of NGM in OCs effectively inhibit ovulation and control uterine bleeding. In the triphasic NGM/ethinyl estradiol (EE) OC, the total monthly load of progestin is only 4.5 mg. NGM has a low androgenic impact and does not interfere with the positive metabolic actions of estrogens, notably the estrogen-induced increase in high-density lipoprotein levels. OCs with NGM and EE increase the serum concentration of sex hormone binding globulin threefold, augmenting the binding of circulating testosterone and reducing free testosterone levels by 50%. Consequently, OCs with NGM are therapeutic for hyperandrogenic symptoms, such as acne. In a new type of HRT three-day dosing with 17 beta-estradiol (E2) alone is followed by three-day dosing with E2 plus NGM. This regimen treats vasomotor symptoms, protects the endometrium from hyperproliferation and is associated with a favorable lipid profile. NGM is a versatile progestin suitable for medical use from adolescence through the reproductive years to menopause.

[The health care revolution in the USA]. / Zdravotnícka revolúcia v USA.

The changes in medical care in the USA have not been completed yet. The government which will be established after the following presidential elections will be compelled to deal with the organisation of medical care in order to make the financial participation of the federal government manageable. The American medical workers must unite in their procedures in order to bring the negotiations with the government institutions, insurers and health maintaining institutions to a successful end. The struggle for medical independence is of great importance as it enables to suppress stereotypes and obsolete traditions, and leads to innovative procedures which represent the basis for progress in medical science. (Fig. 10, Ref. 16.)

Butoconazole nitrate 2% for vulvovaginal candidiasis. New, single-dose vaginal cream formulation vs. seven-day treatment with miconazole nitrate. Gynazole 1 Study Group.

OBJECTIVE: To compare the safety and efficacy of a single vaginal dose of a butoconazole nitrate 2% bioadhesive, sustained-release cream* (butoconazole 1-BSR) with a seven-day schedule of miconazole nitrate vaginal cream 2% (miconazole 7). STUDY DESIGN: The clinical trial was conducted according to a randomized, parallel, investigator-blind, multicenter study design. The patients self-administered the respective creams to the posterior vaginal fornix. Two hundred twenty-three patients started the trial and were analyzed for safety. A total of 205 patients qualified for efficacy analysis, 101 receiving butoconazole 1-BSR and 104 using miconazole 7. Patients receiving butoconazole 1-BSR inserted one applicator full of medication once. Those assigned to receive miconazole 7 inserted one applicator full daily for seven days. Patients were evaluated 7-10 and 30 days after completion of therapy. RESULTS: Butoconazole 1-BSR rapidly relieved the signs and symptoms of vulvovaginal candidiasis. The proportion of patients with severe symptoms declined from the pretreatment 20% to 6% on the 1st day, to 3% on the 4th day, and to 2-1% on the 5th-7th day after single-dose application. Eight to ten days after treatment completion, clinical symptoms regressed in 92%, and fungal cultures were negative in 87% of patients. At the 30-day posttreatment visit, 88% of patients remained clinically cured, and 74% had negative fungal cultures. In the miconazole 7 group, the proportion of patients with severe symptoms declined from 23% to 19% after the first dose; thereafter, symptom relief proceeded more rapidly. Eight to ten days after treatment completion, clinical symptoms regressed in 92% and fungal cultures were negative in 87% of patients. At the 30-day follow-up examination, 86% patients were clinically cured, and 77% were culture negative. After single-dose butoconazole 1-BSR, severe symptoms receded faster than after the first dose of miconazole 7, and the difference was statistically significant (P = .01). In all other efficacy parameters, the differences between the two groups were not statistically significant. Neither treatment regimen caused significant adverse events. CONCLUSIONS: This clinical trial demonstrated that butoconazole 1-BSR is an effective and safe alternative to longer-term therapy with miconazole nitrate (seven days) for vulvovaginal candidiasis.

Reproductive medicine in the second half of the 20th century.

This communication reviews the most important achievements of human reproductive medicine during the last 50 years. The progress in this discipline has been so profound and unexpected that it has raised ethical questions of a fundamental character. Over the last 50 years of this century, new insight into reproductive processes enabled the following development: hormonal contraception, gonadotropin-releasing hormone (GnRH) and its agonistic and antagonistic analogues, prostaglandins: induction of labor and conquering dysmenorrhea, selective estrogen receptor modulators (SERM), assisted reproductive technologies (ART), and recombinant DNA technology and cloning. Currently, safe and effective contraceptive methods are available. Control of the world population growth is not a medical issue anymore: it is a political and social problem. Governments, and national and ideological leaders must share the responsibility for creating a social and economic milieu that facilitates women's education, provides access to birth control methods, and motivates the population to limit its own growth. At the same time, society must foster traditional family and moral values Vis a Vis sex. (Fig. 6, Ref. 22.)

Periovarian peritoneal adhesions in women with endometriosis. Structural patterns.

OBJECTIVE: To draw attention to the structural features of adhesions associated with pelvic endometriosis since they are less well studied than endometriosis proper. STUDY DESIGN: Sixty-two samples of periovarian adhesions were laparoscopically obtained from 24 infertile women 26-38 years of age and were prepared for detailed histologic analyses. RESULTS: Macroscopically, the adhesions were either velamentous or cordlike and grossly were free of endometriosis. Most adhesions were attached to the connective tissue of the ovarian tunica albuginea; in two cases they were attached to the corpus luteum. Upon microscopic analysis, velamentous adhesions consisted of fibrous sheets of collagen connective tissue, with the surface lined with single-layered coelomic epithelium. The cord-like adhesions consisted of "hyalinized" fibrous tissue and were either avascular or vascularized. Irregular cystic or tubular structures that could be regarded as endometriosis were found in four patients. Hyaline cartilage within the tissue of the adhesion was an unexpected finding in one patient. CONCLUSION: Microscopic analysis permitted grouping of the adhesions in the following way: (1) Connective tissue adhesions (23 patients) with the following subcategories: (A) fibrous, either avascular or encompassing degenerating blood vessels (6 patients); (B) vascularized, containing granulomatous tissue (12 patients); (C) vascularized with stromoglandular endometrioid cysts or tubules (4 patients); (D) rare types, such as that encompassing hyaline cartilage (1 patient). (2) Fibrin adhesions (1 patient). From the clinical point of view, the presence of endometrial tissue within adhesions raises the question of whether there is a need for removal, rather than just lysis, of adhesions to avoid persistent pain.

Human issues and medical economics of endometriosis. Three- vs. six-month GnRH-agonist therapy.

OBJECTIVE: To project the efficacy and economic consequence of short-term intranasal gonadotropin-releasing hormone agonist (GnRH-a) for diagnosis of and therapy for endometriosis. STUDY DESIGN: Multicenter, placebo-controlled clinical trials of GnRH-a comparing three vs. six months of treatment, three months of retreatment and three months of postoperative treatment for the symptoms and signs of laparoscopically diagnosed endometriosis. RESULTS: The reduction in symptoms and signs of endometriosis was similar at the end of three months to the relief at six months. Retreatment was as effective as initial treatment, and the return of symptoms after laparoscopic surgery plus postoperative treatment for three months was delayed by approximately 18 months as compared to surgery alone. The projected charges for the surgical approaches (laparoscopy or minilaparoscopy) to diagnosis and therapy were 50-60% greater than those for the medical approach. CONCLUSION: GnRH-a administration for three months could be a cost-effective approach to the presumptive diagnosis and treatment of endometriosis among women with chronic pelvic pain.

Nafarelin vs. leuprolide acetate depot for endometriosis. Changes in bone mineral density and vasomotor symptoms. Nafarelin Study Group.

OBJECTIVE: To compare intranasal nafarelin and intramuscular leuprolide acetate (LA) depot in the management of endometriosis. STUDY DESIGN: A multicenter, prospective, randomized, double-placebo, double-blind study was conducted on subjects who had symptoms and signs of endometriosis and bone mineral density (BMD) within the age-appropriate normal range. For 6 months, 99 subjects received nafarelin, 200 micrograms twice daily, and placebo injections once monthly; 93 subjects received LA depot injections, 3.75 mg once monthly, and placebo nasal spray, twice daily. Subjects were followed throughout treatment and for six months after treatment. The main outcome measures were changes in endometriosis symptoms and signs, BMD measurements, subject-reported and objectively measured hot flushes and circulating estradiol concentrations. RESULTS: Nafarelin was as effective as LA depot in alleviating symptoms and signs of endometriosis. LA depot recipients lost significantly more BMD, had more days with subjective hot flushes and more objectively measured hot flushes than did nafarelin recipients. In the nafarelin group, estradiol levels were consistently higher than in the leuprolide depot group, with significant differences by month 3 of dosing. CONCLUSION: Nafarelin and LA depot were equally effective despite higher estradiol levels in nafarelin recipients. Nafarelin-treated subjects lost less BMD, had fewer days with hot flushes and had fewer objectively measured hot flushes.

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 agonist analog (nafarelin): a useful diagnostic agent for the distinction of constitutional growth delay from hypogonadotropic hypogonadism.

To determine the usefulness of a GnRH agonist analog as a diagnostic test to distinguish between constitutional delay of growth (CGD) in boys with Tanner stage I of sexual development and patients with hypogonadotropic hypogonadism (HH), we evaluated six boys (mean age 15 yr 4 m) and five HH patients (mean age 20 yr 4 m). In addition, 20 normal healthy men aged 21 yr to 50 yr received either nafarelin or GnRH followed two weeks later by the other test in order to compare the efficacy of each of these tests and to evaluate the optimal sampling times for the nafarelin test. All subjects were healthy, and had not received hormonal replacement for at least 2 months prior to enrollment in the study. Each man had four baseline blood samples before and at timed intervals following the administration of either GnRH or nafarelin. Each of the patients had blood withdrawn every 15 min during 12 h overnight followed by a single s.c. injection of nafarelin (1 microgram(s)/kg up to 100 microgram(s)), except two HH patients who did not have an overnight study. Blood samples were obtained at timed intervals for 24 h. LH, FSH, T and E2 were measured by RIA. Baseline concentrations of plasma LH, FSH and T were similar before the administration of either GnRH or nafarelin in the group of normal men. Peak stimulation of plasma LH, FSH and T released by nafarelin was significantly higher, and it took a longer time to reach the peak maximum, than after GnRH (p < 0.001). Mean nocturnal LH was 5.5 +/- 0.9 IU/I for the CGD group, and 2.7 +/- 0.7 IU/I for HH (p < 0.02). Mean nocturnal FSH was 5.1 +/- 1.0 and 2.5 +/- 0.2 IU/I whereas mean nocturnal T concentrations were 4.2 +/- 0.8 and 0.7 +/- 0.2 nmol/I (CGD vs HH, respectively, p < 0.02). Peak LH responses to nafarelin were 36.9 +/- 8.9 IU/I for the CGD group, and 7.0 +/- 2.0 IU/I for the HH group (p < 0.001). Peak FSH released by nafarelin was 14.2 +/- 2.4 IU/I for the CGD group and 4.8 +/- 2.0 IU/I for the HH group (p < 0.02). Peak T was reached 24 h following nafarelin injection and was 5.7 +/- 1.7 nmol/I for the CGD group and 0.3 +/- 0.2 nmol/I for the HH group (p < 0.001). The results obtained indicate that in early stages of puberty (before detectable changes of sexual maturation) the nafarelin test, with measurements of LH, FSH and T in blood or in urine, is superior to and more practical than overnight hormonal estimates to clearly distinguish CGD from HH.

Gonadotropin-releasing hormone analogs: update on new findings.

Clinical trials are under way to investigate the optimal use of nafarelin. In one series of studies, the effect of 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.

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.

Role of nafarelin in the management of endometriosis.

A large, multicenter, double-blind clinical trial established that the gonadotropin releasing hormone analog nafarelin relieves clinical symptoms, decreases laparoscopic scores and improves fertility in women with endometriosis. Side effects were limited to those attributable to hypoestrogenism.

Comparison of three-day butoconazole treatment with seven-day miconazole treatment for vulvovaginal candidiasis.

In this multicenter, parallel, randomized, investigator-blind trial, we compared the safety and efficacy of a three-day regimen of 2% butoconazole vaginal cream with those of a seven-day regimen of 2% miconazole vaginal cream. Enrolled were 271 nonpregnant women with vulvovaginal candidiasis. Each patient administered her assigned study medication to the posterior vaginal fornix for three or seven consecutive nights. All 271 patients were included in the safety evaluation, and 225 (111 receiving butoconazole and 114 receiving miconazole) were included in the efficacy evaluation. Eight to ten days after treatment completion, 88% of the butoconazole-treated patients and 91% of the miconazole-treated patients were Candida negative; 80% of the butoconazole-treated patients and 82% of the miconazole-treated patients were considered clinically cured. Thirty days after treatment completion, 73% of the butoconazole-treated patients and 69% of the miconazole-treated patients remained Candida negative; 78% of the butoconazole-treated patients and 80% of the miconazole-treated patients remained free of clinical symptoms of vulvovaginitis. None of the differences between the two treatment groups was statistically significant. Six patients (four receiving butoconazole and two receiving miconazole) reported increased symptoms of vulvovaginal irritation, and three of them (two receiving butoconazole and one receiving miconazole) withdrew from the trial. Thus, the efficacy and safety of the three-day butoconazole treatment regimen were equivalent to those of the seven-day miconazole treatment regimen. The advantage of the shorter butoconazole treatment is increased patient compliance with maintenance of high efficacy.