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Enhanced sensitivity to steroid-negative feedback during breast-feeding: low-dose estradiol (transdermal estradiol supplementation) suppresses gonadotropins and ovarian activity assessed by inhibin B.

Breast-feeding reduces fertility, and this seems to be related, in part, to an enhancement of the sensitivity of the GnRH system to the negative feedback effects of estradiol related to suckling. Previously, we showed that short-term treatment with small doses of estradiol delivered transdermally suppress plasma gonadotropin concentrations in breast-feeding women. We have now monitored the effects on ovarian function of longer-term low-dose estradiol treatment using plasma inhibin B and inhibin A concentrations and ultrasonography. Breast-feeding women (n = 45) using barrier methods of contraception were enrolled at 6 weeks postpartum and followed up to 18 weeks PP. Nineteen women agreed to being randomized to wear either an estrogen [transdermal estradiol supplementation (TES); n = 10; Estraderm, 50 microg/24 h] or a placebo (PL; n = 9) patch for 12 weeks, whereas the remaining 26 women acted as untreated controls. TES did not significantly increase plasma estradiol concentrations. Plasma FSH levels decreased from 6.1+/-0.8 U/L to 3.3+/-0.6 U/L after 2 weeks of treatment (P < 0.01) and were lower in the TES group compared with the PL group at all times during the treatment (at least P < 0.05). Plasma LH concentrations in the TES group were lower than in the PL group after 4, 6, 8, and 10 weeks of estrogen treatment (at least P < 0.05). Throughout the study, no ovarian follicles detected by ultrasound were greater than 10 mm in diameter. Nevertheless, after 2 weeks of treatment, plasma inhibin B concentrations were significantly lower in the TES group than in the PL group (15.5+/-5.8 vs. 64.9+/-11.1 ng/L; P < 0.01) and remained significantly (P < 0.01) suppressed throughout the treatment, suggesting a suppression of the functional ovarian activity during TES. Inhibin A levels remained low in all groups (3-45 ng/L) but were suppressed further by TES treatment with no levels greater than 7 ng/L. We conclude that low-dose estradiol treatment given as TES suppresses ovarian activity as measured by inhibins B and A by reducing the secretion of LH and FSH during breast-feeding for several weeks. This supports the concept that suckling-induced suppression of the GnRH system is associated with an enhancement of the negative effects of estradiol on the hypothalamic GnRH system. Furthermore, because the contraceptive efficacy of breast-feeding is complicated by the unpredictable early return of ovarian activity in some women, TES could be the basis for the development of a novel contraceptive for breast-feeding women.

Administration, Cutaneous↗

Contraceptive efficacy and cycle control with the Ortho Evra/Evra transdermal system: the analysis of pooled data.

OBJECTIVE: To present efficacy and cycle control data pooled from three pivotal studies of the contraceptive patch (Ortho Evra/Evra). DESIGN: Three multicenter, open-label, contraceptive studies that included up to 13 treatment cycles. SETTING: 183 centers. PATIENT(S): 3,319 women. INTERVENTION(S): Three consecutive 7-day patches (21 days) with 1 patch-free week per cycle. MAIN OUTCOME MEASURE(S): Contraceptive efficacy and cycle control. RESULT(S): Overall and method failure life-table estimates of contraceptive failure through 13 cycles were 0.8% (95% CI, 0.3%-1.3%) and 0.6% (95% CI, 0.2%-0.9%), respectively. Corresponding Pearl indices were 0.88 (95% CI, 0.44-1.33) and 0.7 (95% CI, 0.31-1.10). Contraceptive failure among women with a body weight < 90 kg (<198 lb) was low and uniformly distributed across the weight range. A subgroup of women with body weight > or = 90 kg (> or = 198 lb) may have increased risk of pregnancy. The incidence of breakthrough bleeding was low and decreased over time. CONCLUSION(S): In contraceptive patch users, the overall annual probability of pregnancy was 0.8% and the method failure probability was 0.6%. The efficacy of the patch was high and similar across age and racial groups. Among women < 90 kg (<198 lb), contraceptive failure was low and uniformly distributed across the range of body weights. In women > or = 90 kg (> or = 198 lb), contraceptive failures may be increased. Efficacy and cycle control have been shown to be comparable to an established oral contraceptive.

Administration, Cutaneous↗

[Safety evaluation of a transdermal contraceptive system with an oral contraceptive].

OBJECTIVE: evaluation of the frequency of adverse events during the therapy with a transdermal contraceptive system (TCS) in comparison to an oral contraceptive. MATERIAL AND METHODS: 20 healthy women aged 23.8 +/- 4.1 years without contraindication to steroid hormonal therapy and a history of dermal hypersensitivity to adhesive applications. All patients were treated with either contraceptive patches containing 20 microg ethinyl estradiol (EE) and 150 microg norelgestromin (17-dNGM) or a monophasic oral contraceptive containing 20 microg EE and 150 microg desogestrel during 6 cycles. Safety evaluation was based on the frequency of adverse effects, changes in physical and gynecological examinations. RESULTS: The incidence of most adverse effects was similar between the transdermal and oral contraceptive therapies, except of a higher incidence of breast pain, dysmenorrhoea and application site reactions in the patch group. 50% of patients demonstrated gastro-intestinal complaints in the oral contraceptive group. None of the patients discontinued the hormonal contraceptive therapies due to adverse effects. CONCLUSION: The study suggests that a transdermal contraceptive system is a safe and well tolerated therapy.

Administration, Cutaneous↗

Iontophoretic in vivo transdermal delivery of beta-blockers in hairless rats and reduced skin irritation by liposomal formulation.

PURPOSE: To demonstrate the in vivo transdermal delivery and establish the comparative pharmacokinetics of five beta-blockers in hairless rat. METHODS: Intravenous dosing was initially done via jugular cannula. For iontophoretic delivery, current (0.1 mA/cm2) was applied for 2 h through a drug reservoir patch containing the beta-blocker (10 mg/ml). Blood samples were collected and analyzed by stereoselective HPLC assays. Any irritation resulting from patch application was quantified by a chromameter. Multilamellar liposomal formulation was prepared by the thin-film hydration method and converted to unilamellar liposomes by extrusion. RESULTS: With transdermal iontophoresis, therapeutically relevant amounts of propranolol (83.78 +/- 7.4 ng/ml) were delivered within an hour and lasted for up to 4 h. Cmax (185.1 +/- 56.8 ng/ml) was reached at hour 3. A significantly higher amount (p < 0.05) of sotalol HCl was delivered compared to other beta-blockers. There was no significant difference in the S/R ratio of AUC0-t for enantiomers after both intravenous and transdermal delivery. Skin irritation was significantly reduced (p < 0.05) when a liposomal formulation of the propranolol base was used rather than the base itself. CONCLUSIONS: The comparative pharmacokinetics of intravenous and transdermal iontophoretic delivery of five beta-blockers in hairless rats was established. It was shown that there is no stereoselective permeation.

Administration, Cutaneous↗

Acute effects of transdermal estrogen on hemodynamic and vascular reactivity in elderly postmenopausal healthy women.

OBJECTIVE: The acute effects of estrogen on hemodynamic responses were studied with emphasis on the sympathoadrenal system and peripheral circulation. DESIGN: Eleven healthy postmenopausal women recruited from the population-based study BEDA were included in this randomized, double-blind, cross-over, placebo-controlled hypothesis-generating pilot study, where the effect of transdermal estrogen (17 beta-estradiol, 100 microg/24 h) was tested. METHODS: Twenty-four hours after the patch with estrogen/placebo was attached, the blood pressure during rest and mental stress test was measured, together with blood samples for analysis of P-adrenaline and P-noradrenaline. Twenty-four-hour ambulatory registration of blood pressure and heart rate were recorded. Contractile properties and endothelial function of subcutaneous small arteries from gluteal biopsies were studied with the wire-myograph technique. RESULTS: Estrogen treatment reduced both ambulatory systolic blood pressure (5 mmHg, P = 0.05), diastolic blood pressure (3 mmHg, P < 0.05) and heart rate (6-8 beats/min during morning hours, P < 0.01). Diastolic blood pressure during and after mental stress was significantly reduced after estrogen treatment (p < 0.01). The levels of P-adrenaline and P-noradrenaline were similar in both treatment protocols. The contractile properties of the arteries were not significantly influenced by estrogen. Substance P induced nitric oxide-dependent relaxation in both estrogen-treated and placebo-treated precontracted arteries. Acetylcholine, on the other hand, induced a non-nitric oxide, non-prostanoid-dependent hyperpolarization, which was inhibited by potassium-induced depolarization after placebo but not after estrogen treatment. CONCLUSIONS: Acute administration of transdermal estrogen in clinically relevant doses modulates hemodynamics, probably by an altered parasympathetic balance, which might involve changes at the muscarinic receptor level.

Administration, Cutaneous↗

Clinical evaluation of the contact sensitization potential of a transdermal nicotine system (Nicoderm)

BACKGROUND: Transdermal nicotine therapy has shown promise as a smoking cessation aid, but questions about its contact sensitization potential and long-term topical safety have been raised. The purpose of this study was to determine the contact sensitization potential of one nicotine transdermal system (Nicoderm, Marion Merrell Dow Inc, Kansas City, Mo, and ALZA Corporation, Palo Alto, Calif) in a population who were allowed to continue smoking. METHODS: This study comprised two phases separated by a 2-week rest interval. During phase 1, a 42-day open-label induction period, subjects wore only active transdermal nicotine systems. During phase 2, a 4-day double-blind challenge period, subjects wore active and placebo systems concurrently. Upon removal of each patch, skin sites were evaluated for signs of irritation, and subjective complaints such as itching or burning were recorded. RESULTS: Of the 186 subjects completing the study, 3 (1.6%) exhibited evidence of delayed contact sensitization manifested as erythema with or without infiltration and confined solely to sites of active transdermal nicotine system application. Nonallergic skin irritation was observed in less than 3% of all applications. All reactions resolved without incident. No subjects developed systemic reactions. CONCLUSIONS: The transdermal nicotine system used in this trial had a low contact sensitization incidence and was well tolerated topically with minimal irritation.

Adhesives↗

Transdermal iontophoresis. Part II: Peptide and protein delivery.

The advent of sophisticated biotechnological processes has generated an interest in peptide and protein pharmaceuticals. However, the rapid developments in biotechnology are not matched by the developments in the delivery of these molecules. Presently, most of the peptides and proteins are delivered by parenteral route due to their poor oral bioavailability. The inherent discomforts associated with the parenteral therapy has prompted investigations into other nonparenteral routes and drug delivery techniques. Transdermal iontophoresis is one such technique showing good promise in the controlled and enhanced delivery of peptides and proteins. It offers noninvasive, continuous, pulsatile delivery as well as preprogramed complex dosing regimens. Miniature battery powered and wearable patches for peptides and proteins are expected to be on the market by the turn of this century. In continuation of our earlier review, this review explores the potential of transdermal iontophoresis for the delivery of peptides and proteins with the main focus on the suitability of the technique along with the factors to be considered in the design of this drug delivery system and its future prospects.

Administration, Cutaneous↗

[Hemodynamic effect and duration of action of Deponit 10 in patients with congestive heart insufficiency].

The haemodynamic effect of transdermal nitroglycerin treatment with Deponit 10 was investigated in 10 patients with chronic cardiac failure due to coronary artery disease (8 patients) or congestive cardiomyopathy (2 patients). The patients had elevated mean pulmonary artery (PA) and pulmonary capillary wedge pressures (PC) at rest (32.1 +/- 5.9 and 24.1 +/- 6.6 mm Hg). Heart rate (87 +/- 10), arterial blood pressure (133 +/- 20/77 +/- 8 mm Hg) and cardiac index (3.73 +/- 0.85 l/min/m2) were in the normal range. During treatment with Deponit 10 mean PA and PC pressures decreased significantly (p less than 0.01) to 25.5 +/- 6.3 and 18.1 +/- 6.4 mm Hg, respectively. The effect was seen within 1 hour after application of the transdermal therapeutic system and reached its nadir after 2 hours. PA and PC pressures remained significantly below control for 12-16 hours. Heart rate, arterial blood pressure and cardiac index were not changed. After removal of the patch 4 patients showed a rebound haemodynamic deterioration. Their mean PA pressure rose by more than 4 mm Hg above the respective control values. These patients had the highest control PA pressures of the group studied (37.5 +/- 2.4 mm Hg). Thus, transdermal nitroglycerin treatment with Deponit 10 reduces cardiac preload in patients with congestive heart failure for 12-16 hours, whereas cardiac afterload remains unaffected. After removal of the patch a rebound phenomenon can occur especially in patients with severe cardiac failure.

Administration, Cutaneous↗

Pharmacokinetic-hemodynamic studies of transdermal nitroglycerin in congestive heart failure.

Ten patients with chronic congestive heart failure were studied to assess the hemodynamic effects and bioavailability of a transdermal nitroglycerin delivery system. Nitrate sensitivity was defined by a prior 20 minute infusion of nitroglycerin, 21 micrograms/min. Five patients with a satisfactory hemodynamic response to intravenous nitroglycerin received two nitroglycerin patches of 10 cm2 each and five patients who did not achieve a satisfactory response to intravenous nitroglycerin (that is, greater than or equal to 25% reduction in left ventricular filling pressure) received larger doses of transdermal nitroglycerin. In the five nitrate-sensitive patients who received 20 cm2 of transdermal nitroglycerin, one study was terminated at 90 minutes, at which point there was no detectable hemodynamic response or arterial plasma nitroglycerin evident. Two patients had a minimal hemodynamic response and a peak plasma concentration of 1 ng/ml. A fourth patient had a short-lived hemodynamic response at 60 and 120 minutes and a plasma nitroglycerin concentration of 1 ng/ml at 60 minutes. A fifth patient had a hemodynamic response persisting for 24 hours and plasma concentrations between 0.6 and 1.1 ng/ml. The remaining five patients showed little or no hemodynamic response despite doses of transdermal nitroglycerin from 40 to 60 cm2. The highest plasma concentration achieved in these patients was 2 ng/ml and there was no relation between dose administered and plasma concentration achieved. In 4 of the 10 patients who subsequently received nitroglycerin ointment, there were a greater decrease in left- and right-sided filling pressures and greater increase in plasma nitroglycerin concentrations (from 1.6 to 4.8 ng/ml) than those that occurred with transdermal nitroglycerin.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Cutaneous↗

Safety and efficacy of a testosterone patch for the treatment of hypoactive sexual desire disorder in surgically menopausal women: a randomized, placebo-controlled trial.

BACKGROUND: Oophorectomy reduces serum testosterone levels. We studied the efficacy and safety of transdermal testosterone in treating hypoactive sexual desire disorder in surgically menopausal women. METHODS: A 24-week, randomized, double-blind, placebo-controlled, parallel-group, multicenter trial was conducted in women (aged 24-70 years) who developed distressful low sexual desire after bilateral salpingo-oophorectomy and hysterectomy and who were receiving oral estrogen therapy. Women were randomized to receive placebo (n = 119) or testosterone patches in dosages of 150 microg/d (n = 107), 300 microg/d (n = 110), or 450 microg/d (n = 111) twice weekly for 24 weeks. Sexual desire and frequency of satisfying sexual activity were primary efficacy outcome measures. RESULTS: Of the 447 women randomized, 318 (71%) completed the trial. Compared with placebo, women receiving the 300-microg/d testosterone patch had significantly greater increases from baseline in sexual desire (67% vs 48%; P = .05) and in frequency of satisfying sexual activity (79% vs 43%; P = .049). The 150-microg/d group showed no evidence of a treatment effect. The 450-microg/d group also was not statistically different from the 300-microg/d or placebo groups. Marginally significant linear dose-response trends were observed for total satisfying sexual activity and sexual desire at 24 weeks (P = .06 and .06, respectively). Adverse events occurred with similar frequency in both groups; no serious safety concerns were observed. CONCLUSIONS: The 300-microg/d testosterone patch increased sexual desire and frequency of satisfying sexual activity and was well tolerated in women who developed hypoactive sexual desire disorder after surgical menopause.

Administration, Cutaneous↗

Effect of oral versus transdermal steroidal contraceptives on androgenic markers.

OBJECTIVE: The purpose of this study was to compare biochemical androgen profiles in women treated with the contraceptive patch versus an oral contraceptive (OC). STUDY DESIGN: Twenty-four healthy women were randomly assigned to receive 3 cycles of either the contraceptive patch (ethinyl estradiol [EE] 20 microg/d and norelgestromin 150 microg/d) or OC (EE 35 mug and norgestimate 250 microg). Blood samples were taken at baseline and end of treatment. Serum levels of sex hormone-binding globulin (SHBG), total testosterone (T), androstenedione (A), dehydroepiandrosterone sulfate (DHEAS), dihydrotestosterone (DHT), and 3alpha-androstanediol glucuronide (3alpha-diol G) were quantified by immunoassay methods; free T was calculated. The paired t and Student t tests were used for statistical analysis. RESULTS: Nineteen women completed the study (patch, n = 10; OC, n = 9). Despite a 1.6-fold relative increase in SHBG levels with the patch versus OC (449% vs 274%, P = .03), free T decreased equally in both groups (patch 60%, P < .0001; OC 59%, P < .0001). DHEAS decreased by 26% in the patch group (P < .01) and 32% in the OC group (P < .001). 3alpha-diol G was reduced by 52% in the patch group (P < .0001) and 51% in the OC group (P < .0001). In addition, the OC was associated with significant decreases in A and DHT. CONCLUSION: The contraceptive patch had an effect comparable to the OC on several key androgenic markers. Given these biochemical findings, the contraceptive patch has significant potential as a therapeutic agent for disorders of androgen excess.

Administration, Cutaneous↗

Effects of transdermal and oral contraceptives on estrogen-sensitive hepatic proteins.

OBJECTIVE: The purpose of this study was to evaluate the effects of the contraceptive patch and an oral contraceptive (OC) on serum concentrations of estrogen-sensitive hepatic proteins, ethinyl estradiol (EE) and levonorgestrel (LNG). METHODS: Twenty-four women were randomized to receive three cycles of a contraceptive patch that delivers EE 20 microg/day and norelgestromin 150 microg/day or an OC that contains EE 35 microg and norgestimate 250 microg. Blood samples were taken at baseline and at the end of Cycle 3. Serum levels of sex-hormone-binding globulin (SHBG), thyroxine-binding globulin (TBG), corticosteroid-binding globulin (CBG) and C-reactive protein (CRP) were quantified by immunoassay methods. EE and LNG levels in patch users were measured by radioimmunoassay (RIA) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay. The paired t test and Student's t test were used for statistical analysis. RESULTS: Nineteen women completed the study (patch, n=10; OC, n=9). Treatment with both the patch and OC resulted in significant increases from baseline in SHBG, TBG and CBG. The increase in CRP was significant in the patch group and approached significance in the OC group. The increases in SHBG and TBG observed with the patch were significantly greater than those associated with the OC. By way of RIA and LC-MS/MS assay methods, the patch was associated with mean EE levels of 114 and 111 pg/mL, respectively. CONCLUSIONS: The serum concentrations of estrogen-sensitive hepatic proteins and EE associated with the patch suggest that this new contraceptive system may have relatively large net estrogen effects.

Administration, Cutaneous↗

[Clinical evaluation of tulobuterol patch in patients with mild or moderate persistent bronchial asthma-effects of long-term treatment on airway inflammation and hypersensitivity].

The tulobuterol transdermal therapeutic system (TTS) is the world's first commercially available transdermal preparation of tulobuterol, a beta-2 stimulant, that can maintain effective blood tulobuterol levels for 24 hours when applied once daily. In the present study, a total of 36 adult patients with mildly persistent (Step 2) or moderately persistent (Step 3) bronchial asthma 19 who were using inhalational steroids and 17 who were not used tulobuterol TTS for one year and underwent measurement of peak expiratory flow (PEF) once daily. Peripheral eosinophil count, serum eosinophil cationic protein (ECP) level and airway responsiveness (Dmin) were evaluated at 6 months and 1 year after the start of the study. PEF exhibited significant improvements at 6 months and 1 year in patients treated with or without inhalational steroids, while serum ECP was improved significantly only in the patients on inhalational steroids. Patients not using inhalational steroids exhibited no significant exacerbation of Dmin at either 6 months or 1 year: One-year treatment with tulobuterol TTS did not appear to cause tachyphylaxis. The significant improvements in Dmin at 6 months and 1 year in the patients using inhalational steroids suggested that inhalational steroids offer beneficial effects in controlling airway inflammation. Tulobuterol TTS is considered quite beneficial in improving quality of life (QOL) in patients with bronchial asthma because its incidence of adverse effects including palpitations and shivering is significantly lower than those of oral preparations, because of its remarkable improvement of pulmonary function and symptoms of airway obstruction without increasing airway responsiveness even after repeated use, and because it is simple to use and offers excellent clinical efficacy.

Administration, Cutaneous↗

The transdermal revolution.

Historically, developments in transdermal drug delivery have been incremental, focusing on overcoming problems associated with the barrier properties of the skin, reducing skin irritation rates and improving the aesthetics associated with passive patch systems. More-recent advances have concentrated on the development of non-passive systems to aid delivery of larger drug molecules, such as proteins and nucleotides, as the trend for discovering and designing biopharmaceuticals continues. Fundamentally, improvements in transdermal delivery will remain incremental until there is wider acceptance of this route of administration within the pharmaceutical industry. Only then will the transdermal revolution live up to its true potential.

Administration, Cutaneous↗

Failure of transdermal nitroglycerin to improve exercise capacity in patients with angina pectoris.

Sixteen patients with stable angina pectoris were studied in a double blind crossover manner utilizing treadmill exercise testing with the direct measurement of total body oxygen uptake, 1 and 24 hours after application of a 20 cm2 transdermal nitroglycerin system and identical placebo. Testing was performed after a 3 day lead-in period of treatment with either an active patch or placebo. Points of analysis were peak angina and the submaximal work load occurring at 4 minutes of exercise. No statistically significant differences were observed between nitroglycerin and placebo treatment in any of the rest hemodynamic or peak angina variables at 1 or 24 hours. A significant increase in the rate-pressure product at the submaximal work load was observed 1 hour after transdermal nitroglycerin relative to placebo application. However, no significant differences were observed in any of the other measured variables at the submaximal work load, 1 or 24 hours after nitroglycerin application. The once daily application of a 20 cm2 transdermal nitroglycerin system was ineffective in altering the exercise capacity of patients with angina pectoris. The lack of efficacy at 1 hour appears to be due to inadequate nitroglycerin blood levels; at 24 hours it may be due to tolerance.

Adult↗

Effectiveness and tolerability of the buprenorphine transdermal system in patients with moderate to severe chronic pain: a multicenter, open-label, uncontrolled, prospective, observational clinical study.

BACKGROUND: A new transdermal delivery system (TDS) for the rate-controlled systemic delivery of buprenorphine is available in 3 patch strengths, with release rates of 35, 52.5, and 70 microg/h over 72 hours, delivering daily amounts of 0.8, 1.2, and 1.6 mg, respectively. Randomized, double-blind, placebo-controlled, Phase III clinical trials in >400 patients with severe pain of malignant or nonmalignant origin have shown the analgesic efficacy of buprenorphine TDS. OBJECTIVE: This study investigated the effectiveness and tolerability of buprenorphine TDS for the relief of chronic pain in routine clinical practice. METHODS: This was a multicenter, open-label, uncontrolled, prospective, observational, 3-month follow-up study in patients who were beginning buprenorphine TDS treatment for moderate to severe cancer or noncancer pain that had not responded to nonopioid analgesics. Patches were to be changed every 72 hours. Patients were evaluated at 1 and 3 months after the start of treatment. Those who dropped out were considered treatment failures. Pain relief was assessed on a 5-category verbal rating scale, and quality of life was assessed using the European Quality of Life 5D (EQ-5D) questionnaire. Tolerability was determined based on adverse events recorded during the follow-up period. RESULTS: The study recruited 1223 patients, most of whom were outpatients. Of the 1212 patients for whom sex data were available, 820 (67.7%) were women. In the 1188 patients with age data, the mean (SD) age was 64.9 (12.9) years. In the 1175 patients with data on the etiology of pain, 82.4% had noncancer pain. Six hundred eighty-eight (56.3%) patients completed the 3-month follow-up period. The median daily amount of buprenorphine TDS received at the beginning of the study was 0.8 mg (corresponding to 35 microg/h). Over the study period, there was a significant increase in the proportion of patients reporting very good or good pain relief (P < 0.001), from 3.6% (43/1205) at baseline to 63.2% (762/1205) after 1 month and 56.8% (685/1205) after 3 months. Quality of life also improved, from a mean (SD) EQ-5D score of 40.6 (20.5) at baseline to 56.8 (23.5) at 3 months (P < 0.001). Five hundred seventeen (42.3%) of the original 1223 patients experienced adverse events; the investigator judged 397 (32.5%) of these events possibly or probably related to study drug. The likelihood of experiencing a drug-related adverse event was greater in noncancer patients than in cancer patients. The most common adverse events were nausea (11.0%), vomiting (9.2%), and constipation (7.8%); the most common local adverse events were pruritus (1.4%), dermatitis (1.3%), and erythema (1.3%). CONCLUSION: In the population studied, buprenorphine TDS was effective in alleviating cancer and noncancer pain and was well tolerated overall.

Administration, Cutaneous↗

The effect of supplemental L-arginine on tolerance development during continuous transdermal nitroglycerin therapy.

OBJECTIVES: This study was designed to assess the effect of oral L-arginine on the development of tolerance during continuous transdermal nitroglycerin (TD-GTN) therapy. BACKGROUND: Continuous TD-GTN therapy leads to complete tolerance within 24 to 48 h. The mechanism(s) responsible for nitrate tolerance are unclear, but there is increasing evidence that nitroglycerin (GTN) leads to superoxide anion production. The trigger for this is unknown, but there is evidence that GTN alters nitric oxide synthase (NOS) function and also leads to reduced L-arginine availability at its site of action with NOS. METHODS: Fourteen patients with stable angina pectoris and reproducible treadmill walking time (TWT) until the onset of moderate angina were studied in a placebo-controlled, crossover study. Transdermal GTN (0.4 mg/h) was applied daily for two periods of 5 to 10 days with the patch left in place for 24 h each day. Capsules containing L-arginine (700 mg) or placebo were administered four times daily during a period of TD-GTN therapy. Treadmill walking time was determined before and 4 h after study capsules on day 1 before TD-GTN to assess the effect of L-arginine on exercise performance. On the last day, TWT was determined at 0 h (24 h after TD-GTN and 9 h after study capsule) and 4 h after TD-GTN reapplication and study capsule. After a 5 to 10 day washout period, the study was repeated with the opposite study capsule. RESULTS: Treadmill walking time until the onset of moderate angina was not influenced by the short-term administration of L-arginine. During continuous TD-GTN, the administration of L-arginine increased TWT 4 h and 24 h after patch application. This was significantly greater than TWT during administration of placebo capsules (p < 0.05). CONCLUSIONS: The administration of L-arginine modified or prevented the development of nitrate tolerance during continuous TD-GTN therapy.

Administration, Cutaneous↗

Double blind comparison of transdermal hyoscine and placebo for the prevention of postoperative nausea.

Transdermal hyoscine (Scopoderm, Ciba-Geigy) has been compared with placebo in 283 female patients. The hyoscine patch had no significant effect on postoperative nausea or vomiting. In contrast with earlier studies, there was no correlation between previous experiences of nausea (motion, pregnancy or surgery related) and nausea caused by the surgery or anaesthetic in this study. No correlation was found between nausea or vomiting and the type of operation.

Administration, Cutaneous↗