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Effect of transdermally administered fentanyl on minimum alveolar concentration of isoflurane in normothermic and hypothermic dogs.

OBJECTIVE: To determine whether the minimum alveolar concentration (MAC) of isoflurane was altered by transdermal administration of fentanyl in normothermic and hypothermic dogs. DESIGN: Randomized complete block crossover design. ANIMALS: 6 mature healthy dogs. PROCEDURE: Dogs received each of 4 treatments in random order. Following induction of anesthesia, normothermia was maintained in dogs that were treated with a fentanyl patch (F-NORM) or sham patch (C-NORM), or hypothermia was maintained in dogs that were treated with a fentanyl patch (F-HYPO) or sham patch (C-HYPO). The appropriate patch was applied 24 hours prior to induction of anesthesia. Anesthesia was induced with isoflurane in oxygen; the dogs were intubated and mechanically ventilated. Target esophageal temperatures were maintained within 1 degrees C of baseline values (normothermia) or at 34.5 degrees C (94.1 degrees F; hypothermia) for 1 hour prior to starting MAC determinations. Supramaximal stimulation was achieved with an electrical stimulator attached to needle electrodes placed in the buccal mucosa of the lower jaw of the dog. RESULTS: Mean MAC +/- SEM of isoflurane during C-NORM, C-HYPO, F-NORM, and F-HYPO treatments were 1.20 +/- 0.17, 0.89 +/- 0.18, 0.76 +/- 0.10, and 0.81 +/- 0.17, respectively. The mean MAC during C-NORM was significantly higher than values for the other treatments. There was no significant difference in mean MAC among the C-HYPO, F-NORM, and F-HYPO treatments. CONCLUSIONS AND CLINICAL RELEVANCE: Data suggest that transdermal administration of fentanyl significantly reduces isoflurane requirements in normothermic dogs. The isoflurane MAC-sparing effects of transdermal fentanyl are not apparent in hypothermic dogs.

Administration, Cutaneous↗

Transdermal nicotine on sleep and PGO spikes.

There is conflicting evidence for the role of nicotine in sleep regulation. This study was undertaken to determine the effects of transdermal nicotine at doses of 17.5, 35 and 52.5 mg on sleep and PGO spike activity. Minor effects were observed on sleep with a general increase in waking. PGO spike activity was abolished by all patches. The results are discussed in terms of the mechanisms involved in the disappearance of PGO spikes as a result of nicotine.

Administration, Cutaneous↗

Therapeutic effect and pharmacokinetics of ketotifen transdermal delivery system.

Ketotifen transdermal delivery systems were prepared using polyisobutylene, liquid paraffin, and fatty acid. In vitro skin penetration studies were conducted in Franz diffusion cells using excised porcine skin to determine the skin permeation rates of ketotifen patches. A trend of increased skin penetration of ketotifen was observed as the amount of liquid paraffin in the patch was increased. In addition, we found that lauric acid was a suitable enhancer for percutaneous absorption of ketotifen. Challenge tests were performed in guinea pigs to determine the therapeutic effect of the delivery systems for the inhibition of anaphylactic shock using varied concentrations of chicken ovum albumin as sensitizer. Our results showed that compared with the treatment of intramuscular administration, the skin patch was more effective and produced higher survival rates. The pharmacokinetics of the ketotifen patch were determined by applying the skin patch to the dorsal skin of rabbits. The plasma levels were maintained constant (42.5-36.4 ng/ml) from 9 to 30 hr. From our study, the prepared ketotifen patch may further be developed for the treatment or prevention of allergic asthma.

Adhesives↗

Bioavailability of estradiol from two matrix transdermal delivery systems: Menorest and Climara.

OBJECTIVES: To compare two estradiol transdermal matrix systems with regard to bioavailability, pharmacokinetics and tolerability. METHODS: A single centre, open, randomized, comparative cross-over study in 20 healthy postmenopausal women. Menorest with 3 or 4 days of suggested use and Climara with 7 days of suggested use (both 50 microg/24 h) were compared at steady state. Two 14-day treatment periods were separated by a 4 week washout. Plasma levels of estradiol were monitored during the second week of each treatment. Tolerability was assessed by open questions and inspection of the application site. RESULTS: There were no differences between the two treatments with regards to AUC, Cmax, Cmin, Caverage or fluctuations of plasma estradiol. Tmax was significantly shorter for Menorest than Climara. Cmax and Cmin were significantly higher for the second Menorest patch during the monitoring period compared to the first. All local reactions were mild and there were three cases of erythema with Menorest and a total of 21 skin reactions in 15 subjects with Climara. Systemic tolerability was similar between treatments with eight estrogen-related adverse events in eight subjects (period pains, uterine bleeding, mastodynia, headache and vaginal discharge) with Menorest and 13 events in ten subjects with Climara. CONCLUSIONS: The bioavailability of estradiol from the two matrix transdermal delivery systems Menorest and Climara was similar, but the products were not bioequivalent because Tmax was significantly shorter for Menorest than for Climara. Tolerability of treatment was good for both patches but with a higher number of local reactions and estrogen related adverse events for Climara.

Administration, Cutaneous↗

Effects of transcutaneous scopolamine and depth on diver performance.

Transdermal scopolamine is an effective anti-motion-sickness medication that has less CNS side effects at normal ambient pressure than orally ingested agents. To see whether it has an effect on performance at depth, 24 healthy sport divers were exposed to depths equivalent to 5 m (1.5 ATA) and 36 m (4.8 ATA) in a dry recompression chamber, breathing air and wearing a skin patch containing either scopolamine or inactive placebo. Patches and dive depths were presented in a counterbalanced, double-blind experimental design. Tests of sentence comprehension, simple arithmetic, and manual dexterity were used to evaluate psychometric and cognitive performance. Drug side effects were recorded. The Bennett Hand Tool Dexterity Test was evaluated for its suitability for repeated measures testing, and found to be robust. Manual dexterity and sentence comprehension were significantly impaired at depth whereas arithmetic skills were not. No significant effects on diver performance from transdermal scopolamine were seen. Certain side effects such as blurred vision were more common with scopolamine than with placebo. The use of transdermal scopolamine as an antiemetic during diving operations deserves field evaluation.

Administration, Cutaneous↗

Transdermal systems for overactive bladder: principles and practice.

The transdermal system for delivery of medication to treat overactive bladder may provide an improved efficacy-to-tolerability ratio by regulating serum drug levels; avoiding gastrointestinal and hepatic metabolism, which is important when the metabolite has a lesser therapeutic index than the parent drug; and achieving clinical efficacy with a lower total drug burden. Additional advantages may include increased compliance and obviation of the need for oral drug administration, which is especially beneficial for the patient who is taking multiple oral medications or is caregiver-dependent. An efficient patch system must preserve the physical integrity of the drug layer, provide adequate adhesion, store and release the drug and permeation-enhancing agent in a predictable manner, promote consistent absorption through the skin regardless of location or skin or subcutaneous tissue differences, demonstrate dose proportionality, maintain skin integrity during product use and removal, and be cosmetically acceptable. A novel transdermal delivery system that incorporates an occlusive layer covering an acrylic adhesive containing the active agent oxybutynin and a skin permeation enhancer has been demonstrated in clinical trials to achieve these goals.

Journal Article↗

The effects of transdermal scopolamine on autonomic nervous activity during sleep.

We studied the effect of transdermally applied scopolamine (scopolamine-TTS) on autonomic nervous activity during sleep. The double-blind, randomized, crossover study was carried out in six healthy male volunteers by applying 1.5 mg scopolamine-TTS or placebo patch on the retroauricular skin and by monitoring heart rate, cardiac ballistogram, respiration and body movements by using electrocardiogram and static charge sensitive bed. Scopolamine did not decrease the time the subjects desired to sleep (516 min after TTS, 511 min after placebo) or the number of body movements of 3-5 s duration the subjects spontaneously performed during sleep (47 after TTS, 58 after placebo). No adverse effects of scopolamine were reported spontaneously. Scopolamine-TTS slowed the mean heart rate during quiet sleep from 53.2 to 44.9 beats.min-1, and increased the duration of bradycardia in response to body movements (MIB-reflex) from 12.5 to 14.7 s with a significant difference between scopolamine and placebo effects. The bradycardias were not associated with disturbances in cardiorespiratory or central nervous system functions. The cardiac vagomimetic action of scopolamine-TTS could be explained by low plasma drug concentrations (175 pg/ml) primarily blocking only neuronal inhibitory prejunctional muscarinic receptors which regulate acetylcholine release from the autonomic ganglia and parasympathetic nerve-endings. Because of the central role of acetylcholine in the physiological regulation of sleep, the effect of scopolamine-TTS on sleep merits further investigations.

Administration, Cutaneous↗

A transdermal regimen for continuous combined hormone replacement therapy in the menopause.

Transdermal systems for oestrogen therapy in the menopause have become very popular. The compliance, however, is impeded by the cyclic addition of oral progestins which leads to monthly withdrawal bleeds. In this pilot study a skin patch releasing 0.05 mg oestradiol and 0.25 mg norethisterone acetate per day, which was originally designed for sequential therapy, was used in a continuous manner. Results were quite favourable. Menopausal complaints were efficiently relieved and the Kupperman score dropped from 27.6 to 5.0. Out of 10 women, 1 had mild breakthrough bleeding, and 7 patients recorded one or several spotting episodes, mainly within the first 3 treatment months. No endometrial hyperplasia was observed and there was no significant change in plasma lipids, i.e. cholesterol, triglycerides, HDL-, HDL2-, HDL3-cholesterol, LDL-cholesterol and apolipoproteins A1 and B. The regimen might be a useful alternative to oral continuous combined replacement therapy.

Administration, Cutaneous↗

Contraceptive efficacy, compliance and beyond: factors related to satisfaction with once-weekly transdermal compared with oral contraception.

OBJECTIVE: To investigate contraceptive efficacy, compliance and user's satisfaction with transdermal versus oral contraception (OC). STUDY DESIGN: Randomized, open-label, parallel-group trial conducted at 65 centers in Europe and South Africa. One thousand four hundred and eighty-nine women received a contraceptive patch (n = 846) or an OC (n = 643) for 6 or 13 cycles. RESULTS: Overall/method-failure Pearl Indices were 0.88/0.66 with the patch and 0.56/0.28 with the OC (p = n.s.). Compliance was higher at all age groups with the patch compared to the OC. Significantly more users were very satisfied with the contraceptive patch than with the OC. The percentage of patch users being very satisfied increased with age whereas it did not in the OC group. Likewise, improvements of premenstrual symptoms as well as emotional and physical well-being increased with age in the patch-group in contrast to the OC group. Ratings of satisfaction with the study medication correlated weakly with emotional (r = 0.33) and physical well-being (r = 0.39) as well as premenstrual symptoms (r = 0.30; p < 0.001). CONCLUSION: Contraceptive efficacy of the patch is comparable to OC, but compliance is consistently better at all age groups. Higher satisfaction with the patch at increasing age may be attributed to improvements in emotional and physical well-being as well as reduction of premenstrual symptoms.

Administration, Cutaneous↗

[Basic principles of hormone replacement therapy in the postmenopause].

17 beta-estradiol, conjugated equine estrogens, esterified estrogens, and estriol constitute postmenopausal replacement therapy, all of which are in clinical use as oral preparations. Non-oral routes--matrix and reservoir patches, gel--were developed for estradiol, as was the intravaginal administration of estriol and estradiol. Daily doses of 1 mg estradiol(valerate) or 25 micrograms estradiol delivered via a patch or 0.5 mg gel or 0.3 mg conjugated equine estrogens are often sufficient to alleviate climacteric symptoms. Bone resorption may be effectively reduced and bone mineral density maintained by 1 mg estradiol or 25 micrograms transdermal estradiol. Maximal bone sparing dosages are 2 mg estradiol, 50 micrograms transdermal estradiol, 0.625 mg conjugated equine estrogens, and 1.25 mg estrone Estriol, predominantly used for the prevention and or treatment of urogenital symptoms, has no bone sparing effect at the doses in clinical use. Non-oral administration of estradiol may be superior in diabetic women and those with hypertriglyceridemia due to the different metabolism which does not mainly involve the hepatic first pass effect. Epidemiological data do not support any preference of oral versus non-oral routes of administration regarding side-effects such as venous thromboembolism. Progestogens--natural progesterone, derivatives structurally related to progesterone and testosterone, respectively--are necessary for endometrial protection. Sequential use of a progestogen for at least 10 days per month, preferably 12-14 days abolishes the increased incidence of endometrial hyperplasia which is likely to develop with unopposed use of estrogen. Observational studies do not suggest any superiority of a given progestogen regarding cardiovascular risk, prevention of osteoporosis, and cognitive function in postmenopausal women on estrogen replacement therapy. Tibolone, a derivative of norethindrone, is yet another option for replacement therapy. The recommended dose for treatment of climacteric symptoms and prevention of bone loss is 2.5 mg. Controlled clinical studies do not suggest that this compound is superior in achieving amenorrhea compared with continuous combined estrogen progestogen replacement therapy, as available data are inconsistent. In early postmenopause the sequential use of a progestogen in conjunction with an estrogen is the preferred treatment option. With advancing postmenopausal age either continuous combined replacement or tibolone may be choices in case withdrawal bleeding is no longer acceptable for women. However, there are no rigid age limit when to change treatments, the selection of which is largely influenced by the preference of the individual's acceptance of withdrawal bleeding.

Administration, Cutaneous↗

Transdermal nitroglycerine in the management of pain associated with primary dysmenorrhoea: a multinational pilot study. The Transdermal Nitroglycerine/Dysmenorrhoea Study Group.

Endogenous nitric oxide mediates smooth-muscle relaxation with subsequent vasodilatation in the vascular, pulmonary, gastrointestinal and genitourinary tissues. Transdermal nitroglycerine (a nitric oxide donor) has been found effective in inhibiting uterine contractility during premature labour. Sixty-five women with histories of moderate-to-severe pain associated with menses were treated with nitroglycerine patches that delivered 0.2 or 0.1 mg/h. Patches were applied as necessary during the first 3 days of the menstrual cycle for up to three consecutive cycles. Pain intensity was assessed at baseline and at 30 min and at 1, 2 and 4 h after patch application. Most patients obtained pain relief with the first dose of the first day. Pain relief was satisfactory to excellent in 90% of the patients. Headache was reported by 20% of the patients, most often in patients using two consecutive patches. A randomized, double-blind, placebo-controlled study is underway in an attempt to confirm the above findings.

Administration, Cutaneous↗

Short-term effects of high-dose 17beta-estradiol in postmenopausal PD patients: a crossover study.

OBJECTIVE: To examine the effect of 17beta-estradiol on the severity of the cardinal signs of PD in postmenopausal women. BACKGROUND: Although the impact of estrogens on the manifestations of PD has not been subjected to rigorous study, their use is generally thought to be associated with a detrimental antidopaminergic effect. METHODS: A double-blind, placebo-controlled, two-arm crossover study of high-dose transdermal 17beta-estradiol was conducted in eight postmenopausal women with mild to moderate PD, all but one of whom exhibited levodopa-induced dyskinesias. Patients were randomized initially to either hormonal treatment or placebo for 2 weeks, followed by a 2-week washout period, and then another 2-week crossover treatment period. Active treatment employed four skin patches each releasing 0.1 mg of estradiol daily, replaced every 2 to 3 days. RESULTS: After 10 days of treatment a significant reduction was observed in the antiparkinsonian threshold dose of IV levodopa. Mean duration and magnitude of the antiparkinsonian response to threshold or high doses of levodopa were unchanged, and dyskinesia scores were unaltered during 17beta-estradiol treatment compared with placebo. No worsening in "on" time or motor ratings with estrogen treatment was documented. CONCLUSIONS: 17beta-estradiol appears to display a slight prodopaminergic (or antiparkinsonian) effect without consistently altering dyskinesias. Standard postmenopausal replacement therapy with transdermal 17beta-estradiol is likely to be well tolerated by many female parkinsonian patients.

Administration, Cutaneous↗

Comparison of a transdermal continuous combined and an interrupted progestogen HRT.

OBJECTIVES: Pilot study to compare the effects of a continuous combined hormone replacement therapy (HRT) regimen with an interrupted progestogen regimen administered transdermally, upon the endometrium of postmenopausal women, the incidence of amenorrhoea and relief of menopausal symptoms. METHODS: Fifty-nine postmenopausal women aged 50-63 years were randomised to either (i) continuous combined regimen: combined oestrogen/progestogen skin patches (releasing continuous 50 microg estradiol and 20 microg levonorgestrel/day) or (ii) interrupted regimen: oestrogen-only patches (releasing 80 microg estradiol/day) for 4 days followed by combined oestrogen/progestogen patches (releasing continuous 50 microg estradiol and 20 microg levonorgestrel/day) for 3 days, for 6 months. An endometrial biopsy was performed at end of treatment for histological analysis. RESULTS: Thirty-three women (56%) completed the study. Significantly higher rates of amenorrhoea were observed with the interrupted than continuous combined regimen (P<0.0001; 25% versus 7% at 6 months). The interrupted regimen was also associated with fewer days of bleeding overall (total 20 versus 44 days during months 4-6; P=0.001). Both regimens improved vasomotor symptoms. No endometrial hyperplasia or atypical changes were observed in endometrial biopsies. CONCLUSIONS: Although significantly less bleeding was observed with the interrupted regimen, it did not have a sufficiently high incidence of amenorrhoea to render it clinically useful.

Administration, Cutaneous↗

Use of TTS fentanyl as a single opioid for cancer pain relief: a safety and efficacy clinical trial in patients naive to mild or strong opioids.

BACKGROUND: Up to now, a transdermal therapeutic system (TTS) of fentanyl has been applied to cancer patients on opioid analgesics previously treated with mild opioids or morphine. The aim of this study was to investigate the efficacy and safety of TTS fentanyl (patch) administration as an analgesic to patients treated with opioid analgesics for moderate-to-severe cancer pain, with immediate-release oral morphine only as rescue medication. The prior analgesic medication of the patients did not include mild or strong opioids. METHODS: The study group consisted of 113 patients (54 men and 59 women; age range: 21-87 years, mean +/- SD 61.3 +/- 14.84 years) with undertreated chronic cancer pain. The study period was 42 days. The patients were hospitalized for the first 3 days of the study; thereafter they were transferred to their home for the rest of the study. Daily cards were completed, noting their pain score (0-10 VAS), nausea, vomiting, constipation, skin reactions, dizziness or any other complaints. Vital signs were also recorded. Data assessments were made at baseline, on days 1, 2 and 3 (during hospitalization) and thereafter on days 7, 14, 21, 28, 35, and 42 after hospital discharge. The initial TTS fentanyl delivery rate was chosen depending on the patient's analgesic requirements. All patients were given an oral morphine solution (5-10 mg), every 4-6 h, for the first 12 h, as rescue medication. RESULTS: Baseline pain score was between 6 and 10 (mean +/- SD 7.1 +/- 1.7). The initial TTS fentanyl delivery rate was between 25 and 50 microg/h (mean +/- SD 36.5 +/- 15.7). On day 3, 95 patients (84%) reported a pain score < or = 3 (mean +/- SD 0.5 +/- 0.8), 14 patients (12.4%) a pain score of 4 and 4 patients (3.5%) of 5-8. No adverse effects suggesting the discontinuation of the study were reported. From day 7 until the completion of the study, the mean pain score was between 1.3 and 0.16 while the TTS fentanyl delivery rate on day 42 was between 25 and 400 microg/h (mean +/- SD 122.1 +/- 81.2 microg/h). CONCLUSION: Analgesic treatment with TTS fentanyl used as a single opioid is effective and safe for cancer pain relief, given that is cautiously applied, in patients requiring strong opioid analgesics even if they were naive to strong or mild opioids.

Adult↗

Hypotensive effects of a new transdermal delivery system for clonidine (M-5041T) in spontaneously and renal hypertensive rats.

1. Antihypertensive effects of a new transdermal delivery system for clonidine (clonidine tape; M-50417) were investigated in spontaneously hypertensive rats (SHR), 2-kidney, 1-clip renal hypertensive rats (RHR) and deoxycorticosterone acetate/salt (DOCA/Salt) hypertensive rats. 2. M-5041T (0.5-4.5 mg/kg) elicited long-lasting hypotensive effects and bradycardia in a dose-dependent manner during 24 h patching in three hypertensive models compared with oral clonidine (100 mu g/kg). 3. The most hypotensive effect of M-5041T was observed in DOCA/salt hypertensive rats. 4. Co-administration of M-5041T with either trichloromethiazide (1 mg/kg, orally) or nifedipine (3 mg/kg, orally) at each dose without hypotensive effects per se induced significant hypotension in SHR. 5. Repeated administrations of M-5041T (1.5 mg/kg per day) for a consecutive 7 days produced significant hypotensive effects at postpatching 6 h, and recovered a postpatching 24 h in SHR. 6. Repetitive M-5041T administrations displayed no tolerance on the hypotensive effects and were devoid of any withdrawal syndrome. 7. These findings suggest that M-5041T may serve as an efficiently useful antihypertensive transdermal delivery system in humans.

Administration, Cutaneous↗

The optimal dose of oral norethindrone acetate for addition to transdermal estradiol: a multicenter study.

The effects of adding one of three doses (0.5, 0.75, or 1.0 mg/d) of norethindrone acetate for 12 days each month to continuous, transdermal estradiol (0.05 mg/d) have been determined in a prospective, randomized, multicenter study. Significant symptomatic and psychological improvements were observed and, with one exception, were not opposed by the added progestogen. Distinct redness at the site of last patch application was reported by 10% of patients and faint erythema by 30%. However, less than 5% of patients discontinued treatment because of skin problems. Breakthrough bleeding occurred infrequently and all three doses of norethindrone acetate induced a regular pattern of bleeding with secretory transformation in the endometrium. There was no hyperplasia or carcinoma.

Administration, Cutaneous↗

A dose-ranging trial of a matrix transdermal 17beta-estradiol for the prevention of bone loss in early postmenopausal women. International Study Group.

This international, randomized, double-blind, placebo-controlled, parallel group, dose-ranging trial was designed to determine the efficacy of 2 years of therapy with a new matrix transdermal 17beta-estradiol (Menorest) in preventing bone loss in early postmenopausal women, and to identify an appropriate dose. Two hundred ninety-two ambulatory women with natural or surgical menopause for 1-6 years were randomized to receive patches delivering 17beta-estradiol 50, 75, or 100 microg/day twice weekly for 25 days per 28 day cycle (with dydrogesterone 10 mg twice daily from days 11 to 24) or placebo, for 24 months. The primary outcome measure was the percentage change from baseline in lumbar spine bone mineral density (BMD) at 2 years. Secondary endpoints were percentage changes from baseline in three sites of proximal femur BMD and total body BMD, and in biochemical bone turnover markers. At 2 years, the difference from placebo in percentage change from baseline of L1-4 spine BMD was 6.2%, 7.6%, and 7.8% in the 50, 75, and 100 microg/day groups, respectively. Lumbar spine bone increased in 65.5%, 76.8%, and 81.0% of patients in the respective active treatment groups, compared with 4.9% on placebo. BMD increased significantly relative to placebo in the femoral neck, trochanter, total hip, and total body. Serum osteocalcin, bone alkaline phosphatase and urinary type I collagen C-telopeptide decreased significantly and dose dependently in 17beta-estradiol patients vs. placebo. For example, at 2 years, the difference between placebo and the 50 microg/day group, expressed in percentage change from baseline, was 3.25% at the femoral neck, 3.92% at the trochanter, 3.52% for total hip, and 2.40% for the total body. Breast pain and skin reactions were more common in the actively treated groups, but tolerability was generally good. Therefore, after 2 years, 17beta-estradiol was well-tolerated and highly effective at doses of between 50 and 100 microg/day in preventing bone loss and reducing bone turnover in early postmenopausal women. The dose of 50 microg/day, the lowest dose tested, is a suitable dose. There was little clinical benefit of increasing the dosage from 75 to 100 microg/day.

Absorptiometry, Photon↗