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Cutaneous pharmacodynamics of transdermally delivered isosorbide dinitrate.

Laser doppler velocimetry (LDV) has been used to assess the cutaneous pharmacodynamics of isosorbide dinitrate (ISDN) following transdermal delivery of the drug from prototypal patches. The delivery systems, which were saturated with ISDN, (a) produced various degrees of skin occlusion and (b) spanned a six-fold range of adhesiveness. The patches were applied to the ventral forearm skin of 10 healthy volunteers and the local ISDN-induced increase in local skin blood flow was determined using LDV by locating the probe in a central hole in the delivery system. Measurements were made for 1.5 hr and the pharmacodynamics were quantified by (i) the maximum LDV response and (ii) the area under the LDV response versus time curve. These parameters were not sensitive to patch occlusivity. They were significantly (P less than 0.01) dependent on patch adhesiveness, though, and decreased with increasing adhesion. Although this observation suggested that ISDN diffusion through the adhesive could determine, at least in part, the rate of drug delivery, it was subsequently demonstrated that ISDN release (in vitro, into a perfect "sink") was unaffected by the level of cross-linking in the adhesive polymer. Because the drug was present in all systems at unit thermodynamic activity, these results cannot be explained on the basis of altered ISDN partitioning at the device-stratum corneum interface. We speculate that the in vivo-in vitro discrepancy may be due to the efficiency of skin contact achieved by different adhesives: that is, the more adhesive, less flexible systems make poorer contact with the skin surface, thereby decreasing the effective surface area of drug delivery.(ABSTRACT TRUNCATED AT 250 WORDS)

Adhesives↗

Randomized placebo-controlled trial of testosterone replacement in men with mild Leydig cell insufficiency following cytotoxic chemotherapy.

OBJECTIVE: Testosterone deficiency is associated with significant morbidity, and androgen replacement in overt hypogonadism is clearly beneficial. However, there are few data concerning the response to therapy in young men with mild testosterone deficiency. DESIGN AND PATIENTS: We have identified a cohort of 35 men, mean age 40.9 years, with mild Leydig cell dysfunction, defined by a raised LH level (LH >or= 8 IU/l) and a testosterone level in the lower half of the normal range or frankly subnormal (testosterone < 20 nmol/l), following treatment with cytotoxic chemotherapy for malignancy. Patients were assigned randomly to 12 months treatment with transdermal testosterone (n = 16) (Andropatch 2.5 mg patches, 1-2 patches per day) or placebo patches (n = 19) in a single blinded manner. MEASUREMENTS: Measurements of bone mineral density (BMD) and body composition were performed at baseline, 6 months and 12 months using single and dual energy X-ray absorptiometry (SXA, DXA). In addition, spinal BMD was assessed at baseline and 12 months by quantitative CT (QCT). Subjects were reviewed at 3-monthly intervals; at each visit blood was taken for measurement of testosterone, SHBG, LH, FSH, oestradiol, lipids and IGF-1 and patients completed three questionnaires which assessed energy levels, mood and sexual function. RESULTS: Total testosterone and calculated free testosterone increased significantly in the testosterone-treated group compared with the placebo-treated group (13.3 nmol/l and 342.9 pmol/l at baseline compared with 17.3 nmol/l and 454.8 pmol/l during the study period in the testosterone-treated group; P = 0.05 and P = 0.02, respectively). LH was suppressed into the normal range in 15 of the 16 testosterone-treated men and mean LH significantly reduced from 11.1 IU/l at baseline to 6.8 IU/l during the study. There was no significant change in BMD at the hip, spine or forearm and no change in fat or lean body mass. There was a significant reduction in physical fatigue in the testosterone-treated group compared with the placebo-treated group (P = 0.008) and a borderline improvement in activity score (P = 0.05). There were no significant effects of treatment on mood or sexual function. Neither oestradiol nor IGF-1 levels differed between the two groups during the study. There was no significant change in mean total cholesterol, HDL cholesterol or triglyceride levels, but there was a small, but significant reduction in LDL cholesterol levels in the testosterone-treated group compared with the placebo group (P = 0.02). CONCLUSIONS: These results suggest that testosterone therapy in young men with raised LH levels and low/normal testosterone levels does not result in significant changes in BMD, body composition, lipids or quality of life, apart from a reduction in physical fatigue and a small reduction in LDL cholesterol. This implies that mild hypogonadism defined on this basis is not of clinical importance in the majority of men, and that androgen replacement cannot be recommended for routine use in these patients.

Adult↗

Carboxymethylcellulose-sodium based transdermal drug delivery system for propranolol.

Propranolol, a beta-adrenoceptor blocker, suffers from a high degree of first-pass metabolism resulting in very low bioavailability (< 10%) following administration with conventional oral formulations. To circumvent this significant therapeutic hurdle, we formulated a carboxymethylcellulose-sodium (CMC-Na) based transdermal system for propranolol and evaluated the patch for its in-vitro and in-vivo performance. In-vitro permeation studies using the excised hair-free rat skin model resulted in 66.54% permeation at the end of 24 h in a modified Franz diffusion cell. This zero-order permeation profile was characterized by a drug permeation rate of 52.87 +/- 11.63 micrograms cm-2 h-1. Skin irritation studies in rats (n = 5), evaluated for flare-and-wheal with respect to a formalin control, indicated that the drug-containing patch evoked only a mild response over a 7-day period. Preliminary in-vivo studies in male albino rabbits (n = 3), indicated that plasma drug levels averaged 11.75 +/- 3.40 ng mL-1 in a 24-h study period before patch removal.

Administration, Cutaneous↗

The antigonadotropic activity of progestins (19-nortestosterone and 19-norprogesterone derivatives) is not mediated through the androgen receptor.

To further study the mechanism of the antigonadotropic activity of progestins, the effects of a 19-nortestosterone derivative, norethisterone acetate (NETA), and a 19-norprogesterone derivative, nomegestrol acetate (NOMA), were compared. The aim was to assess whether their action is exerted via the androgen receptor. Ten healthy postmenopausal women were treated for five monthly periods of 24 days separated by 10 days in a randomized cross-over design. Transdermal estradiol, Estraderm TTS (25 micrograms; one patch every 3 days), was given from days 1-24 during the five periods. On the last 12 days, of each estradiol treatment, they all received a placebo, NOMA (5 mg/day), NOMA in association with the nonsteroidal antiandrogen, flutamide (FLU; 250 mg, twice a day), NETA (10 mg/day), or NETA plus FLU. On the other hand, three castrated patients with complete androgen insensitivity (CAI) received NOMA and NETA for two periods of 12 days separated by 3 weeks. In postmenopausal women, the effects of NOMA and NETA on metabolic parameters were studied. Only NETA decreased high density lipoprotein cholesterol. Plasma LH, FSH, and estradiol were measured during each treatment period. A significant decrease in mean plasma LH and FSH levels and their responses to exogenous GnRH was observed with NOMA and NETA treatments compared to placebo (P < 0.001). The pulsatile frequency, but not the amplitude, of LH was significantly decreased during both treatments. Interestingly, the effects of both progestins on gonadotropins were not antagonized by FLU administration. In the patients with CAI, the pulsatile study of gonadotropins was performed before and on day 12 of NOMA and NETA treatments. As in postmenopausal women, both progestins induced similar decreases in LH and FSH. In conclusion, a 19-nortestosterone derivative, NETA, and a 19-norprogesterone derivative, NOMA, have similar antigonadotropic activities. This effect, not antagonized by FLU and observed in patients with CAI, is not mediated via the androgen receptor. The absence of deleterious effects of 19-norprogesterone derivatives on metabolic parameters should favor the therapeutic use of these compounds.

Cholesterol, HDL↗

[Subjective complaints and hormonal reactions in the first 6 weeks after hysterectomy].

Hormone profiles (estradiol, testosterone, FSH, LH) and typical estradiol deficiency phenomena were investigated prospectively in the first 6 weeks after hysterectomy (n = 50) and after additional bilateral adnexectomy (n = 17). In the second group estradiol was replaced transdermally from the 2nd postoperative day (estradiol patch, 0.05 mg daily). In the 1st group 34% of patients showed a significant decrease in estradiol, 28% of patients a significant decrease in testosterone on the 3rd postoperative day which was no longer demonstrable after 6 weeks. In the second group no decrease in hormone levels was found. So the estradiol patch can replace estradiol to a sufficient degree and in particular physiologically even after bilateral oophorectomy Subjective complaints improved in both groups. Psychosomatic influence also seems to be of importance.

Adult↗

[Transdermal nitroglycerin in stable effort angina. II. Administration of continuous high doses and alternate high-low doses. Absence of tolerance].

Aim of this study was to evaluate the efficacy of 2 different schedules of nitroglycerin (N), given by means of transdermal therapeutic system (TTS): continuous (20 mg patch at 8.00 am and at 8.00 pm NTTS/c) and high/low doses therapy (20 mg patch at 8.00 am and 10 mg at 8.00 pm NTTS/a), respectively. Eighteen volunteers, gave informed, written consent; male patients, aged 57 +/- 2 years, with stable effort angina pectoris, were randomly given, in double-blind condition, NTTS/c, NTTS/a or placebo (PL), each for 1 week period, according to a 3 x 3 latin square design. Bicycle exercise tests were performed on the first and on the last day of each period of the study, 12 hours after the last patch. NTTS/c and NTTS/a increased ischemic threshold and decreased the ischemic depression ST at maximal common work, compared to placebo, without differences between tests performed at 1 and 7 day. In conclusion, NTTS/a showed antiischemic activity after 7 days, so no tolerance was observed in those patients.

Administration, Cutaneous↗

Transdermal oestrogen replacement therapy in a Finnish population.

In an open, multicentre study, transdermal administration of oestradiol (E2) by means of skin patches was investigated in a Finnish patient population suffering from typical post-menopausal symptoms. A total of 249 women applied a patch twice weekly for 6 months. Whereas 85% of the subjects were experiencing hot flushes and 83.5% sweating before therapy, only 5.7% and 11.8%, respectively, reported these symptoms at the end of the trial. Furthermore, 97.6%, 95.7% and 94.8% of the subjects reported that depression, headache and sleep disturbances, respectively, had disappeared during therapy. Skin irritation occurred in 18.2% of these predominantly fair-skinned women. Frequent sauna bathing did not interfere with the patch therapy. General acceptance of the treatment was excellent, 84.8% of the patients completing the treatment, of whom 78% were willing to continue the treatment after the trial. These results show that transdermal administration of E2 is effective in relieving post-menopausal symptoms. Local tolerability was good and the majority of the patients considered the transdermal treatment to be superior to their previous oral replacement therapy.

Administration, Cutaneous↗

Clonidine: irritant and allergic contact dermatitis assays.

Clonidine in petrolatum, clonidine transdermal device, and its placebo device were assayed for relative irritancy potential (21-day cumulative irritancy assay) and allergic contact dermatitis potential (Draize repeat insult patch test assay). Both clonidine in petrolatum and the clonidine transdermal device appear to be of minimal irritancy potential. Only the clonidine device demonstrated, in the Draize assay (and in clinical trials), allergic contact dermatitis potential. Its relatively delayed onset of demonstration of allergic contact sensitization in clinical trials requires investigation as to mechanism.

Administration, Topical↗

Transdermal 17 beta-estradiol combined with oral progestogen increases plasma levels of insulin-like growth factor-I in postmenopausal women.

In order to evaluate the effect of postmenopausal estrogen replacement therapy on the plasma levels of the insulin-like growth factor-I (IGF-I) 12 postmenopausal women aged 44 to 59 years were studied. The control group consisted of 15 healthy premenopausal women aged 20-44 years. In the postmenopausal women the plasma levels of IGF-I, gonadotrophins and sex hormones were determined before and after 3 and 6 months cyclic replacement therapy with transdermal 17 beta-estradiol (E2 100 micrograms patches applied twice weekly) combined with oral chlormadinone acetate (2 mg daily for 7 days in each cycle). Basal levels of estradiol (E2), IGF-I, dehydroepiandrosterone sulphate (DHEA-S), testosterone and androstenedione were lower, but gonadotropin levels were higher in postmenopausal than in premenopausal women. In all the women studied age was inversely correlated with IGF-I levels (r = -0.793, p less than 0.001) and with DHEA-S concentrations (r = -0.435, p less than 0.02). In postmenopausal women transdermal estradiol administration restored the circulating E2 levels to the early follicular range and increased the IGF-I levels (from 76.4 +/- 9.2 micrograms/l to 141.8 +/- 20.8 micrograms/l; p less than 0.01). Transdermal estradiol decreased gonadotrophin levels without changes in concentration of DHEA-S, testosterone, androstenedione and SHBG. In postmenopausal women before and during replacement therapy a positive correlation was found between estradiol and IGF-I concentrations (r = -0.439, p less than 0.01). These results suggest that cyclic replacement therapy with transdermal 17 beta-estradiol in combination with chlormadinone acetate given orally increase the plasma levels of IGF-I in postmenopausal women.

Administration, Cutaneous↗

Effects of transdermal testosterone on lipids and vascular reactivity in older men with low bioavailable testosterone levels.

BACKGROUND: Sex hormones are known to affect cholesterol levels and vascular tone in women. The effects of testosterone on cholesterol and vascular tone in men are less well understood. Low testosterone levels have been associated with higher cholesterol levels in epidemiologic studies, but testosterone replacement has resulted in variable changes in cholesterol levels. Similarly, clinical studies suggest that testosterone may be vasodilatory, but few studies have directly evaluated the effects of testosterone on vascular tone. METHODS: Sixty-seven men (mean age 76 +/- 4 years, range 65-87) with bioavailable testosterone levels below 4.44 nmol/l (lower limit for adult normal range) were randomized to receive transdermal testosterone (2-2.5 mg patches/d) or placebo patches for 1 year. Twenty-three men (34%) withdrew from the study; 44 men completed the trial. RESULTS: While total cholesterol, triglyceride, and low-density lipoprotein cholesterol levels did not significantly change during the year of therapy, high-density lipoprotein (HDL) levels (p =.004) and, specifically, HDL(2) subfraction (p =.02) decreased in men receiving testosterone supplementation. Vascular tone was measured by brachial artery reactivity in 36 men. Endothelium-dependent brachial artery reactivity did not change from baseline measurements in men receiving transdermal testosterone (0.3 +/- 6.7% to 1.6 +/- 4.6%; p =.58) or in the placebo group (3.2 +/- 5.5% to 0.7 +/- 5.5%; p =.23). CONCLUSIONS: Transdermal testosterone decreased HDL(2) cholesterol but did not affect vascular reactivity in men older than 65 years selected for low testosterone levels. No study to date has addressed the direct relationship between testosterone replacement and cardiovascular events.

Administration, Cutaneous↗

Transdermal clonidine for hypertensive patients.

Seventeen moderately hypertensive patients, whose blood pressure was previously controlled with hydrochlorothiazide and oral clonidine (blood pressure 129 +/- 8/85 +/- 5 mmHg during therapy), were treated with a transdermal system involving application of one or more clonidine-containing patches (3 mg per patch) to the skin once a week. The patients continued to take 50 mg of oral hydrochlorothiazide daily. By four to eight weeks, 15 of 17 patients using the transdermal system had achieved baseline blood pressure levels (130 +/- 10/84 +/- 6 mmHg, NS). During the maintenance phase of transdermal therapy, plasma clonidine levels measured four hours (0.78 +/- 0.43 ng/ml), four days (0.89 +/- 0.48 ng/ml), and seven days (0.78 +/- 0.41 ng/ml) after patch application did not differ significantly from one another or from trough plasma clonidine levels (0.86 +/- 0.54 ng/ml) measured during oral clonidine therapy. The results suggest that, in moderately hypertensive patients, blood pressure can be controlled with a once-weekly application of clonidine-containing skin patches as effectively as with oral clonidine.

Administration, Oral↗

Hormone replacement therapy lowers plasma Lp(a) concentrations. Comparison of cyclic transdermal and continuous estrogen-progestin regimens.

To study the responses of serum lipoproteins, apoproteins (apo's), and lipoprotein(a) (Lp[a]) to two frequently used hormone replacement therapies (HRTs), 120 postmenopausal women were randomly allocated to receive either transdermal therapy consisting of 28-day cycles with patches that delivered 17 beta-estradiol (50 micrograms/d) combined with cyclic oral medroxyprogesterone acetate (10 mg/d for 12 days per cycle) or continuous oral 17 beta-estradiol (2 mg/d) together with norethisterone acetate (1 mg/d) for 12 months. Blood samples were taken before and at 6 and 12 months of HRT. Concentrations of serum total, low density lipoprotein (LDL) and high density lipoprotein (HDL) cholesterol decreased by 14% (P < .001), 17% (P < .001), and 9% (P < .001) in the oral HRT group. Respective changes were 5.7% (P < .001), 4.8% (P < .05), and 4.7% (NS) in the transdermal group. Serum triglycerides remained unchanged in the oral group but decreased by 15.7% (P < .001) in the transdermal group. We observed only trivial changes in serum apo B levels. The changes in apo A-I levels paralleled those of HDL cholesterol in the oral HRT group. The concentration of serum Lp(a) decreased by 31% (P < .001) and 16% (P < .001) in the two groups. The combination of progestin and transdermal estrogen was not associated with any further change of Lp(a). The decrement in Lp(a) during therapy was positively associated with baseline Lp(a) levels in both groups (r = .96, P < .001 and r = .88, P < .001). Thus, both HRT regimens were highly effective in lowering elevated Lp(a) levels in postmenopausal women. The divergent responses of LDL and HDL cholesterol in the two HRT groups may influence the potential cardioprotective effects of the two HRT regimens. Prospective trials are needed to define the long-term effects with respect to coronary heart disease risk.

Administration, Cutaneous↗

Effect of menopause and different combined estradiol-progestin regimens on basal and growth hormone-releasing hormone-stimulated serum growth hormone, insulin-like growth factor-1, insulin-like growth factor binding protein (IGFBP)-1, and IGFBP-3 levels.

OBJECTIVE: To determine the effects of menopause and three different formulations of E2 plus medroxyprogesterone acetate on serum concentrations of basal and growth hormone-releasing hormone (GHRH)-stimulated growth hormone (GH), insulin-like growth factor-1 (IGF-1), insulin-like growth factor binding protein (IGFBP)-1, IGFBP-3, insulin, and C peptide. DESIGN: Prospective, controlled trial. SETTING: Menopausal outpatient clinic at an academic tertiary care hospital. PATIENT(S): Nineteen postmenopausal women with different menopausal ages. Seventeen premenopausal women were included as controls. INTERVENTION(S): Oral estrogen (E2 valerate, 2 mg/d) or transdermal estrogen (50-microg or 100-microg E2 patch) was administered for 8 weeks. Medroxyprogesterone acetate (5 mg/d) was administered during weeks 3, 4, 7, and 8 of each protocol. Blood samples were collected before treatment and after the completion of each protocol from postmenopausal women, and on cycle days 6-8 from premenopausal women. MAIN OUTCOME MEASURE(S): Levels of GH, IGF-1, IGFBP-1, IGFBP-3, insulin, and C peptide. RESULT(S): Basal GH levels were negatively correlated with age in premenopausal women but not in postmenopausal women. The area under the GHRH-induced GH curve decreased in older postmenopausal women after the oral estrogen protocol. Levels of IGF-1 diminished after the oral E2 protocol in postmenopausal women. CONCLUSION(S): The administration of oral, but not transdermal, E2 plus medroxyprogesterone acetate at the usual clinical doses used in postmenopausal women decreased IGF-1 levels and the response of GH to GHRH in older women. No substantial changes were detected in IGFBP-1, IGFBP-3, insulin, or C peptide levels.

Adult↗

Combination of behavioral smoking cessation with transdermal nicotine substitution.

Effects of a transdermal nicotine substitution on psychological smoking cessation were investigated in a double-blind prospective study. 131 smokers were randomly assigned to three treatment conditions: All smokers underwent nine weeks of self-controlled smoking cessation. During six weeks one group was additionally treated with nicotine patches continuously releasing nicotine through the skin into the blood circuit. The second group received placebo patches; while the third group was treated with behavioral training alone. Treatment effects were measured by daily cigarette consumption. Nicotine-treated subjects reached significantly higher abstinence rates during and at the end of treatment than both placebo- and control-subjects: 69% in the nicotine condition, 51.2% and 44.4% under placebo and control conditions respectively. Effects are influenced by initial cigarette consumption, with the light smokers benefitting most from the nicotine patch. Self-assessments suggest an aversive effect of transdermal nicotine on cigarette taste. Our results, although not yet verified by long-term observations, demonstrate that transdermal nicotine substitution significantly enhances the effectiveness of behavioral smoking cessation methods.

Administration, Cutaneous↗

Transdermal clonidine compared to placebo in painful diabetic neuropathy using a two-stage 'enriched enrollment' design.

Because a variety of mechanisms may generate pain in neuropathic pain syndromes, conventional clinical trial methods may fail to identify some potentially useful drugs; a drug affecting just a single mechanism may work in too few patients to yield a statistically significant result for the trial. To test a previous clinical observation that approximately one-quarter of patients with painful diabetic neuropathy appear responsive to clonidine, we conducted a formal clinical trial of transdermal clonidine in painful diabetic neuropathy patients using a 2-stage enriched enrollment design. In the first stage (study 1), 41 patients with painful diabetic neuropathy completed a randomized, 3-period crossover comparison of transdermal clonidine (titrated from 0.1 to 0.3 mg/day) to placebo patches. Twelve apparent responders from study I were entered into the 'enriched enrollment' second stage (study II), consisting of an additional 4 double-blind, randomized, 1-week treatment periods with transdermal clonidine and placebo. Study I showed that in the overall group of 41 patients, pain intensity differed little during clonidine and placebo treatment. In study II, however, the 12 apparent responders from study I had 20% less pain with clonidine than placebo (95% confidence interval (CI): 4-35% pain reduction; P = 0.015), confirming that their pain was responsive to clonidine. None of the 3 consistent clonidine responders who were tested with the alpha-adrenergic blocker phentolamine had relief of pain, suggesting that clonidine's pain relief is not mediated by a decrease in sympathetic outflow. A post-hoc analysis of many variables suggested that patients who described their pain as sharp and shooting may have a greater likelihood of responding to clonidine.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Cutaneous↗

Clinical experience with a seven-day estradiol transdermal system for estrogen replacement therapy.

OBJECTIVE: To describe the efficacy, safety, and wearability of estrogen replacement therapy of a 7-day estradiol transdermal system (Climara), developed using new drug-in-adhesive technology. STUDY DESIGN: The pharmacokinetics of the 7-day system were investigated in single- and multiple-dose studies, a relative bioavailability study of the two patch sizes, and comparative studies with the twice-weekly transdermal system (Estraderm). Safety and efficacy in the treatment of vasomotor symptoms compared with conjugated equine estrogens (Premarin) and placebo were evaluated in two 11-week, randomized, double-blind, multicenter trials in 603 women; the data are combined in this report. Irritation and adhesion were also evaluated in comparative studies with Estraderm, Micropore (an inert once-weekly tape), and placebo controls. RESULTS: Blood levels were sustained for the full 7 days of patch wear, there was no drug accumulation, and a physiologic estrone to estradiol ratio was maintained. Pharmacokinetics studies showed dose proportionality of the 0.05 and 0.1 mg/day patches. Both patch sizes significantly decreased the frequency of hot flushes compared with placebo and were comparable with conjugated equine estrogens. There was a statistically significant difference between the two patch sizes. The mean overall decline in the hot flush rate was 74.6% for the 0.1 mg patch versus 64.5% for the 0.05 mg patch (p < or = 0.05). The combined data also showed that the onset of efficacy is within 1 to 2 weeks after the start of therapy and that efficacy is fully sustained during the 7-day patch wear period with some diminution of effect during the treatment-free week of each cycle. Treatment was well tolerated. Adverse events led to withdrawal from the studies in 8.9% of subjects. In most of these (6.8% of subjects), the cause was adverse skin reactions. Skin irritation was similar to Estraderm in comparative studies, whereas adhesion was significantly better with Climara. CONCLUSION: The Climara patch delivers estradiol for a full 7 days. Clinical efficacy of both patch sizes is comparable with currently accepted therapy and is sustained for the entire week of patch wear. A significant difference in response between the two doses supports dose titration. The patch is well tolerated and has excellent adhesion.

Administration, Cutaneous↗

Sustained beneficial hemodynamic effects of low transdermal nitroglycerin doses compared with placebo in patients with congestive heart failure.

In an attempt to resolve some of the controversies concerning the dose requirements and duration of effects of transdermal nitroglycerin (NTG) in patients with heart failure (CHF), the short-term hemodynamic responses to transdermal NTG, in a 20 cm2 self-adhesive patch (10 mg/24 h), were evaluated in 10 patients with severe chronic CHF using a randomized, within-patient, double-blind, placebo-controlled cross-over trial. Serial hemodynamic measurements over 24 h revealed sustained effects that began 1 h after the application of nitroglycerin patch and fully persisted throughout the study. The peak effect occurred at 4 h with the pulmonary capillary wedge pressure decreasing from 33.7 +/- 8.4 to 21.4 +/- 9 mmHg (mean +/- SD) (p less than 0.05) and the cardiac index increasing from 2.5 +/- 0.6 to 3 +/- 0.6 l/min/m2 (p less than 0.01). Transdermal nitroglycerin also significantly reduced pulmonary arterial and right atrial pressures (from 43.5 +/- 9.5 to 31 +/- 11.4 and from 7.4 +/- 6.6 to 3.8 +/- 4.7 at peak effect, respectively) as well as pulmonary and systemic vascular resistances (from 10.7 +/- 6.6 to 6.5 +/- 3.2 and from 26.2 +/- 5.1 to 22.5 +/- 5.7, respectively). There was no change in heart rate or systemic arterial pressure. These beneficial hemodynamic responses persisted for 24 h. No rebound deterioration occurred upon withdrawal of the nitroglycerin. No significant hemodynamic changes occurred during placebo treatment period. Thus, low doses (10 mg/24 h) of transdermal nitroglycerin induce significant hemodynamic benefit that is sustained for 24 h in patients with heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Cutaneous↗

Prolonged nicotine patch use in quitters with past abstinence-induced depressed mood.

To test the efficacy of sustained nicotine patch use among at-risk smokers, 55 smokers with a history of abstinence-induced depressed mood were randomly assigned to either Nicotine Maintenance or Standard Treatment following preliminary high-dose patch treatment. The Nicotine Maintenance group received 21 mg transdermal nicotine for 8 additional weeks; the Standard Treatment group followed a tapered dosing regimen. Significant differences favoring the Nicotine Maintenance group were found in self-reported craving but not withdrawal. No difference was observed in continuous abstinence or in relapse rates. When dropouts who did not relapse during patch use were classified as successful, however, the Nicotine Maintenance group had significantly lower relapse rates. Rate of lapse in the Nicotine Maintenance group during post-trial tapering did not differ significantly from that in the Standard Treatment group during tapering in the trial, suggesting that the benefits of sustained dosing may persist only as long as dosing continues.

Administration, Cutaneous↗