SEARCH · Search PubMed
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
We describe two cases with a rare adverse effect of severe allergic contact dermatitis secondary to usage of a disc containing nitroglycerin. The causal agent is most probably trinitroglycerin as was demonstrated by skin patch testing using the North American Contact Dermatitis Group Method.
Mismatch negativity (MMN) is a component of event-related potentials (ERPs) with a wide-ranging applicability to the investigation of neuronal substrates of information processing in normal and psychopathological states. Nicotine has been shown to be implicated in the pathophysiology of psychiatric disorders as schizophrenia or Alzheimer's disease, and has also been proposed as a self-administered drug in schizophrenia. The goal of the present study is to elucidate the effect of nicotine on the auditory automatic processing reflected by MMN. Nicotine was administered transdermally under controlled dosage. Ten healthy volunteers attended the laboratory for one baseline session and two test sessions. The test sessions involved administration of a placebo patch and a nicotine skin patch, which were counter-balanced. The ERPs were recorded passively during an auditory oddball paradigm. Nicotine administration shortened the MMN latencies, and these effects were independent of the earlier ERP components, N100 and P200. In conclusion, nicotine enhances preattentive and automatic processing such as MMN system and these effects appear to be quite specific and independent of earlier cognitive stages than preattentive mismatch processing. The shortened MMN latency may be interpreted as a reduction of the amount of time required to complete a neuronal mismatch process through the ascending auditory pathway.
We tested the hypothesis that transdermal scopolamine increases vagal-cardiac nervous outflow over the long term in 16 healthy young men. Twenty-four hours after application of one scopolamine patch, the average RR interval was increased by 13% and the average standard deviation of the RR interval (taken as an index of the level of vagal-cardiac nervous activity) was increased by 31%. Baroreceptor-cardiac reflex responsiveness (as reflected by prolongation of RR interval provoked by graded neck suction) also was increased substantially. These findings suggest that vagal-cardiac nervous activity can be augmented pharmacologically in man on a long-term basis. Since vagal outflow influences cardiac electrical properties in an important way, these findings may have therapeutic implications.
BACKGROUND: Organic nitrates are widely used in the treatment of chronic heart failure (CHF). No information, however, is available regarding their effect in patients already treated with ACE inhibitors. METHODS AND RESULTS: In a randomized, double-blind, crossover design, we studied the effects of high-dose (50 to 100 mg) transdermal nitroglycerin (NTG) and placebo given daily for 12 hours in 29 patients with CHF (NYHA functional classes II to III). Exercise time (4 hours after patch application) showed a progressive improvement during NTG administration, with an increase of 38+/-35 seconds (9+/-7%) at the end of the first month (P=NS), 76+/-28 seconds (16+/-6%) at the end of the second month (P=0.01), and 117+/-34 seconds (27+/-6%) at the end of the third month (P=0.003). No significant change was seen during placebo administration (12+/-20, 5+/-26, and 19+/-28 seconds, all P=NS). Exercise time 8 hours after NTG application measured at 3 months was also significantly longer, with a difference of 87+/-28 seconds (P=0.006), but not with placebo (23+/-36 seconds, P=0.53). Assessment of quality of life and need for additional diuretics or hospitalizations for CHF failed to demonstrate a significant difference between the 2 treatment periods. In contrast, NTG decreased left ventricular end-diastolic (-2.1+/-0.1%, P<0.05) and end-systolic (-3.2+/-1.3%, P<0.05) dimensions and augmented LV fractional shortening (24.7+/-10.5%, P<0.03). The effect of placebo on these parameters was not statistically significant. CONCLUSION: High-dose nitrate therapy significantly improves exercise tolerance and left ventricular size and systolic function in patients with chronic, mild to moderate CHF already treated with ACE inhibitors. These findings support the role of organic nitrates as an adjunctive therapy to ACE inhibitors in patients with chronic CHF.
We studied the intraocular pressure (IOP)-lowering effect and the side effects of a new transdermal delivery system (TDS) containing pilocarpine. After giving their written informed consent, patients were randomly assigned to receive a pilocarpine TDS or a placebo TDS. Two patches, each containing 30 mg of pilocarpine or placebo, were applied to the supraclavicular skin of 24 patients. The IOP was recorded before and at +12, 16, and 20 h after application. Plasma samples were analyzed for pilocarpine before treatment and 12 and 20 h later via high-performance liquid chromatography. The amount of drug remaining on the dermal patches was analyzed at 20 h. The mean IOP recorded before application was 22.7 +/- 5.8 mmHg. As compared with the placebo TDS, the pilocarpine TDS did not significantly reduce IOP at 12, 16, or 20 h after application (P = 0.42). The mean plasma concentrations were 2.9 ng/ml at 12 h and 1.3 ng/ml at 20 h. The verum TDS showed a residual mean drug concentration of 35.3 mg pilocarpine on the TDS. A substantial amount of pilocarpine was released from the TDS to the dermis, causing detectable plasma levels of pilocarpine at 12 and 20 h after administration. The pilocarpine TDS is a new nonocular pharmaceutical device that should avoid the side effects well known in glaucoma treatment when conventional eye drops are used.
Several transdermal contraceptive device (TCD) formulations were developed to provide a dual-controlled transdermal delivery of levonorgestrel (LN), a potent progestin, and 17 beta-estradiol (E2), a natural estrogen. Using a sensitive HPLC method, the in vitro release and skin permeation profiles of LN and E2 from various TCD formulations were simultaneously characterized in the hydrodynamically well-calibrated Valia-Chien skin permeation cells and both were found to follow zero-order kinetics. The rates of drug release and skin permeation were observed to vary significantly depending upon some formulation parameters. Six-month stability studies were performed on seven formulations at room and elevated temperatures (37 and 45 degrees C), and two (Formulations 4 and 5) were found to be acceptable, based on drug recovery, release rate, and skin permeation rate data. Judging from the 6-month accelerated stability studies, it is projected these two formulations will have shelf-life of at least 2 years. As a result of development of an efficient manufacturing process, Formulation 4 was selected for further evaluation. One-week primary skin irritation evaluation in 6 rabbits indicated that Formulation 4 is nonirritating, and it was thus selected for Phase I clinical bioavailability/dose proportionality studies in 12 healthy female volunteers of child-bearing age. Results of pharmacokinetic and pharmacodynamic analyses demonstrated that it is capable of achieving and maintaining a steady-state serum level of LN throughout the 3-week treatment period by weekly applications of one or two TCD patches (10 or 20 cm2). A dose proportionality was obtained in the serum drug levels, daily dose delivered, and contraception efficacy. An excellent correlation was obtained for the rates of transdermal delivery determined by the in vitro studies using human cadaver skin, the in vivo studies in rabbits, and the clinical studies in living subjects.
PURPOSE: To assess the safety and efficacy of transdermal fentanyl plus im ketorolac vs im ketorolac alone in the treatment of postoperative pain. METHODS: Ninety-two patients scheduled for surgery involving moderate to severe postoperative pain were randomized to one of two groups. Group A (n = 46) received an active fentanyl patch and group P (n = 46) received a placebo patch. Patches remained in place for 24 hr. Each patient received intraoperative ketorolac, 60 mg im. Patients were monitored for 36 hr postoperatively and the groups were analyzed for ketorolac usage, pain scores, vital signs, serum fentanyl concentrations, and adverse events. Intramuscular ketorolac was available on demand. RESULTS: Group A had lower pain scores at 8.12, 16 and 24 hr after patch placement (P < 0.05). Group A had lower heart rates, lower respiratory rates and fewer dropouts due to inadequate pain relief (4.3% vs 21.7% P < 0.05). Group A patients also used less ketorolac than group P patients (P < 0.05). The incidence of pruritus was higher in group A patients (19% vs 2%, P < 0.05), while the incidence of nausea and vomiting was not different between the two groups. Transdermal fentanyl was adequate "stand-alone" analgesia in only 23.8% of group A patients while 93.7% of the remaining group A patients receiving a combination of transdermal fentanyl and ketorolac had adequate pain relief. CONCLUSION: The transdermal fentanyl delivery system plus ketorolac im was more effective in controlling post-operative pain than ketorolac im alone. The two treatment modalities were comparable in safety with no difference in serious adverse events.
OBJECTIVE: The aim of this study was to evaluate the efficacy, safety, and tolerability of 2 years' application of an estradiol matrix transdermal system for the prevention of postmenopausal bone loss. METHODS: In this multicenter, randomized, placebo-controlled, parallel-group study, 261 surgically or naturally postmenopausal women were randomized to apply the estradiol matrix transdermal system (0.025, 0.0375, 0.05, or 0.1 mg/d) or matching placebo twice a week for 2 years. The study was double blind with respect to treatment (active vs placebo) but not to the dose levels of active treatment (because of the differing sizes and shapes of the patches). In addition to receiving the assigned treatment, the 100 nonhysterectomized women received 2.5 mg medroxyprogesterone acetate daily throughout the study. RESULTS: The evaluable group (n = 259) had a mean age of 52 years and a mean duration of menopause of 32 months. Following 2 years of treatment, there were significant differences in favor of estradiol between all doses of the estradiol matrix transdermal system and placebo in terms of the percentage change from baseline in the bone mineral density (BMD) of the L1-L4 anteroposterior lumbar spine (0.1 and 0.05 mg/d, P < 0.001; 0.0375 mg/d, P = 0.024; 0.025 mg/d, P = 0.002). Percentage changes from baseline in the BMD of the femoral neck after 2 years of treatment also consistently demonstrated the efficacy of the estradiol matrix transdermal system compared with placebo (all, P < or = 0.044). The estradiol matrix transdermal system was well tolerated. CONCLUSION: The estradiol matrix transdermal system was effective in preventing postmenopausal bone loss at dosages of 0.025 to 0.1 mg/d, and had a safety profile consistent with the known effects of estrogen/progestin.
The potential of low dose (30 mg t.i.d) pyridostigmine to reduce the ocular side effects of double dose transdermal controlled release hyoscine was evaluated by the study of near visual acuity, accommodation amplitude and pupil diameter in a placebo controlled, double masked study. We studied 47 healthy men (age 18-21 yr) in 3 groups: 16 assigned to placebo hyoscine and placebo pyridostigmine, 15 assigned to double dose hyoscine and placebo pyridostigmine, and 16 to double dose hyoscine and pyridostigmine. Subjects were tested during 48 h of treatment and 48 h of washout period. Blood cholinesterase inhibition level and amount of hyoscine released from the patches were used as parameters of reliability. Difference between groups was assessed using change from baseline scores. Double dose hyoscine caused decrease in near visual acuity to a mean of 14/18. Accommodation amplitude was decreased in the double dose transdermal hyoscine group from 9.19 +/- 1.04 to 4.83 +/- 1.97 diopters of accommodation. This decrease was significant when compared to the placebo group (p < 0.05) and to the pyridostigmine-protected group (p < 0.05). Pyridostigmine, however, did not significantly change the hyoscine-induced mydriasis of 1.47 + 0.15 mm change from baseline (p < 0.05). These results suggest that pyridostigmine administration may be beneficial in shortening recovery time when near vision impairment is experienced following single and double dose transdermal hyoscine administration.
The magnitude of tolerance to the anti-anginal efficacy of transdermal nitroglycerin and the efficacy and safety of short (4 h) and long (10 h) nitrate-free intervals for its prevention, were investigated in a randomized, double-blind, placebo-controlled crossover trial of 4 week-long treatment regimens: placebo, continuous therapy with a 50 mg patch (10 mg.24 h-1), and 4 h and 10 h nitrate-free periods. Only patients showing greater than 1 min increase in time to 1 mm ST depression after acute patch administration were eligible. Twelve men completed the study. One other anti-anginal medication (a beta-blocker in nine and calcium antagonist in two) was permitted in a constant dose throughout the study. Patients underwent exercise testing on days 1 and 7 of each treatment period, and 24 h ambulatory ECG monitoring on day 6. Compared to placebo, transdermal nitroglycerin on day 1 significantly improved time to 1 mm ST depression by 35%, and time to angina, exercise duration and maximal workload by 21%, 13% and 9% respectively. These improvements were totally lost after 7 days' continuous therapy, but completely maintained by a 10 h nitrate-free period (improvements of 35%, 25%, 16% and 11% respectively) but not by a 4 h nitrate-free period (non-significant improvements of 15%, 2%, 4% and 1% respectively). The differences between 10 and 4 h nitrate-free were significant for each end-point. Neither duration of ambulatory ischaemia, nor the proportion of patients experiencing greater than or equal to 5 min ischaemia during the scheduled nitrate-free interval differed between treatments.(ABSTRACT TRUNCATED AT 250 WORDS)
PURPOSE: Active pharmaceutical ingredients (API) in transdermal drug delivery systems (TDS) often causes skin irritation such as erythema and edema. We have studied a possible approach for the reduction of skin irritation by patch formulations that control the rates of skin permeation and elimination of API. METHODS: Loxoprofen (LX-base) was used to induce the skin irritation. The redness value (Deltaa) was evaluated as a measure of erythema by Chroma Meter. The in vitro skin permeation and release profiles were also investigated by using a side-by-side diffusion cell. RESULTS: The redness values were not correlated either with the cumulative amount of API permeated or the concentration of LX-base in the skin, but well correlated with the elimination rate of LX-base from the skin after the removal of the formulation. The formulation with gradual decrease of permeation rate during application accelerated the elimination rate after application, and resulted in the reduction of the skin irritation. CONCLUSIONS: The skin pharmacokinetics of API, not only permeation during application but also release after the patch removal, was found to be a significant factor for skin irritation. To minimize the skin irritation, it's also important to eliminate the residual API in the skin promptly after application.
This study reports findings from an investigation of the efficacy of high-dose nicotine patch (NP) therapy for heavy smokers with a past history of alcohol dependence. One hundred thirty participants were randomly assigned to 42 mg or 21 mg of transdermal nicotine for 4 weeks, followed by an 8-week dose titration. Follow-up assessments were conducted at 4 and 12 weeks. Differences between dose conditions were nonsignificant, although unexpectedly, outcomes favored participants in the 21-mg NP condition. Nicotine abstinence at follow-up was related to longer length of alcohol abstinence at time of enrollment. Future research should investigate ways to improve smoking quit rates in this population, including more frequent counseling sessions and/or other pharmacotherapies. These investigations should focus primarily on smokers in early alcohol recovery.
The transdermal route of administration for medication has many potential advantages over other routes of administration. However, the stratum corneum is an effective barrier to the absorption of most chemicals from the external environment into the body. To evaluate techniques for alteration of transdermal permeability, the authors studied the effect of low levels of electrical current on transport of a protein across the stratum corneum. Transcutaneous insulin absorption was used as an indicator of altered permeability. Twenty-six albino rabbits had acute diabetes mellitus induced by the intravenous administration of 125 mg/kg of alloxan. The animals then received either cutaneous patches containing insulin and an electrical current of 0.4 mA (active) or patches containing an equal amount of insulin but without electrical current (passive). At 10 and 12 hours after the placement of the patches, animals with active patches had significant elevations in serum insulin levels (p less than .05) and reduction in blood glucose levels (p less than .01). No changes were seen in controls. Animals with active patches also had significant differences from control animals in mean insulin response and peak insulin response (p less than .05). No cutaneous toxicity was observed in any of the animals. The authors conclude that low levels of electrical current can induce changes in stratum corneum permeability that are sufficient to produce the transdermal absorption of physiologic doses of a protein such as human insulin.
Eighty-eight patients (84 men and 4 women; mean age 59.3 years) with stable exercise-induced angina pectoris were enrolled in this within-patient, placebo-controlled study aimed at comparing the efficacy of the continuous and intermittent (12 hour on, 12 hour off) application of transdermal nitroglycerin. Eighty-one patients completed the study. After a 1-week placebo run-in period, during which the stability of angina was assessed on a bicycle ergometer, the patients received continuous treatment (two 10 mg/24 hour patches twice daily, at 8 a.m. and 8 p.m.), intermittent treatment (two 10 mg/24 hour patches at 8 a.m. and two placebo patches at 8 p.m.) and placebo (two placebo patches twice daily, at 8 a.m. and 8 p.m.), each given for one week in a double-blind randomised sequence, according to a 3 x 3 latin-square design. A cycloergometric exercise test was performed at the end of each period of treatment, 4 and 10 hours after the application of the morning patch. In comparison with placebo, both schedules of the active treatment induced a significant increase in both the ischemic (duration of exercise to 1 mm ST segment depression) and the angina threshold (duration of exercise to mild angina) at the 4th and at the 10th hours after-dosing. A significant difference was also found between continuous and intermittent treatment at the same times of observation, in favour of the intermittent schedule. The limited number of anginal attacks recorded during placebo prevented any clinical evaluation of the treatments. This study shows that the efficacy of transdermal nitroglycerin is more pronounced when it is given following an intermittent schedule.(ABSTRACT TRUNCATED AT 250 WORDS)
The aim of this study was to increase the skin penetration of two drugs, granisetron hydrochloride and diclofenac sodium, using a microelectronic device based on an ablation of outer layers of skin using radiofrequency high-voltage currents. These radiofrequency currents created an array of microchannels across the stratum corneum deep into the epidermis. The percutaneous penetration studies were first performed in vitro using excised full thickness porcine ear skin. An array of 100 microelectrodes/cm(2) was used in these studies. The skin permeability of both molecules was significantly enhanced after pretreatment with the radiofrequency microelectrodes, as compared to the delivery through the untreated control skin. Steady state fluxes of 41.6 micro g/cm(2)/h (r=0.997) and 23.0 micro g/cm(2)/h (r=0.989) were obtained for granisetron and diclofenac, respectively. The enhanced transdermal delivery was also demonstrated in vivo in rats. It was shown that diclofenac plasma levels in the pretreated rats reached plateau levels of 1.22+/-0.32 micro g/ml after 3 h to 1.47+/-0.33 micro g/ml after 6 h, as compared to 0.16+/-0.04 micro g/ml levels obtained after 6 h in untreated rats. Similarly, application of granisetron patches (3% in crosslinked hydrogel) onto rats' abdominal skin pretreated with radiofrequency electrodes resulted in an averaged peak plasma level of 239.3+/-43.7 ng/ml after 12 h, which was about 30 times higher than the plasma levels obtained by 24-h passive diffusion of the applied drug. The results emphasize, therefore, that the new transdermal technology is suitable for therapeutic delivery of poorly penetrating molecules.
Systemic side effects that result from oral administration of estrogens to postmenopausal women may be minimized by use of the transdermal route. We administered transdermal estradiol, 0.05 mg/day, cyclically for 3 months to 12 postmenopausal and perimenopausal women to study the efficacy, acceptability, and metabolic effects of this dosage form. The results showed that transdermal estradiol significantly increased plasma levels of estradiol and estrone and urinary concentrations of estradiol conjugates, and produced significant improvement in menopausal symptoms and vaginal cytologic findings. The patches were well tolerated and no systemic side effects were reported. No clinically significant adverse biochemical changes were observed. Plasma renin substrate and renin activity were unchanged during therapy.
This correlational study examined the adherence rates of transdermal nicotine (TN) use among a population of males and females 18 years of age and older (N = 619) who received varying levels of behavioral intervention. Rates of patch adherence were assessed for demographic (e.g., gender, ethnicity, and age), income-, smoking- [e.g., baseline carbon monoxide (CO), nicotine dependence, and follow-up quit status], and treatment-related (e.g., condition, and drop status) variables. Loglinear and logistic regression analyses were performed to assess adherence rates. Results indicated that male gender [chi2(2, n = 485) = 20.39, P = .038], not dropping out of the study [chi2(2, n = 485) = 13.94, P < .001], and intensive treatment (compared to the standard care) [chi2(4, n = 485) = 14.96, P = .005] were associated with greater adherence to TN. Furthermore, patch adherence was associated with quit status at 6 months (OR = 2.47, CI = 1.56-3.91, P < .001) and 12 months (OR = 2.12, CI = 1.34-3.37, P = .001). Complete and partial patch adherence (compared to minimal/no adherence) were associated with a greater number of telephone intervention contacts completed (OR = 2.621, CI = 1.421-4.832, P = .002). Noteworthy however, was the lack of association between level of income and patch adherence. These findings suggest characteristics of those more and less likely to adhere to TN in research and clinical settings.
The calcium content of mud patches used for therapy is very small. Several mineral clays originating from Hungary served as a base material for experiments in order to find a suitable drug for transdermal introduction of calcium ions into the body. The Ca++ transport through the pig skin has been investigated in vitro in diffusion cells applying iontophoresis. Studies of electrical and physicochemical factors acting on the permeation kinetics of in vitro experiments were performed. The utilization of direct current has intensified the Ca++ transport through the pig skin (129.78+/-26. 15 microgram Ca/cm2). On using pulsate currents the amount of the Ca++ penetrating through the skin was 5-10 times higher (283.18+/-16.89 microgram Ca/cm2, 388.71+/-19.90 microgram Ca/cm2) than that of the passive transport (36.22+/-14.20 microgram Ca/cm2). The amount of Ca++ cumulated in the receptor compartment was directly proportional to the amount of bentonite (a natural mineral clay with a large cation exchange capacity) in the donor compartment and to the concentration of Ca++ in the lattice of the applied mineral clay. Therefore, the experiments were carried out on a bentonite previously enriched in Ca++ in its lattice (50 mg Ca/g bentonite). The results of the in vitro studies could open a new field of application in the therapy of osteoporosis or in the use of mineral substances.