Rotigotine transdermal patch: a review of its use in the treatment of Parkinson's disease.

PubMed

Sanford, Mark; Scott, Lesley J

2011-08-01

A transdermal patch formulation of the non-ergolinic dopamine agonist rotigotine (Neupro®) is indicated as monotherapy for the treatment of early Parkinson's disease and as combination therapy with levodopa throughout the course of the disease. Daily application of the rotigotine transdermal patch (referred to here as rotigotine) provided predictable release and absorption of rotigotine, with steady-state rotigotine concentrations reached within 1-2 days. In six large, well designed clinical trials, rotigotine was an efficacious treatment for Parkinson's disease. In early Parkinson's disease, rotigotine initiated without levodopa produced significantly greater improvements than placebo in the Unified Parkinson's Disease Rating Scale (UPDRS) summed motor and activities of daily living (ADL) scores, as well as significantly higher response rates. In a comparison with oral ropinirole, rotigotine did not meet a prespecified response-rate noninferiority criterion, although this may reflect the dosages used, which may not have been directly comparable. In advanced Parkinson's disease, rotigotine in combination with levodopa reduced 'off' time and improved motor functioning and ADL significantly more than levodopa plus placebo. Rotigotine was noninferior to oral pramipexole in reducing 'off' time, although it did not meet a response-rate noninferiority criterion. A recent trial focused on both motor and non-motor endpoints in patients with inadequate early morning motor control despite antiparkinsonian treatment (most received levodopa). Rotigotine improved morning motor functioning and reduced sleep disturbances, night-time motor symptoms, depressive symptoms, pain and functioning, and quality of life to a significantly greater extent than placebo. Rotigotine was generally well tolerated across the trials and in longer-term extension studies, with the most common treatment-emergent adverse events being application-site reactions, gastrointestinal disturbances, somnolence and headache. Application-site reactions were generally mild to moderate in severity; where reported, up to 3% of patients had severe skin reactions. Thus, rotigotine offers a novel approach to the treatment of Parkinson's disease and, given its ease of administration, efficacy in reducing disabling motor and non-motor symptoms, and acceptable tolerability profile, it has the potential to be an attractive treatment option for this highly debilitating disease.

Drug Delivery and Transport into the Central Circulation: An Example of Zero-Order In vivo Absorption of Rotigotine from a Transdermal Patch Formulation.

PubMed

Cawello, Willi; Braun, Marina; Andreas, Jens-Otto

2018-01-13

Pharmacokinetic studies using deconvolution methods and non-compartmental analysis to model clinical absorption of drugs are not well represented in the literature. The purpose of this research was (1) to define the system of equations for description of rotigotine (a dopamine receptor agonist delivered via a transdermal patch) absorption based on a pharmacokinetic model and (2) to describe the kinetics of rotigotine disposition after single and multiple dosing. The kinetics of drug disposition was evaluated based on rotigotine plasma concentration data from three phase 1 trials. In two trials, rotigotine was administered via a single patch over 24 h in healthy subjects. In a third trial, rotigotine was administered once daily over 1 month in subjects with early-stage Parkinson's disease (PD). A pharmacokinetic model utilizing deconvolution methods was developed to describe the relationship between drug release from the patch and plasma concentrations. Plasma-concentration over time profiles were modeled based on a one-compartment model with a time lag, a zero-order input (describing a constant absorption via skin into central circulation) and first-order elimination. Corresponding mathematical models for single- and multiple-dose administration were developed. After single-dose administration of rotigotine patches (using 2, 4 or 8 mg/day) in healthy subjects, a constant in vivo absorption was present after a minor time lag (2-3 h). On days 27 and 30 of the multiple-dose study in patients with PD, absorption was constant during patch-on periods and resembled zero-order kinetics. Deconvolution based on rotigotine pharmacokinetic profiles after single- or multiple-dose administration of the once-daily patch demonstrated that in vivo absorption of rotigotine showed constant input through the skin into the central circulation (resembling zero-order kinetics). Continuous absorption through the skin is a basis for stable drug exposure.

[Local effects of transdermal treatment with rotigotine].

PubMed

Bermejo, Pedro Emilio; Zea, María Ascensión; Alba-Alcántara, Lucía; Ruiz-Huete, Cristina

2013-04-01

Rotigotine is the first transdermal non-ergolinic dopaminergic agonist used in the treatment of Parkinson's disease. It has several important advantages such as once-daily administration, absence of interactions with food, steady levels in plasma and continuous dopaminergic stimulation. Although its systemic side effects are similar to those seen in other dopaminergic agonists, rotigotine also has local side effects derived from the site of application. The aim of this paper is to review those local problems. A retrospective analysis was carried out in order to identify the first 165 patients treated with rotigotine. Patients with intracranial lesions, psychiatric pathology or dementia were excluded. Patients were evaluated before and at two, four and six months after beginning treatment with rotigotine. In all, 94 males and 71 females were identified, with an average age of 65.2 and an average rotigotine daily dose of 11.3 mg. Local side effects were present in 21 patients and they were usually mild. Two patients abandoned the treatment because of these local adverse events, presenting erythema and prurigo. Thirty patients complained about lack of adherence of the patch, specially when it was hot, and 36 about the formation of wrinkles in the patch. None of these problems was associated to motor fluctuations or other complications. Local complications of transdermal rotigotine are mild but frequent. We consider it is necessarily to take them into account to get a better treatment of patients suffering from Parkinson's disease.

Overnight switch from ropinirole to transdermal rotigotine patch in patients with Parkinson disease

PubMed Central

2011-01-01

Background A recent trial involving predominantly Caucasian subjects with Parkinson Disease (PD) showed switching overnight from an oral dopaminergic agonist to the rotigotine patch was well tolerated without loss of efficacy. However, no such data have been generated for Korean patients. Methods This open-label multicenter trial investigated PD patients whose symptoms were not satisfactorily controlled by ropinirole, at a total daily dose of 3 mg to 12 mg, taken as monotherapy or as an adjunct to levodopa. Switching treatment from oral ropinirole to transdermal rotigotine was carried out overnight, with a dosage ratio of 1.5:1. After a 28-day treatment period, the safety and tolerability of switching was evaluated. Due to the exploratory nature of this trial, the effects of rotigotine on motor and nonmotor symptoms of PD were analyzed in a descriptive manner. Results Of the 116 subjects who received at least one treatment, 99 (85%) completed the 28-day trial period. Dose adjustments were required for 11 subjects who completed the treatment period. A total of 76 treatment-emergent adverse events (AEs) occurred in 45 subjects. No subject experienced a serious AE. Thirteen subjects discontinued rotigotine prematurely due to AEs. Efficacy results suggested improvements in both motor and nonmotor symptoms and quality of life after switching. Fifty-two subjects (46%) agreed that they preferred using the patch over oral medications, while 31 (28%) disagreed. Conclusions Switching treatment overnight from oral ropinirole to transdermal rotigotine patch, using a dosage ratio of 1.5:1, was well tolerated in Korean patients with no loss of efficacy. Trial registration This trial is registered with the ClincalTrails.gov Registry (NCT00593606). PMID:21831297

Rotigotine Transdermal Patch Improves Swallowing in Dysphagic Patients with Parkinson's Disease.

PubMed

Hirano, Makito; Isono, Chiharu; Sakamoto, Hikaru; Ueno, Shuichi; Kusunoki, Susumu; Nakamura, Yusaku

2015-08-01

Abnormal swallowing, dysphagia, is a potentially fatal symptom in Parkinson's disease (PD) and is characterized by frequent silent aspiration, an unrecognized risk of suffocation and aspiration pneumonia. Several studies have reported that the injection of apomorphine, a dopamine agonist, alleviated dysphagia in some patients with PD. The effects of other antiparkinson medications against dysphagia remain controversial. Rotigotine is another dopamine agonist with non-oral administration, i.e., a transdermal patch. Its noninvasiveness seems to render this medicine even more suitable than apomorphine for dysphasic patients. However, no direct evidence has been reported. In the present retrospective open-label study, we for the first time objectively showed that rotigotine improved swallowing on videofluoroscopic examination in dysphagic patients with PD.

Transdermal Patches for the Treatment of Neurologic Conditions in Elderly Patients: A Review

PubMed Central

Somogyi, Monique

2011-01-01

Objective: The mode of drug delivery can be an important consideration in optimizing drug therapy, as it can affect treatment compliance and outcomes. It is particularly important to develop optimal drug formulations for chronic diseases or conditions in the elderly for which treatment compliance is known to be low. In this review, the features and benefits of transdermal formulations for treating neurologic conditions in elderly patients are described. Data Sources: English-language articles were identified by searching MEDLINE in November 2010 (there were no search parameters on date of publication) using the search terms transdermal patch, transdermal system, neurology, rivastigmine, rotigotine, selegiline, lidocaine, capsaicin, compliance, and neuropathic pain. Data Selection: Articles describing the development, use, efficacy, and safety of licensed transdermal patch treatments for neurologic conditions that affect the elderly were included. Data Extraction: The features of transdermal systems and comparisons between transdermal and oral formulations for the treatment of specific neurologic conditions in elderly patients were reviewed. Data Synthesis: There are 5 transdermal patch systems currently available for neurologic conditions in adults: rivastigmine, rotigotine, selegiline, lidocaine, and capsaicin. These are all modern formulations in matrix patches, developed to provide appropriate drug dosage in an acceptable and well-tolerated form. Conclusions: Transdermal patches can offer benefits to patients over oral formulations in terms of ease of use, simple treatment regimens, avoidance of the first-pass effect, and avoidance of high maximum plasma concentrations with rapid changes in drug levels, without the invasive procedures associated with intravenous treatment. PMID:22454804

Spotlight on rotigotine transdermal patch in Parkinson's disease.

PubMed

Sanford, Mark; Scott, Lesley J

2011-12-01

Rotigotine transdermal patch (Neupro(®)) [referred to here as rotigotine] is a non-ergolinic dopamine agonist that is available in the EU as monotherapy for the treatment of early Parkinson's disease and as combination therapy with levodopa throughout the course of the disease. Daily application of the rotigotine patch provided predictable release and absorption of rotigotine, with steady-state rotigotine concentrations reached within 1-2 days. In early Parkinson's disease, compared with placebo, rotigotine monotherapy produced significantly greater improvements in the Unified Parkinson's Disease Rating Scale summed motor and activities of daily living (ADL) scores (primary endpoint), as well as significantly higher response rates. In advanced Parkinson's disease, rotigotine in combination with levodopa reduced 'off' time (primary endpoint) and improved motor functioning and ADL significantly more than levodopa plus placebo. In patients with inadequate early morning motor control despite antiparkinsonian treatment, rotigotine improved morning motor functioning and reduced sleep disturbances, night-time motor symptoms, depressive symptoms, pain and functioning, and quality of life to a significantly greater extent than placebo. The efficacy of rotigotine relative to other treatments requires further evaluation, as there were inconsistent results in noninferiority analyses that compared rotigotine to other dopamine agonists. Rotigotine was generally well tolerated across the trials, with the most common treatment-emergent adverse events being application-site reactions, gastrointestinal disturbances, somnolence and headache. No unexpected adverse effects were observed in extension studies of up to 6 years. Thus, rotigotine offers a novel approach to the treatment of Parkinson's disease and, given its ease of administration, efficacy in reducing disabling motor and non-motor symptoms, and acceptable tolerability profile, it has the potential to be an attractive treatment option for this highly debilitating disease.

Rotigotine transdermal patch and sleep in Parkinson's disease: where are we now?

PubMed

Rosa-Grilo, Miguel; Qamar, Mubasher A; Taddei, Raquel N; Pagonabarraga, Javier; Kulisevsky, Jaime; Sauerbier, Anna; Chaudhuri, K Ray

2017-01-01

A wide range of sleep dysfunction complicates Parkinson's disease during its course from prodromal to palliative stage. It is now increasingly acknowledged that sleep disturbances are thus integral to the disease and pose a significant burden impacting on quality of life of patients. Sleep fragmentation, restless legs syndrome, nocturia, and nocturnal pain are regarded as one of the main components of night-time sleep dysfunction with possible secondary impact on cognition and well-being. The role of dopaminergic therapies, particularly using a continuous drug delivery strategy in managing some of these sleep issues, have been reported but the overall concept remains unclear. This review provides an overview of several aspects of night-time sleep dysfunction in Parkinson's disease and describes all available published open-label and blinded studies that investigated the use of rotigotine transdermal patch targeting sleep. Blinded studies have suggested beneficial effects of rotigotine transdermal patch on maintenance insomnia and restless legs syndrome in Parkinson's disease patients. Open-label studies support these observations and also suggest beneficial effects on nocturia and nocturnal pain.

Influence of hepatic impairment on the pharmacokinetics of the dopamine agonist rotigotine.

PubMed

Cawello, Willi; Fichtner, Andreas; Boekens, Hilmar; Braun, Marina

2014-09-01

The transdermally applied dopamine receptor agonist rotigotine is extensively metabolized in the liver. An open-label, parallel-group study was conducted to evaluate the effects of moderate hepatic impairment on the pharmacokinetics, safety and tolerability of rotigotine. Eight subjects with normal hepatic function and nine with moderate hepatic impairment (Child-Pugh class B) received one rotigotine transdermal patch (providing a dose of 2 mg/24 h) daily for 3 days with a 24-h patch-on period. Blood and urine samples were collected to evaluate pharmacokinetic parameters characterizing drug bioavailability and elimination. Primary variables included plasma and urine concentrations of unconjugated rotigotine (active parent compound) and total rotigotine (unconjugated rotigotine plus sulfate and glucuronide conjugates) under steady-state (SS) conditions. For unconjugated rotigotine, point estimates for the ratios of AUC(0-24)SS and C max,SS between the two groups (normal vs. impaired hepatic function) were near 1: AUC(0-24)SS, 0.90 (90 % CI 0.59, 1.38) and C max,SS, 0.94 (90 % CI 0.66, 1.35); t max,SS and t 1/2 were lower in subjects with hepatic impairment, while renal clearance was unaffected and overall clearance was higher. For total rotigotine, C max,SS was higher in subjects with hepatic impairment compared with those with normal hepatic function (P = 0.0239, ANOVA). A tendency to reduced non-renal clearance was observed in subjects with hepatic impairment, consistent with their higher plasma concentrations of total rotigotine. Thus, moderate hepatic impairment did not influence the pharmacokinetics of unconjugated rotigotine under steady-state conditions suggesting that dose adjustment will not be required for patients with mild or moderate hepatic insufficiency. In addition, the rotigotine patch was well tolerated in subjects with moderate hepatic impairment.

Transdermal rotigotine for the perioperative management of restless legs syndrome

PubMed Central

2012-01-01

Background Immobilisation, blood loss, sleep deficiency, and (concomitant) medications during perioperative periods might lead to acute exacerbation of symptoms in patients with the restless legs syndrome (RLS). Continuous transdermal delivery of the dopamine agonist rotigotine provides stable plasma levels over 24 h and may provide RLS patients with a feasible treatment option for perioperative situations. To assess the feasibility of use of rotigotine transdermal patch for the perioperative management of moderate to severe RLS, long-term data of an open-label extension of a rotigotine dose-finding study were retrospectively reviewed. Methods The data of all 295 patients who had entered the 5-year study were screened independently by two reviewers for the occurrence of surgical interventions during the study period. The following data were included in this post-hoc analysis: patient age, sex, surgical intervention and outcome, duration of hospital stay, rotigotine maintenance dose at the time of surgery, rotigotine dose adjustment, and continuation/discontinuation of rotigotine treatment. All parameters were analysed descriptively. No pre-specified efficacy assessments (e.g. IRLS scores) were available for the perioperative period. Results During the study period, 61 surgical interventions were reported for 52 patients (median age, 63 years; 67% female); the majority of patients (85%) had one surgical intervention. The mean rotigotine maintenance dose at time of surgery was 3.1 ± 1.1 mg/24 h. For most interventions (95%), rotigotine dosing regimens were maintained during the perioperative period. Administration was temporarily suspended in one patient and permanently discontinued in another two. The majority (96%) of the patients undergoing surgery remained in the study following the perioperative period and 30 of these patients (61%) completed the 5-year study. Conclusions Although the data were obtained from a study which was not designed to assess rotigotine use in the perioperative setting, this post-hoc analysis suggests that treatment with rotigotine transdermal patch can be maintained during the perioperative period in the majority of patients and may allow for uninterrupted alleviation of RLS symptoms. Trial Registration The 5-year rotigotine extension study is registered with ClinicalTrials.gov, identifier NCT00498186. PMID:23009552

Transdermal rotigotine for the perioperative management of restless legs syndrome.

PubMed

Högl, Birgit; Oertel, Wolfgang H; Schollmayer, Erwin; Bauer, Lars

2012-09-25

Immobilisation, blood loss, sleep deficiency, and (concomitant) medications during perioperative periods might lead to acute exacerbation of symptoms in patients with the restless legs syndrome (RLS). Continuous transdermal delivery of the dopamine agonist rotigotine provides stable plasma levels over 24 h and may provide RLS patients with a feasible treatment option for perioperative situations. To assess the feasibility of use of rotigotine transdermal patch for the perioperative management of moderate to severe RLS, long-term data of an open-label extension of a rotigotine dose-finding study were retrospectively reviewed. The data of all 295 patients who had entered the 5-year study were screened independently by two reviewers for the occurrence of surgical interventions during the study period. The following data were included in this post-hoc analysis: patient age, sex, surgical intervention and outcome, duration of hospital stay, rotigotine maintenance dose at the time of surgery, rotigotine dose adjustment, and continuation/discontinuation of rotigotine treatment. All parameters were analysed descriptively. No pre-specified efficacy assessments (e.g. IRLS scores) were available for the perioperative period. During the study period, 61 surgical interventions were reported for 52 patients (median age, 63 years; 67% female); the majority of patients (85%) had one surgical intervention. The mean rotigotine maintenance dose at time of surgery was 3.1 ± 1.1 mg/24 h. For most interventions (95%), rotigotine dosing regimens were maintained during the perioperative period. Administration was temporarily suspended in one patient and permanently discontinued in another two. The majority (96%) of the patients undergoing surgery remained in the study following the perioperative period and 30 of these patients (61%) completed the 5-year study. Although the data were obtained from a study which was not designed to assess rotigotine use in the perioperative setting, this post-hoc analysis suggests that treatment with rotigotine transdermal patch can be maintained during the perioperative period in the majority of patients and may allow for uninterrupted alleviation of RLS symptoms. The 5-year rotigotine extension study is registered with ClinicalTrials.gov, identifier NCT00498186.

Transdermal rotigotine in advanced Parkinson's disease: a randomized, double-blind, placebo-controlled trial.

PubMed

Nomoto, Masahiro; Mizuno, Yoshikuni; Kondo, Tomoyoshi; Hasegawa, Kazuko; Murata, Miho; Takeuchi, Masahiro; Ikeda, Junji; Tomida, Takayuki; Hattori, Nobutaka

2014-10-01

Rotigotine, a non-ergot dopamine receptor agonist, offers potential for continuous dopaminergic stimulation that could avoid the fluctuations observed with traditional treatments. We conducted a randomized, double-blind, placebo-controlled trial in Japanese patients with advanced Parkinson's disease (PD) to investigate the efficacy and safety of rotigotine. Inclusion criteria included the presence of motor complications, such as wearing off, on-off, delayed-on/no-on, any circumstances that could interfere with levodopa dose escalation because of side effects, or declining levodopa efficacy. The enrolled patients received once-daily applications of rotigotine transdermal patches or matched placebo patches. A total of 174 patients were randomly assigned to rotigotine (87 patients) or placebo (87 patients). The full analysis set included 172 patients (86 for the rotigotine group and 86 for the placebo group). The maximum maintenance dose of rotigotine was set at 16 mg/24 h. The changes in unified PD rating scale Part III scores from baseline to the end of the trial were -10.1 ± 9.0 (mean ± standard deviation) in the rotigotine group and -4.4 ± 7.4 in the placebo group (p < 0.001). There was a significantly greater reduction in the off-time (p = 0.014) in the rotigotine group. Rotigotine was well tolerated, with serious adverse events being reported in only three patients in each group. Rotigotine at doses of up to 16 mg/24 h is efficacious and safe in Japanese patients with advanced PD.

Clinical pharmacology and efficacy of rotigotine (Neupro® patch) in the treatment of restless leg syndrome.

PubMed

Ferini-Strambi, Luigi; Marelli, Sara; Galbiati, Andrea

2016-08-01

Restless legs syndrome/Willis Ekbom disease (RLS/WED) is a sensorimotor disorder characterized by unpleasant sensations in the legs accompanied by an urge to move them, that typically occurs and tend to worsen in the evening/night or during period of inactivity. Standard medications for RLS/WED are dopamine agonists and calcium channel α-2-δ ligands. The clinical spectrum of RLS/WED is very broad, ranging from individuals suffering from the disease during limited periods up to those severely affected, with daily symptoms. In such cases a long-acting drug like rotigotine should be considered. The clinical pharmacology and efficacy of rotigotine was examined to evaluate the evidence supporting its use in RLS/WED. The rotigotine transdermal patch provides constant delivery of the drug, maintaining a stable plasma concentration over 24 hours by means of a single daily application. Several randomized, double-blind, placebo-controlled trials have demonstrated the efficacy of rotigotine in improving moderate-to-severe RLS/WED symptoms. Rotigotine is generally well tolerated. The most common adverse effects were application-site reactions, dose-dependent, more frequently reported in the first period of treatment. Incidence of augmentation in RLS/WED patients treated with oral dopamine agonists is higher when compared with the use of transdermal rotigotine.

Switching from an oral dopamine receptor agonist to rotigotine transdermal patch: a review of clinical data with a focus on patient perspective.

PubMed

Chung, Sun Ju; Asgharnejad, Mahnaz; Bauer, Lars; Benitez, Arturo; Boroojerdi, Babak; Heidbrede, Tanja; Little, Allison; Kim, Han Joon

2017-07-01

Dopamine receptor agonists (DAs) are commonly used to treat Parkinson's disease (PD) and restless legs syndrome (RLS). In certain situations, switching from oral DAs to rotigotine transdermal patch may be beneficial for the patient (e.g., optimal symptom control/side effects/perioperative management, preference for once-daily/non-oral administration, RLS augmentation treatment). Areas covered: This narrative review summarizes available data on DA dose equivalency, dose conversions, switching schedules, safety, tolerability, efficacy and patient treatment preferences of switching from oral DAs to rotigotine (and vice versa) in patients with PD/RLS. The studies were identified in a PubMed search (up to 8 November 2016) using terms ('dopamine receptor agonist' OR 'rotigotine') AND 'switch'. Expert commentary: Randomized controlled studies often do not address the challenges clinicians face in practice, e.g., switching medications within the same class when dosing is not a one-to-one ratio. The authors describe three open-label studies in PD where oral DAs were successfully switched to rotigotine, and review three studies in RLS where oral DAs/levodopa were switched to rotigotine. Finally, the authors provide a suggested tool for switching from oral DAs to rotigotine, which includes dose conversion factors and switching schedules. The authors' view is that low-dose oral DAs (equivalent to ≤8 mg/24 h rotigotine) may be switched overnight.

Influence of transdermal rotigotine on ovulation suppression by a combined oral contraceptive

PubMed Central

Braun, Marina; Elshoff, Jan-Peer; Andreas, Jens-Otto; Müller, Louise Ischen; Horstmann, Rolf

2009-01-01

AIMS To assess the influence of the transdermally applied dopamine agonist rotigotine on ovulation suppression by a combined oral contraceptive (0.03 mg ethinyloestradiol and 0.15 mg levonorgestrel) in a randomized, double-blind crossover study in 40 healthy females. METHODS Treatment A consisted of the combined oral contraceptive for 28 days plus rotigotine for the first 13 days (2 mg (24 h)−1 on days 1–3, 3 mg (24 h)−1 maintenance dose thereafter). During treatment B, subjects received matching placebo patches instead of rotigotine. Pharmacodynamic parameters (progesterone, oestradiol, luteinizing hormone, and follicle stimulating hormone serum concentrations), pharmacokinetic parameters for ethinyloestradiol/levonorgestrel and rotigotine, and safety and tolerability of the treatment were assessed. RESULTS Progesterone serum concentrations remained below 2 ng ml−1 in all subjects during the luteal phase. Median serum concentrations of all other pharmacodynamic parameters were similar during both treatments. Pharmacokinetic parameters Cmax,ss and AUC(0,24 h)ss at steady state were similar with or without co-administration of rotigotine for both ethinyloestradiol and levonorgestrel with geometric mean ratios close to 1 and 90% confidence intervals within the acceptance range of bioequivalence (0.8, 1.25): Cmax,ss 1.05 (0.93, 1.19), AUC(0,24 h)ss 1.05 (0.9, 1.22) for ethinyloestradiol; Cmax,ss 1.01 (0.96, 1.06), AUC(0,24 h)ss 0.98 (0.95, 1.01) for levonorgestrel. Mean plasma concentrations of unconjugated rotigotine remained stable throughout the patch-on period (day 13). CONCLUSIONS Concomitant administration of 3 mg (24 h)−1 transdermal rotigotine had no impact on the pharmacodynamics and pharmacokinetics of a combined oral contraceptive containing 0.03 mg ethinyloestradiol and 0.15 mg levonorgestrel, suggesting that the dopamine agonist does not influence contraception efficacy. PMID:19740396

Rotigotine improves restless legs syndrome: a 6-month randomized, double-blind, placebo-controlled trial in the United States.

PubMed

Hening, Wayne A; Allen, Richard P; Ondo, William G; Walters, Arthur S; Winkelman, John W; Becker, Philip; Bogan, Richard; Fry, June M; Kudrow, David B; Lesh, Kurt W; Fichtner, Andreas; Schollmayer, Erwin

2010-08-15

This randomized, double-blinded, placebo-controlled trial (NCT00135993) assessed efficacy and safety of the dopamine agonist rotigotine in the treatment of idiopathic restless legs syndrome (RLS) over a 6-month maintenance period. A total of 505 eligible participants with moderate to severe RLS (IRLS sum score >or= 15) were randomly assigned to five groups to receive either placebo or rotigotine (0.5, 1, 2, or 3 mg/24 hr) delivered by once-daily transdermal patch (fixed-dose regimen). The two co-primary efficacy parameters decreased from baseline to end of maintenance in IRLS sum score and in clinical global impressions (CGI-1) score. On both primary measures, 2 and 3 mg/24 hr rotigotine was superior to placebo (P < 0.001). Adjusted treatment differences to placebo for the IRLS sum score were -4.5 (95% CI: -6.9, -2.2) for 2 mg/24 hr rotigotine, -5.2 (95% CI: -7.5, -2.9) for 3 mg/24 hr rotigotine, and for CGI item 1 -0.65 (95% CI: -1.0, -0.3) and -0.9 (95% CI: -1.3, -0.5) for the 2 and 3 mg/24 hr doses, respectively. Skin reactions (27%) and known dopaminergic side effects such as nausea (18.1%) and headache (11.6%) were mostly mild or moderate in rotigotine subjects. Rotigotine transdermal patches releasing 2 to 3 mg/24 hr significantly reduced the severity of RLS symptoms. Treatment efficacy was maintained throughout the 6-month double-blind period.

Rotigotine transdermal patch in combination therapy for Parkinson's disease--observations in routine clinical practice.

PubMed

Ceballos-Baumann, Andres; Häck, Hermann-Josef

2011-10-01

The dopamine agonist rotigotine has shown efficacy and safety for the treatment of early and advanced Parkinson's disease (PD) in controlled clinical trials. This observational study evaluated rotigotine administration in combination with other antiparkinsonian medication in routine clinical practice. Data were collected by 688 German practice-based neurologists, initiating rotigotine treatment in patients with idiopathic Parkinson's disease. Assessments included rotigotine maintenance dose, changes in concomitant PD medication, changes in sleep quality, and rotigotine tolerability over an observation period of 12-16 weeks. The median rotigotine maintenance dose was 6 mg/24 h (n = 969, full analysis set). The proportion of all other prescribed PD medications declined over the observation period; combination therapy decreased by 18.7%. Daily levodopa intake was markedly reduced by 87 mg (18.9%) in 47.6% of the patients with levodopa documentation; 7% no longer required levodopa after 12-16 weeks. Mean overall sleep quality (PD Sleep Scale item 1) improved by 21.4 points, the occurrence of nocturias (PDSS item 8) by 13.4 points, and 'turning in bed' (Unified Parkinson's Disease Rating Scale part II) by 0.6 points. Drug-related adverse events were reported for 7.9% of all patients (n = 1152, safety population). Application site reactions were the most common adverse events (2.2%) resulting in early discontinuation in 1.4% of patients. In routine clinical practice, treatment initiation with rotigotine transdermal patch was associated with a reduction of other prescribed PD medications and with an improvement of self-reported sleep quality.

Rotigotine Transdermal Patch

MedlinePlus

... other sources of heat such as heating pads, electric blankets and heated waterbeds; or direct sunlight. Do ... you suddenly fall asleep. Do not drive a car or operate machinery at the beginning of your ...

Rotigotine for nocturnal hypokinesia in Parkinson's disease: Quantitative analysis of efficacy from a randomized, placebo-controlled trial using an axial inertial sensor.

PubMed

Bhidayasiri, Roongroj; Sringean, Jirada; Chaiwong, Suchapit; Anan, Chanawat; Penkeaw, Nuntiwat; Leaknok, Amarinee; Boonpang, Kamolwan; Saksornchai, Karn; Rattanachaisit, Watchara; Thanawattano, Chusak; Jagota, Priya

2017-11-01

Nocturnal hypokinesia is a common symptom in Parkinson's disease (PD), negatively affecting quality of life of both patients and caregivers. However, evidence-based treatment strategies are limited. To evaluate the efficacy of rotigotine transdermal patch, using a wearable sensor, in the management of nocturnal immobility. 34 PD subjects with nocturnal immobility were randomized to receive rotigotine transdermal patch (mean ± SD of 10.46 ± 4.63 mg/24 h, n = 17) or placebo patch (n = 17). Treatment was titrated to an optimal dose over 1-8 weeks, then maintained for 4 weeks. Primary endpoints were objective parameters assessing axial rotation measured using an axial inertial sensor (the NIGHT-Recorder) over two nights at the patients' home. Scale-based assessments were also performed. There was a significant difference, in favor of rotigotine, in change from baseline score in the number of turns in bed (ANCOVA, p = 0.001), and degree of axial turn (p = 0.042). These objective improvements were mirrored by significantly greater improvements in clinical scale-based assessments, including the Unified Parkinson's Disease Rating Scale (UPDRS) total scores (p = 0.009), UPDRS-motor scores (p < 0.001), UPDRS-axial scores (p = 0.01), the Modified Parkinson's Disease Sleep Scale (p < 0.001), the Nocturnal Akinesia Dystonia and Cramp Scale (p = 0.003) and the eight-item PD Questionnaire (PDQ-8) scores (p = 0.01) from baseline to end of treatment in patients given rotigotine compared to placebo. We show that the rotigotine patch provides a significant improvement in nocturnal symptoms as assessed using both objective measures and clinical rating scales. The study demonstrates the feasibility of using wearable sensors to record objective outcomes in PD-related clinical trials. Copyright © 2017 Elsevier Ltd. All rights reserved.

Rotigotine and specific non-motor symptoms of Parkinson's disease: post hoc analysis of RECOVER.

PubMed

Ray Chaudhuri, K; Martinez-Martin, Pablo; Antonini, Angelo; Brown, Richard G; Friedman, Joseph H; Onofrj, Marco; Surmann, Erwin; Ghys, Liesbet; Trenkwalder, Claudia

2013-07-01

Non-motor symptoms of Parkinson's disease (PD) represent major causes of morbidity. RECOVER, a randomized controlled trial of rotigotine transdermal system, was the first prospective controlled trial to use the Non-Motor Symptoms Scale (NMSS) as an exploratory outcome for assessment of treatment effects on non-motor symptoms in PD. Rotigotine improved NMSS total score compared with placebo, and the "Sleep/fatigue" and "Mood/apathy" domains. This post hoc analysis further characterizes the effects of rotigotine on sleep/fatigue and mood/apathy. Patients with PD and unsatisfactory early-morning motor impairment were randomized to transdermal patches of rotigotine (2-16 mg/24 h) or placebo. Treatment was titrated to optimal dose over 1-8 weeks, maintained for 4 weeks. The NMSS was assessed at baseline and end of treatment. Post hoc analyses are presented for individual items of the "Sleep/fatigue" and "Mood/apathy" domains. The interpretation of p-values is considered exploratory in nature. Of 287 patients randomized, NMSS data were available for 267 patients (178 rotigotine, 89 placebo). Within the "Sleep/fatigue" domain there was a significant difference, in favor of rotigotine, in change from baseline score in 1 of 5 items: "fatigue (tiredness) or lack of energy" (ANCOVA, p < 0.0001). Within the "Mood/apathy" domain, there were significant differences in favor of rotigotine in 4 of 7 items: "lost interest in surroundings" (p < 0.0001), "lost interest in doing things" (p < 0.0001), "seems sad or depressed" (p < 0.01), and "difficulty experiencing pleasure" (p < 0.05). Rotigotine transdermal system may improve non-motor symptoms such as fatigue, symptoms of depression, anhedonia, and apathy in patients with PD; further prospective controlled studies are required to confirm this post hoc analysis. Copyright © 2013 Elsevier Ltd. All rights reserved.

Long-term safety and efficacy of rotigotine transdermal patch for moderate-to-severe idiopathic restless legs syndrome: a 5-year open-label extension study.

PubMed

Oertel, Wolfgang; Trenkwalder, Claudia; Beneš, Heike; Ferini-Strambi, Luigi; Högl, Birgit; Poewe, Werner; Stiasny-Kolster, Karin; Fichtner, Andreas; Schollmayer, Erwin; Kohnen, Ralf; García-Borreguero, Diego

2011-08-01

Safety and efficacy of non-ergot dopamine agonists for the treatment of idiopathic restless legs syndrome have been shown in short-term trials. We did a prospective open-label extension of a 6-week, double-blind randomised trial to assess the safety, tolerability, and efficacy of rotigotine transdermal patch for up to 5 years in patients with restless legs syndrome. Patients (aged 18-75 years) with moderate-to-severe idiopathic restless legs syndrome were treated with once-daily rotigotine transdermal patch in 33 centres in Austria, Germany, and Spain between July 31, 2003, and April 15, 2009. The dose was titrated in weekly increments (up to 4 weeks) from 0·5 mg/24 h to a maximum of 4 mg/24 h, and was followed by up to 5 years of maintenance at the optimum dose. Primary safety outcomes included occurrence of adverse events and dropouts. Efficacy assessments were secondary and included the International Restless Legs Syndrome study group severity rating scale (IRLS). Augmentation of symptoms was assessed by means of standard diagnostic criteria and was confirmed by an international expert panel. All patients who received at least one dose of study drug were included in assessments. This study is registered with ClinicalTrials.gov, number NCT00498186. 295 patients entered the open-label study, of whom 126 (43%) completed 5 years of follow-up. 169 (57%) patients discontinued treatment, 89 (30%) because of adverse events and 31 (11%) because of lack of efficacy. 70 patients (24%) discontinued during year 1 of maintenance. The most common adverse events were application site reactions, which occurred in 37% (106/290) of patients in year 1, 17% (38/220) of patients in year 2, 14% (27/191) of patients in year 3, and in less than 6% of patients during year 4 (8/159) and year 5 (8/147). 56 patients (19%) discontinued because of application site reactions. Mean rotigotine dose was 2·43 mg/24 h (SD 1·21) after initial titration and 3·09 mg/24 h (1·07) at the end of maintenance. Of 89 patients who discontinued because of adverse events, 28 (31%) were on 4 mg/24 h rotigotine. Mean IRLS score of patients entering the open-label study was 27·8 (SD 5·9) at baseline of the double-blind trial. In patients who completed the maintenance period, mean IRLS score was reduced from a baseline score of 27·7 (SD 6·0) by a mean of 18·7 points (SD 9·5) to a score of 9·0 (SD 9·2) at the end of maintenance. 39% (48/123) of patients who completed the trial were classified as symptom free according to the IRLS. Clinically significant augmentation was recorded in 39 patients (13%), of whom 15 (5%) were receiving a dose of rotigotine within the range approved by the European Medicines Agency (EMA; 1-3 mg/24 h) and 24 (8%) were receiving 4 mg/24 h rotigotine. Rotigotine transdermal patch is generally well tolerated after 1 year and provides sustained efficacy for patients with moderate-to-severe restless legs syndrome at a stable dose for up to 5 years. Thus, rotigotine transdermal patch is an appropriate long-term treatment option for moderate-to-severe restless legs syndrome, a disorder that often requires lifelong treatment. UCB BioSciences, on behalf of Schwarz Pharma, Ireland. Copyright © 2011 Elsevier Ltd. All rights reserved.

Levodopa, placebo and rotigotine change biomarker levels for oxidative stress.

PubMed

Muhlack, Siegfried; Kinkel, Manuel; Herrman, Lennard; Müller, Thomas

2017-05-01

Homocysteine increase and glutathione derivative cysteinyl-glycine fall are indirect biomarkers for oxidative stress, for instance due to dopamine D 1 receptor stimulation. To investigate the influence of the D 1 receptor agonists levodopa and rotigotine compared with placebo on homocysteine and cysteinyl-glycine in plasma of patients with Parkinson's disease. Patients received 100 mg levodopa, 4 mg rotigotine or placebo. Cysteinyl-glycine and homocysteine were measured every 30 min over three hours. Homocysteine rose during levodopa- and placebo administration. Rotigotine had no effect. Cysteine-glycine only increased after placebo- but not after levodopa- or rotigotine. Homocysteine elevation results from hepatic and gastrointestinal methylation processes. Transdermal rotigotine circumvents these methylation locations. Turnover of segregated alkyl residuals from rotigotine serves as methyl group donors, which counteract homocysteine increment. The placebo-related cysteinyl-glycine increase results from reduced free radical exposure. Low levodopa dosing and antioxidants in the rotigotine patch matrix prevented cysteinyl-glycine fall.

Treatment of moderate to severe restless legs syndrome: 2-year safety and efficacy of rotigotine transdermal patch

PubMed Central

2010-01-01

Background Rotigotine is a unique dopamine agonist with activity across D1 through D5 receptors as well as select adrenergic and serotonergic sites. This study reports the 2-year follow-up safety and efficacy data of an ongoing open-label multicenter extension study (NCT00498186) of transdermal rotigotine in patients with moderate to severe restless legs syndrome (RLS). Methods Patients received a once-daily patch application of an individually optimized dose of rotigotine between 0.5 mg/24 h to 4 mg/24 h. Safety assessments included adverse events (AEs) and efficacy was measured by the International RLS Study Group Severity Rating Scale (IRLS), RLS-6 scales and Clinical Global Impression (CGI). Quality of life (QoL) was measured by QoL-RLS. Results Of 310 patients who completed a 6-week placebo-controlled trial (SP709), 295 (mean age 58 ± 10 years, 66% females) were included in the open-label trial SP710. 64.7% (190/295 patients) completed the 2-year follow-up; 29 patients discontinued during the second year. Mean daily rotigotine dose after 2 years was 2.93 ± 1.14 mg/24 h with a 2.9% dose increase from year 1. Rotigotine was generally well tolerated. The rate of typical dopaminergic side effects, nausea and fatigue, was low (0.9% and 2.3%, respectively) during the second year; application site reactions were frequent but lower than in year 1 (16.4% vs. 34.5%). The IRLS total score improved from baseline of SP709 (27.8 ± 5.9) by 17.2 ± 9.2 in year 2 completers. Similar improvements were observed in RLS-6 scales, CGI scores and QoL-RLS. The responder rate in the CGI change item 2 ("much" and "very much" improved) was 95% after year 2. Conclusions Transdermal rotigotine is an efficacious and well-tolerated long-term treatment option for patients with moderate to severe RLS with a high retention rate during 2 years of therapy. Trial registration NCT00498186 PMID:20920156

Effects of Night-Time Use of Rotigotine on Nocturnal Symptoms in Parkinson's Disease

PubMed Central

Vallderiola, Francesc; Compta, Yaroslau; Aparicio, Javier; Tarradellas, Jaume; Salazar, Gabriel; Oliver, Josep María; Callén, Antonio; Delgado, Tania; Nobbe, Fritz

2015-01-01

Objectives. This open-label study assessed the efficacy and safety of exclusive night-time administration of transdermal rotigotine in patients with nocturnal and early morning PD symptoms. Methods. Patients with PD and nocturnal and early morning symptoms received transdermal rotigotine patches (2–16 mg/24 h) applied in the evening and removed in the morning for 3 months. Sleep disturbance was assessed with modified Parkinson's Disease Sleep Scale (PDSS-2). Other outcomes included a pain visual analogue scale (VAS) and short-form Parkinson's Disease Questionnaire (PDQ-8) for quality of life. Results. 74 patients completed treatment in this study. At the end of treatment, PDSS-2 total score had improved by mean 10.9 points from baseline (p < 0.001). All three PDSS-2 domain scores (sleep disturbances, nocturnal motor symptoms, and nocturnal symptoms) were also significantly improved by 41%, 56%, and 48%, respectively (p < 0.001). VAS-pain score decreased from 3.2 to 2.3 (p < 0.001). PDQ-8 score decreased from 23.8 to 18.1 (p < 0.001). The most frequently reported adverse events included nausea (9%), anxiety (4%), and dizziness (4%). Conclusions. Night-time administration of transdermal rotigotine is an effective and well tolerated treatment for nocturnal symptoms in patients with PD. PMID:26576319

Effectiveness and tolerability of rotigotine transdermal patch for the treatment of restless legs syndrome in a routine clinical practice setting in Germany.

PubMed

Stiasny-Kolster, Karin; Berg, Daniela; Hofmann, Werner E; Berkels, Reinhard; Grieger, Frank; Lauterbach, Thomas; Schollmayer, Erwin; Bachmann, Cornelius G

2013-06-01

We aimed to assess effectiveness and tolerability of rotigotine in patients with moderate to severe idiopathic restless legs syndrome (RLS) under daily practice conditions in Germany. In this 3-month noninterventional study, effectiveness was assessed using RLS-6 (primary variables were symptom severity when falling asleep [item 2] and during the night [item 3]). Data were collected at baseline and at the end of treatment. Safety assessments included adverse events (AEs). Six hundred and eighty-four patients were treated with rotigotine and 418 (61%) completed the study. The full analysis set (FAS) comprised 564 patients (106 de novo; 458 pretreated [454 had complete rotigotine dosing data]). Mean rotigotine dose of longest duration was 2.4±1.4 mg/24 h. Rotigotine improved all RLS-6 items (mean change from baseline [item 2], -2.4±3.6; [item 3], -2.7±3.4), with the most pronounced improvement observed in daytime symptoms while at rest (item 4, -2.9±3.2). AEs were typical of dopaminergic treatment and transdermal administration. De novo patients generally started rotigotine on 1 mg/24 h (85% [90/106]) and pretreated patients on 1 (50% [227/454]) or 2 mg/24 h (40% [183/454]). Most patients who were pretreated with levodopa (57%), pramipexole (84%), or ropinirole (78%) monotherapy discontinued these medications on initiation of rotigotine. Rotigotine was effective and well-tolerated when used in routine clinical practice. Copyright © 2013 Elsevier B.V. All rights reserved.

Effects of Rotigotine on REM Sleep Behavior Disorder in Parkinson Disease.

PubMed

Wang, Yan; Yang, Yuechang; Wu, Huijuan; Lan, Danmei; Chen, Ying; Zhao, Zhongxin

2016-10-15

REM sleep behavior disorder (RBD) is a common manifestation of Parkinson disease (PD). In this study, we assessed the effects of rotigotine transdermal patch on RBD features in patients with PD. In this prospective open-label study, eleven PD patients with untreated RBD were administered rotigotine patches for up to seven months to ameliorate their parkinsonism. The severities of their RBD symptoms before and after rotigotine therapy were evaluated through patient and bed partner interviews, a validated evaluation scale (REM sleep behavior disorder questionnaire-Hong Kong, RBDQ-HK), and blinded assessments based on video-polysomnographic (VPSG) measure. Rotigotine improved parkinsonism and subjective sleep quality in PD patients with RBD. The RBDQ-HK total score, especially the Factor 2 score, was decreased, which demonstrated that the subjective severity of RBD symptoms was improved after rotigotine treatment, especially the frequency and severity of abnormal RBD-related motor behaviors. The VPSG analyses showed that the total sleep time (TST) and stage 1% were increased and that the PLMS index was decreased. However, no differences in the RBD-related sleep measures were observed. The improved RBD symptoms and VPSG measures of PD patients in this study (TST, stage 1%, and PLMS index) suggest that, in PD, rotigotine may partially improve RBD-related symptoms. Rotigotine should be considered to be an optional drug for the treatment of RBD symptoms in PD. © 2016 American Academy of Sleep Medicine

From bench to bedside: An overview of rotigotine for the treatment of restless legs syndrome.

PubMed

Bogan, Richard K

2014-03-01

Restless legs syndrome (RLS) is a common chronic neurologic disorder. Symptoms are most prevalent during the evening and at night, although daytime symptoms may emerge as the disease progresses. Dopamine agonists are currently considered first-line therapy for moderate to severe idiopathic RLS. Most dopamine agonists have short half-lives and are administered in the evening, shortly before the onset of RLS symptoms. Rotigotine is a non-ergot dopamine receptor agonist that has been specifically developed as a transdermal patch to provide continuous drug delivery over a 24-hour period. This review details the development of rotigotine, from the preclinical studies that established its pharmacokinetic profile to large-scale clinical trials in patients with RLS. Placebo-controlled trials that demonstrated the efficacy and tolerability of rotigotine are discussed, in addition to open-label studies that investigated long-term therapy. Studies were identified by a PubMed search using the key word rotigotine in conjunction with restless legs syndrome and by reviewing reference lists of retrieved publications. All clinical trials of rotigotine in RLS published before September 2013 were included. Preclinical studies have established activity of rotigotine as a dopamine receptor agonist, and pharmacokinetic data have shown that transdermal delivery maintains stable plasma levels over 24 hours. Rotigotine has demonstrated efficacy in improving moderate to severe RLS symptoms in randomized, placebo-controlled trials, based on scores on the International RLS Study Group rating scale, the RLS-6 scale, and the Clinical Global Impression-Severity subscale. Results of an open-label extension study suggest that efficacy may be maintained for up to 5 years. A polysomnographic study demonstrated an improvement in periodic limb movement index with rotigotine, and subjective assessments have suggested beneficial effects in terms of amelioration of sleep disturbances. Premature discontinuations from rotigotine treatment have ranged from 8% to 38% in studies of 6 weeks to 12 months in duration; 57% of patients discontinued prematurely during a 5-year study. In each trial, adverse events were typical of dopaminergic stimulation and use of a transdermal patch. The most common adverse events were application-site reactions, with a reported prevalence ranging from 17% (1-month sleep laboratory trial) to 58% (5-year open-label extension study). Clinically significant augmentation was recorded in 39 of 295 patients (13%) receiving rotigotine during the 5-year study, of whom 15 (5%) were receiving a dose within the US Food and Drug Administration-approved range of 1 to 3 mg/24 h. Findings from clinical studies have suggested that rotigotine is efficacious in improving RLS symptoms and is generally well-tolerated. The risk of developing clinically significant augmentation appears to be low. As such, rotigotine represents an important addition for RLS treatment. Copyright © 2014 The Authors. Published by EM Inc USA.. All rights reserved.

Evaluation of rotigotine transdermal patch for the treatment of apathy and motor symptoms in Parkinson's disease.

PubMed

Hauser, Robert A; Slawek, Jaroslaw; Barone, Paolo; Dohin, Elisabeth; Surmann, Erwin; Asgharnejad, Mahnaz; Bauer, Lars

2016-06-07

This multicenter, double-blind, placebo-controlled study assessed the efficacy of rotigotine transdermal patch on apathy and motor symptoms in patients with Parkinson's disease (PD). Patients with PD-associated apathy (Unified Parkinson's Disease Rating Scale [UPDRS] I item 4 [motivation] ≥2 and patient-rated Apathy Scale [AS] ≥14) were randomized 1:1:1 to "low-dose" rotigotine (≤6 mg/24 h for early PD [those not receiving levodopa] or ≤8 mg/24 h for advanced PD [those receiving levodopa]), "high-dose" rotigotine (≤8 mg/24 h for early PD or ≤16 mg/24 h for advanced PD), or placebo, and maintained at optimal/maximal dose for 12 weeks. Coprimary efficacy variables were: change from baseline to End of Maintenance in patient-rated AS and UPDRS II + III total score. Recruitment was stopped after an interim futility analysis; therefore, all p values are exploratory. Of 122 patients randomized, 81.1 % completed the study (placebo, n = 32/40 [80.0 %]; low-dose rotigotine, n = 30/41 [73.2 %]; high-dose rotigotine, n = 37/41 [90.2 %]). No treatment difference was observed in the change in patient-rated AS (least squares mean [95 % confidence interval (CI)] difference: low-dose, 0.04 [-2.42, 2.50], p =0.977; high-dose, -0.22 [-2.61, 2.18], p = 0.859). Rotigotine improved UPDRS II + III total scores versus placebo (least squares mean [95 % CI] treatment difference: low-dose, -7.29 [-12.30, -2.28], p = 0.005; high-dose, -6.06 [-10.90, -1.21], p = 0.015), and the "mood/apathy" domain of the Non-Motor Symptom Scale as rated by the investigator (secondary outcome). The most frequent adverse events in rotigotine-treated patients were application site reactions, somnolence, and nausea. Rotigotine did not improve PD-associated apathy as rated by the patient but provided clinically relevant improvement in motor control and activities of daily living. ClinicalTrials.gov identifier NCT01782222 . Trial registration date: January 30, 2013.

Pharmacokinetics of rotigotine transdermal system in adolescents with idiopathic restless legs syndrome (Willis-Ekbom disease).

PubMed

Elshoff, Jan-Peer; Hudson, John; Picchietti, Daniel L; Ridel, Keith; Walters, Arthur S; Doggett, Kimberly; Moran, Kimberly; Oortgiesen, Marga; Ramirez, Francisco; Schollmayer, Erwin

2017-04-01

To investigate the pharmacokinetics (PK) of rotigotine transdermal system in adolescents with moderate-to-severe idiopathic restless legs syndrome (RLS). This multicenter, open-label, dose-escalation study enrolled patients ≥13 to <18 years of age. Rotigotine transdermal patches were applied daily and up-titrated weekly: 0.5, 1, 2, 3 mg/24 h. Blood samples were collected on the final day of each dose step. Primary PK variables were the apparent total body clearance (CL/f; L/h) and volume of distribution at steady state (V SS /f; L) of unconjugated rotigotine for each dose step, calculated for the PK per-protocol set (PKPPS). Other PK, safety, and efficacy variables (International RLS Study Group Rating Scale [IRLS]; Clinical Global Impressions Item 1 [CGI-1]) were assessed. Of 24 patients who received rotigotine, 23 completed all dose steps and 17 formed the PKPPS. Least-squares mean (95% confidence interval) CL/f and V SS /f values were broadly similar across all dose steps (CL/f: 0.5 mg/24 h: 676.86 [408.50-1121.51]; 1 mg/24 h: 671.72 [459.11-982.80]; 2 mg/24 h: 937.56 [658.50-1334.89]; 3 mg/24 h: 1088.77 [723.47-1638.53]; V SS /f: 5403.16 [2850.67-10,241.17]; 6220.79 [3842.05-10,072.28]; 7114.01 [4547.88-11,128.07]; 6037.92 [3598.36-10,131.41]). Among 23 patients with efficacy data, mean IRLS and CGI-1 scores improved at each dosage level. Adverse events reported by ≥3 patients were nausea (seven) and application site reactions (four). Key PK properties of rotigotine in adolescent patients with moderate-to-severe idiopathic RLS were comparable to those previously observed in adults. Rotigotine improved RLS symptoms and was well tolerated. ClinicalTrials.gov: NCT01495793. Copyright © 2016 Elsevier B.V. All rights reserved.

Continuous dopaminergic stimulation in a patient treated with daytime Levodopa-carbidopa intestinal gel and overnight Rotigotine: a case report.

PubMed

Imbriani, Paola; Schirinzi, Tommaso; D'Elia, Alessio; Pisani, Antonio

2017-08-23

Patients with Parkinson's disease (PD) receiving long-term L-Dopa therapy eventually develop motor complications with unpredictable "on-off" response fluctuations and involuntary movements, leading to progressive disability. Hence, the search for alternative therapeutic choices based on continuous dopaminergic stimulation (CDS) becomes crucial for the treatment of advanced PD. Here, we describe the case of a 70-year-old man with a 9-year history of PD, treated with daytime levodopa-carbidopa intestinal gel (LCIG) and overnight Rotigotine transdermal patch. LCIG monotherapy significantly reduced motor fluctuations and prevented the appearance of unpredictable off periods; concurrently, overnight Rotigotine improved his sleep quality and morning akinesia. Both LCIG and Rotigotine induce CDS, which conceptually mimics physiologic striatal dopamine receptor function. Hence, they both represent a good therapeutic option for the treatment of advanced PD.

Effects of Rotigotine on REM Sleep Behavior Disorder in Parkinson Disease

PubMed Central

Wang, Yan; Yang, Yuechang; Wu, Huijuan; Lan, Danmei; Chen, Ying; Zhao, Zhongxin

2016-01-01

Study Objectives: REM sleep behavior disorder (RBD) is a common manifestation of Parkinson disease (PD). In this study, we assessed the effects of rotigotine transdermal patch on RBD features in patients with PD. Methods: In this prospective open-label study, eleven PD patients with untreated RBD were administered rotigotine patches for up to seven months to ameliorate their parkinsonism. The severities of their RBD symptoms before and after rotigotine therapy were evaluated through patient and bed partner interviews, a validated evaluation scale (REM sleep behavior disorder questionnaire-Hong Kong, RBDQ-HK), and blinded assessments based on video-polysomnographic (VPSG) measure. Results: Rotigotine improved parkinsonism and subjective sleep quality in PD patients with RBD. The RBDQ-HK total score, especially the Factor 2 score, was decreased, which demonstrated that the subjective severity of RBD symptoms was improved after rotigotine treatment, especially the frequency and severity of abnormal RBD-related motor behaviors. The VPSG analyses showed that the total sleep time (TST) and stage 1% were increased and that the PLMS index was decreased. However, no differences in the RBD-related sleep measures were observed. Conclusions: The improved RBD symptoms and VPSG measures of PD patients in this study (TST, stage 1%, and PLMS index) suggest that, in PD, rotigotine may partially improve RBD-related symptoms. Rotigotine should be considered to be an optional drug for the treatment of RBD symptoms in PD. Citation: Wang Y, Yang Y, Wu H, Lan D, Chen Y, Zhao Z. Effects of rotigotine on REM sleep behavior disorder in Parkinson disease. J Clin Sleep Med 2016;12(10):1403–1409. PMID:27568909

No influence of the CYP2C19-selective inhibitor omeprazole on the pharmacokinetics of the dopamine receptor agonist rotigotine.

PubMed

Elshoff, Jan-Peer; Cawello, Willi; Andreas, Jens-Otto; Braun, Marina

2014-05-01

Rotigotine, a non-ergolinic dopamine receptor agonist administered transdermally via a patch, is metabolized by several cytochrome P-450 (CYP450) isoenzymes, including CYP2C19. This open-label, multiple-dose study evaluated the effect of omeprazole, a competitive inhibitor of CYP2C19, on the pharmacokinetics of rotigotine and its metabolites under steady-state conditions in healthy male subjects (of the extensive metabolizer phenotype, CYP2C19). Subjects received rotigotine 2 mg/24 hours on days 1-3, 4 mg/24 hours on days 4-12, and omeprazole 40 mg once daily on days 7-12 immediately after patch application. Blood and urine samples were collected on days 6 and 12 to evaluate rotigotine pharmacokinetic parameters alone and in the presence of omeprazole. Data from 37 subjects were available for pharmacokinetic analysis. Point estimates (90% confidence intervals, CI) for the ratios of AUC(0-24)SS and Cmax,SS of unconjugated rotigotine for the comparison rotigotine + omeprazole:rotigotine alone were close to 1 (0.9853 [0.9024, 1.0757] for AUC(0-24)SS and 1.0613 [0.9723, 1.1585] for Cmax,SS ) with 90% CIs within the acceptance range for bioequivalence (0.80, 1.25). Selective inhibition of CYP2C19 by omeprazole did not alter the steady-state pharmacokinetic profile of rotigotine or its metabolites. Thus, rotigotine dose adjustment is not required in patients receiving omeprazole, or other CYP2C19 inhibitors. © 2014, The American College of Clinical Pharmacology.

Rotigotine transdermal system: developing continuous dopaminergic delivery to treat Parkinson's disease and restless legs syndrome.

PubMed

Benitez, Arturo; Edens, Heather; Fishman, Jesse; Moran, Kimberly; Asgharnejad, Mahnaz

2014-11-01

Rotigotine is a nonergoline dopamine receptor agonist with structural similarity to dopamine. Rotigotine binds to the D1 through D5 dopamine receptors, having several times more affinity than dopamine does to the D2 and D3 receptors. Although rotigotine was demonstrated to restore locomotor activity in animal models of Parkinson's disease (PD), the rapid metabolism of rotigotine limited the development of an orally administered formulation. Rotigotine's high lipid solubility and extended duration of action when applied to the skin in experimental models of PD suggested that rotigotine was a candidate for transdermal application. The constant transdermal delivery of rotigotine over 24 h is hypothesized to approximate continuous agonist-receptor stimulation, which conceptually more closely mimics physiologic striatal dopamine receptor function. Randomized clinical studies have demonstrated rotigotine's efficacy, safety, and tolerability in patients with early- and advanced-stage PD, including improvements in motor symptoms and off-time. Although the etiology is unknown, restless legs syndrome (RLS) is thought to involve dopaminergic dysregulation. Randomized clinical studies also have demonstrated the efficacy of rotigotine in improving the symptoms of moderate-to-severe primary RLS. This review examines rotigotine's developmental history for transdermal administration leading to its approval for the treatment of early- and advanced-stage PD and moderate-to-severe primary RLS. © 2014 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals Inc. on behalf of The New York Academy of Sciences.

The Efficacy Profile of Rotigotine During the Waking Hours in Patients With Advanced Parkinson's Disease: A Post Hoc Analysis

PubMed Central

LeWitt, Peter A.; Poewe, Werner; Elmer, Lawrence W.; Asgharnejad, Mahnaz; Boroojerdi, Babak; Grieger, Frank; Bauer, Lars

2016-01-01

Objectives Transdermal delivery of rotigotine maintains stable plasma concentrations for 24 hours. Three phase 3 studies of rotigotine as add-on to levodopa in advanced Parkinson's disease showed a significant reduction in “off” time from baseline to end of maintenance (EoM). However, detailed analyses over the range of a day have not yet been performed. The objective was to examine the time course of the efficacy profile of rotigotine throughout the day. Methods Post hoc analysis of diary data from 3 double-blind, placebo-controlled studies of rotigotine in patients with advanced Parkinson's disease inadequately controlled with levodopa, with average “off” time of ≥2.5 h/d (CLEOPATRA-PD [NCT00244387], 16-week maintenance; PREFER, 24-week maintenance; SP921 [NCT00522379], 12-week maintenance). Patients marked 30-minute intervals as “off,” “on without troublesome dyskinesia,” “on with troublesome dyskinesia,” or “sleep.” Diaries completed on the 3 days before EoM were analyzed. A 2-sample t test was performed for comparison of rotigotine + levodopa versus placebo + levodopa for mean percentage of time per status during four 6-hour periods: 12:00am (midnight) to 6:00am, 6:00am to 12:00pm (noon), noon to 6:00pm, and 6:00pm to midnight. Results Data were available for 967 patients (placebo + levodopa, 260; rotigotine + levodopa, 707). During the 24-hour period at EoM, an advantage in mean percentage time spent “off” and “on without troublesome dyskinesia” was observed with rotigotine + levodopa versus placebo + levodopa during the three 6-hour periods from 6:00am to midnight (P < 0.05; exploratory analysis). Conclusions These exploratory analyses of patients with motor fluctuations suggest that the efficacy of rotigotine transdermal patch, as captured by diary data, in reducing “off” time and increasing “on time without troublesome dyskinesia” may cover the full waking day. PMID:26882318

The Efficacy Profile of Rotigotine During the Waking Hours in Patients With Advanced Parkinson's Disease: A Post Hoc Analysis.

PubMed

LeWitt, Peter A; Poewe, Werner; Elmer, Lawrence W; Asgharnejad, Mahnaz; Boroojerdi, Babak; Grieger, Frank; Bauer, Lars

2016-01-01

Transdermal delivery of rotigotine maintains stable plasma concentrations for 24 hours. Three phase 3 studies of rotigotine as add-on to levodopa in advanced Parkinson's disease showed a significant reduction in "off" time from baseline to end of maintenance (EoM). However, detailed analyses over the range of a day have not yet been performed. The objective was to examine the time course of the efficacy profile of rotigotine throughout the day. Post hoc analysis of diary data from 3 double-blind, placebo-controlled studies of rotigotine in patients with advanced Parkinson's disease inadequately controlled with levodopa, with average "off" time of ≥2.5 h/d (CLEOPATRA-PD [NCT00244387], 16-week maintenance; PREFER, 24-week maintenance; SP921 [NCT00522379], 12-week maintenance). Patients marked 30-minute intervals as "off," "on without troublesome dyskinesia," "on with troublesome dyskinesia," or "sleep." Diaries completed on the 3 days before EoM were analyzed. A 2-sample t test was performed for comparison of rotigotine + levodopa versus placebo + levodopa for mean percentage of time per status during four 6-hour periods: 12:00AM (midnight) to 6:00AM, 6:00AM to 12:00PM (noon), noon to 6:00PM, and 6:00PM to midnight. Data were available for 967 patients (placebo + levodopa, 260; rotigotine + levodopa, 707). During the 24-hour period at EoM, an advantage in mean percentage time spent "off" and "on without troublesome dyskinesia" was observed with rotigotine + levodopa versus placebo + levodopa during the three 6-hour periods from 6:00AM to midnight (P < 0.05; exploratory analysis). These exploratory analyses of patients with motor fluctuations suggest that the efficacy of rotigotine transdermal patch, as captured by diary data, in reducing "off" time and increasing "on time without troublesome dyskinesia" may cover the full waking day.

Rotigotine transdermal patch in Chinese patients with advanced Parkinson's disease: A randomized, double-blind, placebo-controlled pivotal study.

PubMed

Zhang, Zhen-Xin; Liu, Chun-Feng; Tao, En-Xiang; Shao, Ming; Liu, Yi-Ming; Wang, Jian; Asgharnejad, Mahnaz; Xue, Hai-Bo; Surmann, Erwin; Bauer, Lars

2017-11-01

Rotigotine was demonstrated to be efficacious and well-tolerated in three placebo-controlled studies (CLEOPATRA-PD/PREFER/SP921) of patients with advanced-stage Parkinson's disease (PD), most of whom were Caucasian. This multicenter phase 3 study (SP1037; NCT01646255) was the first to investigate the efficacy and safety of rotigotine in Chinese patients with advanced-stage PD. Chinese patients with PD, inadequately controlled on levodopa (stable dose ≥200 mg/day), with ≥2.5 h/day "off" time, and Hoehn & Yahr stage 2-4, were randomized 1:1 to receive transdermal rotigotine or placebo, titrated over ≤7 weeks, maintained at optimal/maximum dose (4-16 mg/24 h) for 12 weeks. Primary efficacy variable: mean change in absolute "off" time (according to patient diaries) from baseline to end of maintenance. Safety variables included adverse events (AEs) and discontinuations due to AEs. 346 patients were randomized and 89.9% completed the study (87.8% placebo; 92.0% rotigotine). All were Chinese (58.7% male; mean ± SD age: 62.2 ± 8.9 years; mean ± SD time since PD diagnosis: 6.62 ± 3.70 years). Rotigotine significantly reduced "off" time vs placebo (LS mean [95% CI] treatment difference: -1.20 h/day [-1.83, -0.57]; p = 0.0002), and resulted in more responders (≥30% decrease in "off" time: 36.9% placebo; 48.8% rotigotine; p = 0.0269). AEs were reported for 86 (50.0%) placebo- and 103 (59.2%) rotigotine-treated patients; 15 discontinued due to AEs (placebo 7; rotigotine 8). The most common AEs (≥5%) were dizziness, nausea, pruritus, and dyskinesia. Rotigotine was efficacious in Chinese patients with advanced-stage PD as add-on therapy to levodopa, significantly reducing "off" time vs placebo; the treatment difference was similar to that observed in previous studies of mainly Caucasian patients. Rotigotine was generally well-tolerated and had a similar AE profile to those observed in previous studies. Copyright © 2017 Elsevier Ltd. All rights reserved.

Comparison of the bioavailability and adhesiveness of different rotigotine transdermal patch formulations.

PubMed

Elshoff, Jan-Peer; Timmermann, Lars; Schmid, Miriam; Arth, Christoph; Komenda, Michael; Brunnert, Marcus; Bauer, Lars

2013-12-01

Rotigotine transdermal patch is approved for the treatment of early and advanced idiopathic Parkinson's disease (PD) and moderate-to-severe idiopathic restless legs syndrome (RLS). A cold chain manufacturing and distribution process was temporarily implemented in 2008, as this reduced the crystal formation reported within patches stored at room temperature. In order to overcome the crystallization issue and meet EMA and FDA requirements, a new room temperature stable formulation was developed. The three studies reported here were conducted to determine whether the new room temperature stable patch demonstrated similar bioavailability and adhesiveness to the original and intermediate patches. Data are reported from three cross-over studies that compared the original, cold chain and room temperature stable patch. Two open-label bioequivalence studies investigated the 2 mg/24 h dosage in healthy individuals (SP951, n = 52 [Clinicaltrials.gov: NCT00881894]; SP0987, n = 50 [NCT01059903]) and a double-blind patch adhesiveness study investigated the 8 mg/24 h dosage in patients with PD (SP1066, n = 56 [NCT01338896]). Plasma concentration-time curves and geometric means for pharmacokinetic parameters were similar for the cold chain vs. original patch in SP951 (AUC(0-tz): 2.68 vs. 2.71 ng/mL*h; point estimate: 0.99 [90% confidence interval (CI): 0.91, 1.07]) (Cmax: 0.131 vs. 0.136 ng/mL; 0.96 [0.89, 1.04]) and for the room temperature stable vs. cold chain patch in SP0987 (AUC(0-tz): 4.51 vs. 4.87 ng/mL*h; 0.90 [0.84, 0.97]) (Cmax: 0.23 vs. 0.23 ng/mL; 0.95 [0.88, 1.02]). In both studies, 90% CIs for ratios of AUC(0-tz) and Cmax were within the bioequivalence acceptance range (0.8-1.25). In SP1066, overall median adhesiveness scores were similar for cold chain (0.5 [range: 0-4]) and room temperature stable (0 [0-4]) formulations. These results demonstrated bioequivalence and indicated similar adhesiveness of the approved room temperature stable rotigotine patch with the original and cold chain patches. Potential limitations include the enrolment of healthy volunteers in the bioequivalence studies, as these individuals were likely to be younger than the general PD or RLS population.

Lower irritation microemulsion-based rotigotine gel: formulation optimization and in vitro and in vivo studies.

PubMed

Wang, Zheng; Mu, Hong-Jie; Zhang, Xue-Mei; Ma, Peng-Kai; Lian, Sheng-Nan; Zhang, Feng-Pu; Chu, Sheng-Ying; Zhang, Wen-Wen; Wang, Ai-Ping; Wang, Wen-Yan; Sun, Kao-Xiang

2015-01-01

Rotigotine is a potent and selective D1, D2, and D3 dopaminergic receptor agonist. Due to an extensive first-pass effect, it has a very low oral bioavailability (approximately 0.5% in rats). The present investigation aimed to develop a microemulsion-based hydrogel for transdermal rotigotine delivery with lower application site reactions. Pseudoternary phase diagrams were constructed to determine the region of oil in water (o/w)-type microemulsion. Central composite design was used to support the pseudoternary phase diagrams and to select homogeneous and stable microemulsions with an optimal amount of rotigotine permeation within 24 hours. In vitro skin permeation experiments were performed, using Franz diffusion cells, to compare rotigotine-loaded microemulsions with rotigotine solutions in oil. The optimized formulation was used to prepare a microemulsion-based hydrogel, which was subjected to bioavailability and skin irritancy studies. The selected formulations of rotigotine-loaded microemulsions had enhanced flux and permeation coefficients compared with rotigotine in oil. The optimum microemulsion contained 68% water, 6.8% Labrafil(®), 13.44% Cremophor(®) RH40, 6.72% Labrasol(®), and 5.04% Transcutol(®) HP; the drug-loading rate was 2%. To form a microemulsion gel, 1% Carbomer 1342 was added to the microemulsion. The bioavailability of the rotigotine-loaded microemulsion gel was 105.76%±20.52% with respect to the marketed rotigotine patch (Neupro(®)). The microemulsion gel irritated the skin less than Neupro. A rotigotine microemulsion-based hydrogel was successfully developed, and an optimal formulation for drug delivery was identified. This product could improve patient compliance and have broad marketability.

Effect of 24-h continuous rotigotine treatment on stationary and non-stationary locomotion in de novo patients with Parkinson disease in an open-label uncontrolled study.

PubMed

Serrao, Mariano; Ranavolo, Alberto; Conte, Carmela; Davassi, Chiara; Mari, Silvia; Fasano, Alfonso; Chini, Giorgia; Coppola, Gianluca; Draicchio, Francesco; Pierelli, Francesco

2015-11-01

The aim of this study was to investigate the effect of a rotigotine transdermal patch on stationary and non-stationary locomotion in de novo Parkinson disease (PD) patients in an open-label uncontrolled study. A 3-D gait analysis system was used to investigate four different locomotor tasks: steady-state linear walking, gait initiation, gait termination and 180°-turning. A series of gait variables were measured for each locomotor task. PD patients who received rotigotine treatment (4-8 mg) displayed: (1) increased step length, gait speed, cadence and arm oscillations, and reduced double support duration and step asymmetry during steady-state linear gait; (2) increased initial step length during gait initiation; (3) increased final step length and gait speed, and decreased stability index during gait termination; (4) decreased duration of turning and head-pelvis delays during 180°-turning. The main finding that emerges from the present study is that the dopamine agonist rotigotine can improve various aspects of gait in de novo PD patients.

A Randomized Controlled Exploratory Pilot Study to Evaluate the Effect of Rotigotine Transdermal Patch on Parkinson's Disease-Associated Chronic Pain.

PubMed

Rascol, Olivier; Zesiewicz, Theresa; Chaudhuri, K Ray; Asgharnejad, Mahnaz; Surmann, Erwin; Dohin, Elisabeth; Nilius, Sigrid; Bauer, Lars

2016-07-01

Pain is a troublesome nonmotor symptom of Parkinson's disease (PD). This double-blind exploratory pilot study (NCT01744496) was the first to specifically investigate the effect of a dopamine agonist on PD-associated pain as primary outcome. Patients with advanced PD (ie, receiving levodopa) and at least moderate PD-associated chronic pain (≥3 months, ≥4 points on 11-point Likert pain scale) were randomized to rotigotine (optimal/maximum dose ≤16 mg/24h) or placebo and maintained for 12 weeks. Primary efficacy variable was change in pain severity (Likert pain scale) from baseline to end of maintenance. Secondary variables included percentage of responders (≥2-point Likert pain scale reduction), King's PD Pain Scale (KPPS) domains, and PD Questionnaire (PDQ-8). Statistical analyses were exploratory. Of 68 randomized patients, 60 (rotigotine, 30; placebo, 30) were evaluable for efficacy. A numerical improvement in pain was observed in favor of rotigotine (Likert pain scale: least-squares mean [95%CI] treatment difference, -0.76 [-1.87 to 0.34]; P = .172), and proportion of responders was 18/30 (60%) rotigotine vs 14/30 (47%) placebo. An ∼2-fold numerical improvement in KPPS domain "fluctuation-related pain" was observed with rotigotine vs placebo. Rotigotine improved PDQ-8 vs placebo (-8.01 [-15.56 to -0.46]; P = .038). These results suggest rotigotine may improve PD-associated pain; a large-scale confirmatory study is needed. © 2015, The American College of Clinical Pharmacology.

Evaluation of rotigotine transdermal patch for the treatment of depressive symptoms in patients with Parkinson's disease.

PubMed

Chung, Sun Ju; Asgharnejad, Mahnaz; Bauer, Lars; Ramirez, Francisco; Jeon, Beomseok

2016-08-01

To evaluate the dopamine receptor agonist, rotigotine, for improving depressive symptoms in patients with Parkinson's disease (PD). Patients were randomized 1:1 to rotigotine or placebo, titrated for ≤7 weeks, and maintained at optimal/maximum dose for 8-weeks. Primary efficacy variable: 17- item Hamilton Depression Rating Scale (HAM-D 17) total score change from baseline to end-of-maintenance. Secondary variables: changes in Beck Depression Inventory-II, Unified Parkinson's Disease Rating Scale (UPDRS) II (activities of daily living [ADL]) and III (motor) subscores, UPDRS II+III total, patient-rated Apathy Scale (AS), and Snaith-Hamilton Pleasure Scale. Of 380 patients randomized, 149/184 (81.0%) rotigotine-treated and 164/196 (83.7%) placebo-treated patients completed the study. mean (±SD) age 65.2 (±8.5) years; time since PD-diagnosis 2.74 (±3.08) years; 42.6% male. The treatment difference (LS mean [95% CI]) in change from baseline HAM-D 17 was -1.12 (-2.56, 0.33; p = 0.1286). UPDRS II, III, II+III and AS scores improved numerically with rotigotine versus placebo. Common adverse events with higher incidence with rotigotine: nausea, application/instillation site reactions, vomiting, and pruritus. Forty-one (10.8%) patients discontinued owing to adverse events (25 rotigotine/16 placebo). No statistically significant improvement in depressive symptoms were observed with rotigotine versus placebo. ADL, motor function, and patient-rated apathy improved numerically. ClinicalTrials.gov: NCT01523301.

Lower irritation microemulsion-based rotigotine gel: formulation optimization and in vitro and in vivo studies

PubMed Central

Wang, Zheng; Mu, Hong-Jie; Zhang, Xue-Mei; Ma, Peng-Kai; Lian, Sheng-Nan; Zhang, Feng-Pu; Chu, Sheng-Ying; Zhang, Wen-Wen; Wang, Ai-Ping; Wang, Wen-Yan; Sun, Kao-Xiang

2015-01-01

Background Rotigotine is a potent and selective D1, D2, and D3 dopaminergic receptor agonist. Due to an extensive first-pass effect, it has a very low oral bioavailability (approximately 0.5% in rats). Purpose The present investigation aimed to develop a microemulsion-based hydrogel for transdermal rotigotine delivery with lower application site reactions. Methods Pseudoternary phase diagrams were constructed to determine the region of oil in water (o/w)-type microemulsion. Central composite design was used to support the pseudoternary phase diagrams and to select homogeneous and stable microemulsions with an optimal amount of rotigotine permeation within 24 hours. In vitro skin permeation experiments were performed, using Franz diffusion cells, to compare rotigotine-loaded microemulsions with rotigotine solutions in oil. The optimized formulation was used to prepare a microemulsion-based hydrogel, which was subjected to bioavailability and skin irritancy studies. Results The selected formulations of rotigotine-loaded microemulsions had enhanced flux and permeation coefficients compared with rotigotine in oil. The optimum microemulsion contained 68% water, 6.8% Labrafil®, 13.44% Cremophor® RH40, 6.72% Labrasol®, and 5.04% Transcutol® HP; the drug-loading rate was 2%. To form a microemulsion gel, 1% Carbomer 1342 was added to the microemulsion. The bioavailability of the rotigotine-loaded microemulsion gel was 105.76%±20.52% with respect to the marketed rotigotine patch (Neupro®). The microemulsion gel irritated the skin less than Neupro. Conclusion A rotigotine microemulsion-based hydrogel was successfully developed, and an optimal formulation for drug delivery was identified. This product could improve patient compliance and have broad marketability. PMID:25609965

Long-term safety and tolerability of rotigotine transdermal system in patients with early-stage idiopathic Parkinson's disease: a prospective, open-label extension study.

PubMed

Elmer, Lawrence W; Surmann, Erwin; Boroojerdi, Babak; Jankovic, Joseph

2012-06-01

This prospective, open-label extension (SP702; NCT00594165) of a 6-month double-blind, randomized study investigated the long-term safety and tolerability of rotigotine transdermal system in early Parkinson's disease (PD). Patients with early-stage idiopathic PD received transdermal rotigotine for up to 6 years at optimal dose (up to 16 mg/24h). Adjunctive levodopa was allowed. Primary outcomes included adverse events (AEs) and extent of rotigotine exposure. Other outcomes included time to levodopa, incidence of dyskinesias, and efficacy using the Unified Parkinson's Disease Rating Scale (UPDRS) II+III total score. Of 217 patients entering the open-label study, 47% were still in the study upon closure; 24% withdrew because of AEs and 6% because of lack of efficacy. The median exposure to rotigotine was 1910 days (≈ 5 years, 3 months; range 1-2188 days). Most common AEs were somnolence (23% per patient-year), falls (17%), peripheral edema (14%), nausea (12%), and application site reactions (ASRs; 12%). 3% withdrew because of ASRs. 26% patients did not initiate levodopa; of those who did, fewer than half started levodopa in the first year. Dyskinesias were reported by 25% patients; the majority (83%) reported their first episode after initiating levodopa. Mean UPDRS II+III total scores remained below double-blind baseline for up to 2 years of open-label treatment. This is the longest interventional study of rotigotine conducted to date. Transdermal rotigotine was generally well tolerated for up to 6 years; AEs reported were similar to those observed in shorter studies and led to discontinuation in only 24% patients. Copyright © 2012 Elsevier Ltd. All rights reserved.

Transdermal rotigotine for the perioperative management of Parkinson’s disease

PubMed Central

Kassubek, Jan; Odin, Per; Schwarz, Michael; Naumann, Markus; Häck, Hermann-Josef; Boroojerdi, Babak; Reichmann, Heinz

2010-01-01

Continuous delivery of antiparkinsonian medication during a perioperative period is desirable to avoid ‘off’-symptom complications in surgical patients with concomitant Parkinson’s disease (PD). Fourteen PD patients undergoing surgery under general anesthesia were switched from oral dopaminergic medication to transdermally delivered 24-h rotigotine (median dose 12 mg/24 h) for the perioperative period. Rotigotine treatment was considered feasible by patients, their anesthesiologists and neurologists with good control of PD symptoms and easy switching and re-switching of PD medication. PMID:20535621

Restless legs syndrome: differential diagnosis and management with rotigotine

PubMed Central

Merlino, Giovanni; Serafini, Anna; Robiony, Francesca; Valente, Mariarosaria; Gigli, Gian Luigi

2009-01-01

RLS is a common sleep disorder with distinctive clinical features. The prevalence of RLS in Caucasians and North Americans ranges from 5% to 10%. However, only some of these subjects (almost the 3% of the general population) report being affected by a frequent and severe form of the sleep disorder. RLS is diagnosed clinically by means of four internationally recognized criteria that summarize the main characteristics of the sleep disorder. Besides the essential criteria, supportive and associated features of RLS have been established by experts in order to help physicians treat patients with doubtful symptoms. Several clinical conditions may mimic this sleep disorder. In order to increase the sensibility and specificity of RLS diagnosis, doctors should perform a meticulous patient history and then an accurate physical and neurological examination. Dopamine agonists are recognized as the preferred first-line treatment for RLS. Rotigotine is a non-ergoline dopamine agonist with selectivity for D1, D2 and D3 receptors. The drug is administered via transdermal patches which release rotigotine for 24 hours. Four clinical trials demonstrated that this compound is able to improve RLS symptomatology with few and moderate adverse events. Head to head trials are required to compare the efficacy and tolerability of rotigotine with other dopamine agonists administered via oral intake. Rotigotine has been approved by the FDA and EMEA for Parkinson’s disease. For the treatment of moderate to severe idiopathic RLS, rotigotine has been recommended for approval by the EMEA and is under review by the FDA. PMID:19557102

Efficacy of Rotigotine at Different Stages of Parkinson's Disease Symptom Severity and Disability: A Post Hoc Analysis According to Baseline Hoehn and Yahr Stage.

PubMed

Giladi, Nir; Nicholas, Anthony P; Asgharnejad, Mahnaz; Dohin, Elisabeth; Woltering, Franz; Bauer, Lars; Poewe, Werner

2016-10-19

The efficacy of rotigotine has been demonstrated in studies of patients with early (i.e. not receiving levodopa) and advanced (i.e. not adequately controlled on levodopa; average 2.5 h/day in 'off' state) Parkinson's disease (PD). To further investigate the efficacy of rotigotine transdermal patch across different stages of PD symptom severity and functional disability, according to baseline Hoehn and Yahr (HY) staging. Post hoc analysis of six placebo-controlled studies of rotigotine in patients with early PD (SP506, SP512, SP513; rotigotine ≤8 mg/24 h) or advanced-PD (CLEOPATRA-PD, PREFER, SP921; rotigotine ≤16 mg/24 h). Data were pooled and analyzed according to baseline HY stage (1, 2, 3 or 4) for change from baseline to end of maintenance in Unified Parkinson's Disease Rating Scale (UPDRS) II (activities of daily living), UPDRS III (motor) and UPDRS II+III; statistical tests are exploratory. Data were available for 2057 patients (HY 1 : 262; HY 2 : 1230; HY 3 : 524; HY 4 : 41). Patients at higher HY stages were older, had a longer time since PD diagnosis and higher baseline UPDRS II+III scores vs patients at lower HY stages. Rotigotine improved UPDRS II+III versus placebo for each individual HY stage (p < 0.05 for each HY stage), with treatment differences increasing with increasing HY stages. Similar results were observed for UPDRS II and UPDRS III. This post hoc analysis suggests that rotigotine may be efficacious across a broad range of progressive stages of PD symptom severity and functional disability (HY stages 1-4).

An observational study of rotigotine transdermal patch and other currently prescribed therapies in patients with Parkinson's disease.

PubMed

Müller, Thomas; Tolosa, Eduardo; Badea, Letitia; Asgharnejad, Mahnaz; Grieger, Frank; Markowitz, Michael; Nondonfaz, Xavier; Bauer, Lars; Timmermann, Lars

2018-06-01

Real-world data from large cohorts of patients with Parkinson's disease on the long-term effectiveness of different dopamine-substituting drug therapies are rare. The objective of this study was to obtain information on real-world management of PD with dopamine-substituting drugs. SP0854 (NCT00599339) was a prospective, multicenter, non-interventional, multiple-cohort, post-authorization safety study of rotigotine versus other dopaminergic therapies. The study was also part of a European Medicines Agency risk-management plan for the non-ergoline dopamine agonist rotigotine, focussing on cardiovalvular fibrosis. Eligible patients requiring monotherapy with a dopamine agonist, or levodopa in combination with a dopamine agonist were followed for ≤ 33 months; 1531 of 2195 patients completed the study. Mean motor scores improved for all dopamine-substituting treatments. Patients with more severe motor-symptoms/increased disability were more likely to receive levodopa alone or in combination with a DA at study onset. More patients who started on combination therapy with levodopa remained on this treatment versus those starting on dopaminergic monotherapy. This real-world study showed that the dopamine-substituting therapies were efficacious, with a safety profile consistent with that expected of dopaminergic treatments. Cardiovalvular pathology was rare and not found to be causally-related to rotigotine.

Rotigotine transdermal patch in Chinese patients with early Parkinson's disease: A randomized, double-blind, placebo-controlled pivotal study.

PubMed

Zhang, Zhen-Xin; Shang, Hui-Fang; Hu, Xingyue; Chen, Shengdi; Zhao, Zhongxin; Du, Xinlu; Surmann, Erwin; Bauer, Lars; Asgharnejad, Mahnaz

2016-07-01

Two phase3 studies (SP512; SP513) involving mostly Caucasian patients showed that rotigotine (≤8 mg/24 h) was efficacious and welltolerated in early-stage Parkinson's disease (PD). We report results from a phase 3 study (SP0914/NCT01646268) investigating rotigotine in Chinese patients with early-stage PD. Patients were randomized 1:1 to rotigotine or placebo, titrated over 1-4 weeks, maintained at optimal/maximum dose (≤8 mg/24 h) for 24 weeks. Primary efficacy variable: change in Unified Parkinson's Disease Rating Scale (UPDRS) II + III total score from Baseline to End-of-Maintenance. Secondary variables: UPDRS II + III responders (≥20% decrease in UPDRS II + III) and changes in UPDRS II (activities of daily living [ADL]) and III (motor examination) subscores. Of 247 patients randomized, 113/124 (91.1%) rotigotine- and 107/123 (87.0%) placebo-treated patients completed the study. mean (SD) age: 59.4 (10.2) years; time since PD diagnosis: 1.01 (1.22) years, 60.7% male. Rotigotine significantly improved UPDRS II + III total score (change from Baseline LSmean [95%CI] treatment difference, -4.82 [-7.18 to -2.45]; P < 0.0001). UPDRS II + III responder rates were higher with rotigotine (42.3% vs 22.3%; P = 0.0006). UPDRS II and III subscores improved with rotigotine (both subscores: P < 0.0005 vs. placebo). Most frequent adverse events (AEs): nausea (8.9% rotigotine, 3.3% placebo), dizziness (8.1%, 5.7%), pruritus (8.1%, 4.1%), somnolence (8.1%, 3.3%), erythema (6.5%, 1.6%), and vomiting (5.6%, 1.6%). Thirteen (5.3%) patients discontinued due to AEs (6 rotigotine, 7 placebo). Rotigotine was efficacious in Chinese patients with early-stage PD, providing benefits to control of ADL and motor function. Rotigotine was generally welltolerated, with similar AEs to those observed in Caucasian patients. Copyright © 2016 Elsevier Ltd. All rights reserved.

The safety and tolerability of rotigotine transdermal system over a 6-year period in patients with early-stage Parkinson's disease.

PubMed

Giladi, Nir; Boroojerdi, Babak; Surmann, Erwin

2013-09-01

This open-label extension (SP716; NCT00599196) of a 6-month, double-blind, randomized study (SP513) investigated the safety and tolerability of rotigotine transdermal system over up to ~6 years in patients with Parkinson's disease (PD; early-stage PD at double-blind enrollment). Eligible patients completing the 6-month study received optimal dose open-label rotigotine (≤ 16 mg/24 h) for up to ~6 years. Adjunctive levodopa was permitted. Primary outcomes included adverse events (AEs) and extent of rotigotine exposure. Analysis of adjunctive levodopa use, dyskinesias [unified Parkinson's disease rating scale (UPDRS) IV], and efficacy (UPDRS II + III total score) were also assessed. Of 381 patients enrolled in the open-label extension, 52 % were still in the study at time of closure; 24 % withdrew because of AEs and 6 % because of lack of efficacy. Patients received rotigotine for a median duration of 1,564.5 days (~4 years, 3 months; range 5-2, 145 days). 69 % of patients started supplemental levodopa; median time to levodopa was 485 days (~1 year, 4 months). Most common AEs (% per patient-year) were somnolence (18 %), application site reactions (12 %), nausea (9 %), peripheral edema (7 %), and fall (7 %). AEs indicative of impulsive-compulsive behavior were recorded in 25 (7 %) patients. Dyskinesias were experienced by 65 (17 %) patients; the majority [47 of 65 (72 %)] reported first dyskinesia after starting levodopa. Mean UPDRS II + III total scores remained below double-blind baseline for 4 years (assessment of all patients). In conclusion, rotigotine was generally well tolerated for up to ~6 years in patients with early-stage PD. The AEs reported were in line with previous studies of rotigotine transdermal system, with typical dopaminergic side effects and application site reactions seen.

Patients' perception of Parkinson's disease-associated pain following initiation of rotigotine: a multicenter non-interventional study.

PubMed

Timmermann, Lars; Oehlwein, Christian; Ransmayr, Gerhard; Fröhlich, Holger; Will, Edgar; Schroeder, Hanna; Lauterbach, Thomas; Bauer, Lars; Kassubek, Jan

2017-01-01

To evaluate Parkinson's disease (PD)-associated pain as perceived by the patients (subjective characterization), and how this may change following initiation of rotigotine transdermal patch. SP1058 was a non-interventional study conducted in routine clinical practice in Germany and Austria in patients experiencing PD-associated pain (per the physician's assessment). Data were collected at baseline (ie, before rotigotine initiation) and at a routine visit after ≥25 days (-3 days allowed) of treatment on a maintenance dose of rotigotine (end of study [EoS]). Pain perception was assessed using the 12-item Pain Description List of the validated German Pain Questionnaire (each item ranked 0 = 'not true' to 3 = 'very true'). Primary effectiveness variable: change from baseline to EoS in the sum score of the 4 'affective dimension' items of the Pain Description List. Secondary effectiveness variables: change from baseline to EoS in Unified Parkinson's Disease Rating Scale (UPDRS) II, III, and II+III scores, and Parkinson's Disease Questionnaire (PDQ-8) total score (PD-related quality-of-life). Other variables included scores of the eight 'sensory dimension' items of the Pain Description List. Of 93 enrolled patients (mean [SD] age: 71.1 [9.0] years; male: 48 [52%]), 77 (83%) completed the study, and 70 comprised the full analysis set. The mean (SD) change from baseline in the sum score of the four 'affective dimension' items was -1.3 (2.8) indicating a numerical improvement (baseline: 3.9 [3.4]). In the 'sensory dimension', pain was mostly perceived as 'pulling' at baseline (49/70 [70%]); 'largely true'/'very true'). Numerical improvements were observed in all UPDRS scores (mean [SD] change in UPDRS II+III: -5.3 [10.5]; baseline: 36.0 [15.9]), and in PDQ-8 total score (-2.0 [4.8]; baseline: 10.7 [5.9]). Adverse drug reactions were consistent with dopaminergic stimulation and transdermal administration. The perception of the 'affective dimension' of PD-associated pain numerically improved in patients treated with rotigotine. ClinicalTrials.gov identifier: NCT01606670; https://clinicaltrials.gov/ct2/show/NCT01606670?term=NCT01606670&rank=1.

Transdermal rotigotine in early stage Parkinson's disease: a randomized, double-blind, placebo-controlled trial.

PubMed

Mizuno, Yoshikuni; Nomoto, Masahiro; Kondo, Tomoyoshi; Hasegawa, Kazuko; Murata, Miho; Takeuchi, Masahiro; Ikeda, Junji; Tomida, Takayuki; Hattori, Nobutaka

2013-09-01

We conducted a randomized, double-blind, placebo-controlled trial to determine the safety and efficacy of transdermal rotigotine at doses up to 16 mg/24 hours in patients with early stage Parkinson's disease (PD) in Japan. Patients received once-daily rotigotine 2 to 16 mg/24 hours (mean dose, 12.8 mg/24 hours; n = 82) or placebo (n = 90) for 12 weeks. The primary endpoint was the change in Unified Parkinson's Disease Rating Scale (UPDRS) part II (activities of daily living) and part III (motor function) scores from baseline to the end of treatment. The mean (± standard deviation) changes in UPDRS part II and III scores were -8.4 ± 9.7 in the rotigotine group and -4.1 ± 8.2 in the placebo group and were significantly different (P = 0.002). More patients in the rotigotine group than in the placebo group had a ≥ 20% score reduction. No serious drug-related adverse events were reported. Rotigotine at doses up to 16 mg/24 hours was well tolerated and improved function in patients with early stage PD. © 2013 International Parkinson and Movement Disorder Society.

[Efficacy of Topical Agents for Symptomatic Treatment of Rotigotine Patch-Induced Skin Disorders].

PubMed

Yasutaka, Yuki; Fujioka, Shinsuke; Shibaguchi, Hirotomo; Kiyomi, Fumiaki; Hara, Koyomi; Ogata, Kentaro; Tsuboi, Yoshio; Kamimura, Hidetoshi

2017-09-01

Since the effect of a percutaneous absorption-type dopamine agonist (DA) preparation, rotigotine patch, stably persists by once-a-day application, this dosage form is appropriate for Parkinson's disease patients showing levodopa induced wearing off phenomenon. On the other hand, skin disorders, mainly application site reaction, are characteristic problems associated with use of the patch. In this study, to clarify the influence of a topical agent used to prevent or treat rotigotine patch-induced skin disorder on continuation of the patch application, patients who started rotigotine patch application at our hospital were retrospectively surveyed. The one-year continuation rate of rotigotine patch application was 37.3% (53 of 142 cases). It was insufficient to prevent skin disorders, only by the pre-treatment of a moisturizing agent alone. Regarding the effective rate of topical agents used to treat skin disorders, that of very strong-class steroids was 89.5%, being significantly higher than those of weak steroids, moisturizing agents, and antihistamines. It was suggested that for countermeasures against rotigotine patch-induced skin disorders, treatment with very strong-class steroids for external use early after development of skin disorders is more effective than preventive treatment with topical agents regardless of the type. (Received March 30, 2017; Accepted May 16, 2017; Published September 1, 2017).

A method to switch from oral dopamine agonists to rotigotine in patients with restless legs syndrome and mild augmentation.

PubMed

Winkelman, John W; Mackie, Susan E; Mei, Leslie A; Platt, Samuel; Schoerning, Laura

2016-08-01

We examined the short- and long-term efficacy and tolerability of a cross-titration algorithm from oral dopamine agonists to the rotigotine transdermal patch in patients dissatisfied with their restless legs syndrome (RLS) treatment, predominantly with mild augmentation. Patients with RLS (n = 20) were recruited at a single site. The cross-titration consisted of decreasing oral dopaminergic agents (ropinirole by 1 mg or pramipexole by 0.25 mg) and increasing rotigotine by 1 mg every two days. Efficacy and adverse events (AEs) were assessed at one, three, six and 12 months after the switch. Patients had moderate-severe RLS symptoms at the baseline (mean international restless legs syndrome (IRLS) score 19.4 ± 5.5); 85% had augmentation and 45% reported afternoon RLS symptoms. The baseline mean pramipexole equivalent dose was 0.6 ± 0.3 mg. At Week 5, 85% (17/20) had successfully switched from their oral dopamine agonist to rotigotine (mean dose 2.5 ± 0.6 mg; change in IRLS score: -6.7 ± 8.4, p = 0.002); 14 patients were CGI-I responders (much or very much improved). Three patients withdrew due to lack of efficacy. Twelve months after cross-titration, 10 patients continued on rotigotine, of whom four required either higher doses of rotigotine or supplemental RLS medication compared with their optimal Week 5 dose; five patients withdrew due to AEs and two due to lack of efficacy. A cross-titration to rotigotine was efficacious after five weeks in 70% of patients dissatisfied with RLS treatment, most of whom had mild augmentation. At one year following the medication switch, 50% had discontinued rotigotine due to lack of continued efficacy or side effects. Copyright © 2016 Elsevier B.V. All rights reserved.

Management of augmentation of restless legs syndrome with rotigotine: a 1-year observational study.

PubMed

Trenkwalder, Claudia; Canelo, Monica; Lang, Michael; Schroeder, Hanna; Kelling, Daniela; Berkels, Reinhard; Schollmayer, Erwin; Heidbrede, Tanja; Benes, Heike

2017-02-01

The aim of this study is to assess the effect of switching to rotigotine transdermal patch on severity of restless legs syndrome (RLS) in patients who experienced acute augmentation with previous oral dopaminergics. In this 13-month observational study, adults with moderate-to-severe RLS and augmentation were switched to rotigotine per the physician's independent decision. Assessments included Clinical Global Impression severity score (CGI-1); (primary), treatment regimen for switching (secondary), RLS-6, International RLS Study Group Rating Scale (IRLS), and augmentation severity rating scale (ASRS). A total of 99 patients received rotigotine, of whom 46 completed observational period, and 43 were assessed for effectiveness. A total of 5 patients switched to rotigotine after a >1-day drug holiday, 23 switched overnight, 9 had an overlapping switch, and 6 received ongoing oral dopaminergics with rotigotine for ≥28 days. Of the 99 patients, 57 took concomitant RLS medications (excluding switching medications) on at least 1 day. At the final visit, median change in CGI-1 (Hodges-Lehman estimate [95% CI]) was -2.0 (-2.5, -1.50); 37 of the 43 patients improved by ≥1 CGI-1 category, and 16 of 43 were responders (≥50% improvement). RLS-6 and IRLS scores also improved. Patients had median ASRS of 0 at the final visit indicating "no worsening/occurrence of augmentation." ASRS item 1 showed a shift in mean time of symptom onset (24-h clock) from 12:38 (baseline) to 18:25 (final visit). Most common reasons for withdrawal of rotigotine were adverse events (26 patients) and lack of efficacy (14 patients). Switching from oral therapies to rotigotine was effective in improving RLS symptoms in 37 of the 43 patients (from the original population of 99 patients) who remained in the study over 13 months. ClinicalTrials.govNCT01386944. Copyright © 2015 Elsevier B.V. All rights reserved.

Efficacy of Rotigotine at Different Stages of Parkinson’s Disease Symptom Severity and Disability: A Post Hoc Analysis According to Baseline Hoehn and Yahr Stage

PubMed Central

Giladi, Nir; Nicholas, Anthony P.; Asgharnejad, Mahnaz; Dohin, Elisabeth; Woltering, Franz; Bauer, Lars; Poewe, Werner

2016-01-01

Background: The efficacy of rotigotine has been demonstrated in studies of patients with early (i.e. not receiving levodopa) and advanced (i.e. not adequately controlled on levodopa; average 2.5 h/day in ‘off’ state) Parkinson’s disease (PD). Objective: To further investigate the efficacy of rotigotine transdermal patch across different stages of PD symptom severity and functional disability, according to baseline Hoehn and Yahr (HY) staging. Methods: Post hoc analysis of six placebo-controlled studies of rotigotine in patients with early PD (SP506, SP512, SP513; rotigotine ≤8 mg/24 h) or advanced-PD (CLEOPATRA-PD, PREFER, SP921; rotigotine ≤16 mg/24 h). Data were pooled and analyzed according to baseline HY stage (1, 2, 3 or 4) for change from baseline to end of maintenance in Unified Parkinson’s Disease Rating Scale (UPDRS) II (activities of daily living), UPDRS III (motor) and UPDRS II+III; statistical tests are exploratory. Results: Data were available for 2057 patients (HY 1 : 262; HY 2 : 1230; HY 3 : 524; HY 4 : 41). Patients at higher HY stages were older, had a longer time since PD diagnosis and higher baseline UPDRS II+III scores vs patients at lower HY stages. Rotigotine improved UPDRS II+III versus placebo for each individual HY stage (p < 0.05 for each HY stage), with treatment differences increasing with increasing HY stages. Similar results were observed for UPDRS II and UPDRS III. Conclusions: This post hoc analysis suggests that rotigotine may be efficacious across a broad range of progressive stages of PD symptom severity and functional disability (HY stages 1–4). PMID:27567886

Impulse control disorder related behaviours during long-term rotigotine treatment: a post hoc analysis.

PubMed

Antonini, A; Chaudhuri, K R; Boroojerdi, B; Asgharnejad, M; Bauer, L; Grieger, F; Weintraub, D

2016-10-01

Dopamine agonists in Parkinson's disease (PD) are associated with impulse control disorders (ICDs) and other compulsive behaviours (together called ICD behaviours). The frequency of ICD behaviours reported as adverse events (AEs) in long-term studies of rotigotine transdermal patch in PD was evaluated. This was a post hoc analysis of six open-label extension studies up to 6 years in duration. Analyses included patients treated with rotigotine for at least 6 months and administered the modified Minnesota Impulse Disorders Interview. ICD behaviours reported as AEs were identified and categorized. For 786 patients, the mean (±SD) exposure to rotigotine was 49.4 ± 17.6 months. 71 (9.0%) patients reported 106 ICD AEs cumulatively. Occurrence was similar across categories: 2.5% patients reported 'compulsive sexual behaviour', 2.3% 'buying disorder', 2.0% 'compulsive gambling', 1.7% 'compulsive eating' and 1.7% 'punding behaviour'. Examining at 6-month intervals, the incidence was relatively low during the first 30 months; it was higher over the next 30 months, peaking in the 54-60-month period. No ICD AEs were serious, and 97% were mild or moderate in intensity. Study discontinuation occurred in seven (9.9%) patients with ICD AEs; these then resolved in five patients. Dose reduction occurred for 23 AEs, with the majority (73.9%) resolving. In this analysis of >750 patients with PD treated with rotigotine, the frequency of ICD behaviour AEs was 9.0%, with a specific incidence timeline observed. Active surveillance as duration of treatment increases may help early identification and management; once ICD behaviours are present rotigotine dose reduction may be considered. © 2016 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.

Augmentation in the treatment of restless legs syndrome with transdermal rotigotine.

PubMed

Beneš, Heike; García-Borreguero, Diego; Ferini-Strambi, Luigi; Schollmayer, Erwin; Fichtner, Andreas; Kohnen, Ralf

2012-06-01

To assess the risk of augmentation under treatment with the transdermally delivered dopamine agonist rotigotine for restless legs syndrome (RLS). Experts in RLS augmentation retrospectively reviewed data from two double-blind, placebo-controlled 6-month trials (745 rotigotine and 214 placebo subjects, NCT00136045 and NCT00135993) and from two open-label 1-year trials (620 rotigotine subjects, NCT00498108 and NCT00263068). All study visits were systematically evaluated applying the Max Planck Institute (MPI) criteria for the diagnosis of both augmentation and clinically relevant augmentation. MPI criteria for augmentation were met on at least one visit by 8.2% of all subjects in the double-blind trials with 12 subjects meeting the criteria for clinically relevant augmentation: 11 under rotigotine (1.5%) and one under placebo treatment. In the open-label trials, 9.7% of all subjects met the MPI criteria for augmentation and 2.9% met the criteria for clinically relevant augmentation. None of the patients treated with rotigotine for up to 1.5 years (double-blind plus open-label trial) discontinued prematurely owing to augmentation. Neither could dose-dependency or a time pattern for clinically relevant augmentation episodes be detected. Our analyses suggest that the risk for clinically relevant augmentation for the duration of up to 18 months of rotigotine treatment is low. Copyright © 2012 Elsevier B.V. All rights reserved.

Outcomes of rotigotine clinical trials: effects on motor and nonmotor symptoms of Parkinson's disease.

PubMed

Lyons, Kelly E; Pahwa, Rajesh

2013-08-01

Rotigotine transdermal system is a nonergot, 24-hour dopamine agonist approved for the treatment of early and advanced Parkinson's disease (PD). Recent studies have demonstrated significant improvements with rotigotine in motor function in early PD and significant improvements in daily off-time and motor function in advanced PD. In addition to motor improvements, nonmotor symptoms have been shown to be improved with rotigotine in both early and advanced PD. Rotigotine has been shown in large, controlled studies to be safe and efficacious for the treatment of motor and some nonmotor symptoms of early and advanced PD. Copyright © 2013 Elsevier Inc. All rights reserved.

Rotigotine in Combination with the MAO-B Inhibitor Selegiline in Early Parkinson's Disease: A Post Hoc Analysis.

PubMed

Giladi, Nir; Asgharnejad, Mahnaz; Bauer, Lars; Grieger, Frank; Boroojerdi, Babak

2016-04-02

Monoamine oxidase B (MAO-B) inhibitors and dopamine receptor agonists are common first-line treatment options in early Parkinson's disease (PD). To evaluate the efficacy and safety of rotigotine transdermal patch as an add-on therapy to an MAO-B inhibitor in patients with early-PD. In two Phase III, randomized, double-blind, placebo-controlled studies in early-PD (SP512, SP513), patients were randomized to rotigotine (titrated to optimal dose ≤8 mg/24 h) or placebo, and maintained for 24 (SP512) or 33 (SP513) weeks. Post hoc analyses were performed on pooled data for patients receiving an MAO-B inhibitor (selegiline) at a stable dose at randomization and throughout the studies, with groups defined as "Selegiline+Rotigotine" and "Selegiline+Placebo". Outcome measures included change from baseline in Unified Parkinson's Disease Rating Scale (UPDRS) II (activities of daily living), III (motor), UPDRS II+III and responders (patients achieving ≥20%, ≥25% or ≥30% decrease in UPDRS II+III). As post hoc analyses, p-values are exploratory. 130 patients were evaluable for efficacy analyses ("Selegiline+Rotigotine": 84, "Selegiline+Placebo": 46). Combined treatment with rotigotine and selegiline improved UPDRS III and UPDRS II+III scores versus selegiline alone (LS-mean [95% CI] treatment difference for UPDRS III: -4.89 [-7.87 to -1.91], p = 0.0015; for UPDRS II+III: -5.76 [-9.71 to -1.82], p = 0.0045). Higher proportion of patients in the "Selegiline+Rotigotine" group were classified as ≥20%, ≥25% or ≥30% responders (all p < 0.001). Combined treatment appeared more effective in patients aged ≤65 years versus > 65 years (although patient numbers in the subgroups were low). Adverse event profile was consistent with the known safety profile of rotigotine. In these post hoc analyses, adjunctive treatment with rotigotine in patients already receiving an MAO-B inhibitor improved UPDRS II+III score; this appeared to be largely driven by improvements in the motor aspects of PD.

Effects of rotigotine transdermal patch in patients with Parkinson's disease presenting with non-motor symptoms - results of a double-blind, randomized, placebo-controlled trial.

PubMed

Antonini, A; Bauer, L; Dohin, E; Oertel, W H; Rascol, O; Reichmann, H; Schmid, M; Singh, P; Tolosa, E; Chaudhuri, K Ray

2015-10-01

Non-motor symptoms (NMS) of Parkinson's disease (PD) have a major impact on health-related quality of life. This is the first randomized controlled trial to use the NMS Scale (NMSS) as a primary outcome to assess treatment effects on NMS in PD. In this double-blind trial (NCT01300819), patients with PD and a total NMSS score ≥40 were randomized (2:1) to rotigotine or placebo, titrated over 1-7 weeks to optimal dose (≤8 mg/24 h for patients not receiving levodopa, ≤16 mg/24 h for patients receiving levodopa), maintained for 12 weeks. The primary outcome was change in NMSS total score from baseline to end of maintenance. Secondary outcomes were the nine NMSS domains, Unified Parkinson's Disease Rating Scale (UPDRS) III (motor) and the 39-item Parkinson's Disease Questionnaire (PDQ-39). In total, 283/349 (81.1%) randomized patients completed the trial; 211 rotigotine and 122 placebo were included in the full analysis set. The NMSS total score decreased by 23 (rotigotine) and 19 (placebo) points; the treatment difference was not statistically significant (-3.58; 95% confidence interval -8.43, 1.26; P = 0.147). Numerically greater than placebo improvements were detected in the 'mood/apathy' and 'miscellaneous' NMSS domains (P < 0.05). Treatment differences in UPDRS III (-2.60; -4.27, -0.92; P = 0.002) and PDQ-39 (-2.79; -5.21, -0.37; P = 0.024) favoured rotigotine. Adverse events reported more frequently with rotigotine were nausea, application site reactions, somnolence and headache. Rotigotine improvement in the multi-domain NMSS total score was not superior to placebo. A different sensitivity of individual NMSS domains to dopaminergic therapy and a large placebo effect may have contributed to these findings. © 2015 EAN.

Effects of long-term treatment with rotigotine transdermal system on dyskinesia in patients with early-stage Parkinson's disease.

PubMed

Giladi, Nir; Ghys, Liesbet; Surmann, Erwin; Boroojerdi, Babak; Jankovic, Joseph

2014-12-01

In two 6-month, double-blind, placebo-controlled studies, rotigotine transdermal system was well-tolerated and efficacious monotherapy in early-stage PD. This post hoc analysis of the long-term open-label extensions (NCT00594165; NCT00599196) of these studies assessed incidence and severity of dyskinesia in participants treated with rotigotine, with or without concomitant levodopa, for up to 6 years. Open-label rotigotine was titrated to optimal dose (≤16 mg/24 h). Concomitant levodopa was permitted. Dyskinesia data, recorded using the Unified Parkinson's Disease Rating Scale Part IV, were pooled from the two open-label studies. Of 596 participants who received open-label rotigotine, 299 (50%) remained at trial closure; no patient discontinued due to dyskinesia. In the two studies, median exposure to rotigotine was 1910 days (∼5 years, 3 months), and 1564.5 days (∼4 years, 3 months). During up to 6 years of open-label rotigotine, 423/596 (71%) received levodopa. Dyskinesias were reported in 115/596 (19%) participants, 90/115 (78%) of who developed dyskinesia after levodopa was added; 25 reported dyskinesia in the absence of levodopa (includes patients who never received open-label levodopa, and those who reported dyskinesia before starting concomitant levodopa). Dyskinesia severity data were available for 107 of the 115 participants. In 56/107 (52%) participants, dyskinesia was considered 'not disabling' for all occurrences; the worst-case severity was 'mildly disabling' for 33/107 (31%), and 'moderately' or 'severely disabling' for 18/107 (17%; 3% of total participants). During treatment with rotigotine in patients with PD for up to 6 years the incidence of dyskinesia was low, and the dyskinesia was generally 'not disabling' or 'mildly disabling'. Copyright © 2014 Elsevier Ltd. All rights reserved.

Effects of rotigotine on daytime symptoms in patients with primary restless legs syndrome: a randomized, placebo-controlled study.

PubMed

Garcia-Borreguero, Diego; Allen, Richard; Hudson, John; Dohin, Elisabeth; Grieger, Frank; Moran, Kimberly; Schollmayer, Erwin; Smit, René; Winkelman, John

2016-01-01

This 12 week double-blind, placebo-controlled study (ClinicalTrials.gov: NCT01569464) was conducted to evaluate the effects of rotigotine transdermal patch on daytime symptoms in patients with idiopathic restless legs syndrome (RLS). Adult patients with moderate-to-severe RLS were randomized to rotigotine (optimal dose: 1-3 mg/24 h) or placebo. A modified four-assessment version (4:00 pm, 6:00 pm, 8:00 pm, and 10:00 pm) of the Multiple Suggested Immobilization Test (m-SIT) was performed at baseline and end of 4 week maintenance (EoM). Primary study outcomes were change from baseline to EoM in International Restless Legs Syndrome Rating Scale (IRLS) and in average of means for the m-SIT Discomfort Scale (m-SIT-DS) (combined average of mean values from each of the individual assessments). Secondary outcomes included average of means of Periodic Limb Movement during Wakefulness Index (PLMWI; PLM/hour) for the combination of m-SIT. A total of 150 patients were randomized and 137 (rotigotine: 92/101 [91.1%]; placebo: 45/49 [91.8%]) completed maintenance. All 150 randomized patients were assessed for efficacy. At EoM, mean change in IRLS was -14.9 ± 9.3 with rotigotine vs. -12.7 ± 7.6 with placebo (ANCOVA, LS mean treatment difference [95% CI]: -0.27 [-2.96, 2.42]; p = 0.8451). Changes in average of means of m-SIT-DS values of each individual SIT were comparable with rotigotine (-2.68 ± 2.31) vs. placebo (-2.62 ± 2.61) (ANCOVA, LS mean treatment difference [95% CI]: 0.07 [-0.61, 0.75]; p = 0.8336) and comparable reductions in PLMWI were observed in both treatment groups (8.34 [-8.50, 25.17]; p = 0.3290). Rotigotine was generally well tolerated. Application site reactions (rotigotine: 20 patients [19.8%]; placebo: 4 [8.2%]) and nausea (16 [15.8%]; 3 [6.1%]) were the most common AEs. Rotigotine was beneficial in improving overall RLS symptom severity (assessed by IRLS) and RLS symptom severity at various times of the day (m-SIT-DS); however, superiority to placebo was not established.

Rotigotine transdermal system as add-on to oral dopamine agonist in advanced Parkinson's disease: an open-label study.

PubMed

Kim, Jong-Min; Chung, Sun Ju; Kim, Jae Woo; Jeon, Beom Seok; Singh, Pritibha; Thierfelder, Stephan; Ikeda, Junji; Bauer, Lars

2015-02-28

Achieving optimal symptom control with minimal side effects is a major goal in clinical practice. Dual-agent dopamine receptor agonist (DA) therapy in Parkinson's disease (PD) may represent a promising approach to treatment, as the combination of different pharmacokinetic/pharmacological profiles may result in a lesser need for high dosages and, accordingly, may be well tolerated. The objective of the current study was to investigate safety and efficacy of rotigotine transdermal system as add-on to oral DA in patients with advanced PD inadequately controlled with levodopa and low-dose oral DA. PD0015 was an open-label, multinational study in patients with advanced-PD and sleep disturbance or early-morning motor impairment. Patients were titrated to optimal dose rotigotine (≤8 mg/24 h) over 1-4 weeks and maintained for 4-7 weeks (8-week treatment). Dosage of levodopa and oral DA (pramipexole ≤1.5 mg/day, ropinirole ≤6.0 mg/day) was stable. Primary variable was Clinical Global Impressions (CGI) item 4: side effects, assessing safety. Other variables included adverse events (AEs), Patient Global Impressions of Change (PGIC), Unified Parkinson's Disease Rating Scale (UPDRS) II and III, Parkinson's Disease Sleep Scale (PDSS-2), Pittsburgh Sleep Quality Index (PSQI), and "off" time. Of 90 patients who received rotigotine, 79 (88%) completed the study; 5 (6%) withdrew due to AEs. Most (83/89; 93%) had a CGI-4 score <3 indicating that rotigotine add-on therapy did not interfere with functioning; 6 (7%) experienced drug-related AEs that interfered with functioning (score ≥3). AEs occurring in ≥5% were application site pruritus (13%), dizziness (10%), orthostatic hypotension (10%), nausea (8%), dyskinesia (8%), and nasopharyngitis (6%). Numerical improvements in motor function (UPDRS III), activities of daily living (UPDRS II), sleep disturbances (PDSS-2, PSQI), and reduction in "off" time were observed. The majority (71/88; 81%) improved on PGIC. Addition of rotigotine transdermal system to low-dose oral DA in patients with advanced-PD was feasible and may be associated with clinical benefit. ClinicalTrials.gov identifier NCT01723904 . Trial registration date: November 6, 2012.

The effects of transdermal rotigotine on non-motor symptoms of Parkinson's disease: a multicentre, observational, retrospective, post-marketing study.

PubMed

Valldeoriola, Francesc; Salvador, Antonio; Gómez-Arguelles, José Maria; Marey, José; Moya, Miguel; Ayuga, Ángel; Ramírez, Francisco

2018-04-01

This study evaluated the effect of ≥6 months of transdermal rotigotine on non-motor and motor symptoms of patients with advanced Parkinson's disease. The study was conducted in Spain between September 2011 and December 2012 (ClinicalTrials.gov: NCT01504529). The primary efficacy variable was the change from baseline in non-motor symptoms, as assessed by changes in Parkinson's Disease Non-Motor Symptoms Questionnaire total scores at 6 months. Secondary endpoints included the assessment of motor symptoms by Unified Parkinson's Disease Rating Scale III scores. Data from 378 patients (mean age: 70.2 years; 56.9% male) with Parkinson's disease receiving rotigotine from were collected. Mean disease duration was 6.1 years, and mean rotigotine treatment duration was 45.6 months. Rotigotine reduced non-motor symptoms by 14.6% (mean change from baseline in Parkinson's Disease Non-Motor Symptoms Questionnaire: -1.5 ± 3.4; p < 0.0001). The majority of patients (58.2%) had improved non-motor symptoms at 6 months. Comparing the baseline versus study end, fewer patients experienced events in the urinary (78.6% vs. 73.3%; p = 0.0066), sleep (82.8% vs. 72.8%; p < 0.0001) and mood/cognition (77.3% vs. 66.4%; p < 0.0001) domains of the Parkinson's Disease Non-Motor Symptoms Questionnaire. Mean motor symptoms were reduced from baseline by 8.0% (mean change from baseline in Unified Parkinson's Disease Rating Scale III: -2.6 ± 8.0; p < 0.0001). In clinical practice in Spain, rotigotine may be an effective treatment to reduce the non-motor and motor symptoms in patients with advanced Parkinson's disease.

Rotigotine in Combination with the MAO-B Inhibitor Selegiline in Early Parkinson’s Disease: A Post Hoc Analysis

PubMed Central

Giladi, Nir; Asgharnejad, Mahnaz; Bauer, Lars; Grieger, Frank; Boroojerdi, Babak

2016-01-01

Background: Monoamine oxidase B (MAO-B) inhibitors and dopamine receptor agonists are common first-line treatment options in early Parkinson’s disease (PD). Objective: To evaluate the efficacy and safety of rotigotine transdermal patch as an add-on therapy to an MAO-B inhibitor in patients with early-PD. Methods: In two Phase III, randomized, double-blind, placebo-controlled studies in early-PD (SP512, SP513), patients were randomized to rotigotine (titrated to optimal dose ≤8 mg/24 h) or placebo, and maintained for 24 (SP512) or 33 (SP513) weeks. Post hoc analyses were performed on pooled data for patients receiving an MAO-B inhibitor (selegiline) at a stable dose at randomization and throughout the studies, with groups defined as “Selegiline+Rotigotine” and “Selegiline+Placebo”. Outcome measures included change from baseline in Unified Parkinson’s Disease Rating Scale (UPDRS) II (activities of daily living), III (motor), UPDRS II+III and responders (patients achieving ≥20%, ≥25% or ≥30% decrease in UPDRS II+III). As post hoc analyses, p-values are exploratory. Results: 130 patients were evaluable for efficacy analyses (“Selegiline+Rotigotine”: 84, “Selegiline+Placebo”: 46). Combined treatment with rotigotine and selegiline improved UPDRS III and UPDRS II+III scores versus selegiline alone (LS-mean [95% CI] treatment difference for UPDRS III: –4.89 [–7.87 to –1.91], p = 0.0015; for UPDRS II+III: –5.76 [–9.71 to –1.82], p = 0.0045). Higher proportion of patients in the “Selegiline+Rotigotine” group were classified as ≥20%, ≥25% or ≥30% responders (all p < 0.001). Combined treatment appeared more effective in patients aged ≤65 years versus > 65 years (although patient numbers in the subgroups were low). Adverse event profile was consistent with the known safety profile of rotigotine. Conclusions: In these post hoc analyses, adjunctive treatment with rotigotine in patients already receiving an MAO-B inhibitor improved UPDRS II+III score; this appeared to be largely driven by improvements in the motor aspects of PD. PMID:27061066

Switch from oral pramipexole or ropinirole to rotigotine transdermal system in advanced Parkinson's disease: an open-label study.

PubMed

Chung, Sun Ju; Kim, Jong-Min; Kim, Jae Woo; Jeon, Beom Seok; Singh, Pritibha; Thierfelder, Stephan; Ikeda, Junji; Bauer, Lars

2015-05-01

Investigate safety, feasibility and efficacy of switching therapy in patients with advanced-stage Parkinson's disease (PD) inadequately controlled with pramipexole (≤ 3.5 mg/day) or ropinirole (≤ 14 mg/day) to rotigotine transdermal system (≤ 14 mg/24 h; dose adjustments ≤ 16 mg/24 h permitted). PD0009 (ClinicalTrials.gov: NCT01711866) was an open-label study in patients with advanced-stage PD receiving levodopa, and experiencing sleep disturbance or early-morning motor impairment. Pramipexole/ropinirole was switched to equivalent dose rotigotine overnight or in two stages. During the 4-week treatment period rotigotine dose adjustments were permitted (up to 16 mg/24 h). Primary variable: Clinical Global Impressions (CGI) item 4: side effects (assessing safety) at end of treatment. 79/87 (91%) patients completed the study; 2 (2%) withdrew due to adverse events (AEs). Most (84; 97%) had CGI item 4 score < 3 indicating switch did not interfere with functioning; three experienced drug-related AEs interfering with functioning (score = 3). 62% patients improved on Patient Global Impression of Change, assessing effectiveness. AEs occurring ≥ 5%: application site pruritus (10%), application site erythema (7%), dizziness (7%), dyskinesia (7%), erythema (6%), pruritus (6%). Unified Parkinson's Disease Rating Scale II and III, Parkinson's Disease Sleep Scale-2 and Pittsburgh Sleep Quality Index were unchanged. Numerical improvements in 'off' time, awakenings and nocturias were observed. Switch from pramipexole or ropinirole to rotigotine (up to 14 mg/24 h) was feasible and possibly associated with some benefit.

Rotigotine transdermal system and evaluation of pain in patients with Parkinson's disease: a post hoc analysis of the RECOVER study.

PubMed

Kassubek, Jan; Chaudhuri, Kallol Ray; Zesiewicz, Theresa; Surmann, Erwin; Boroojerdi, Babak; Moran, Kimberly; Ghys, Liesbet; Trenkwalder, Claudia

2014-03-06

Pain is a troublesome non-motor symptom of Parkinson's disease (PD). The RECOVER (Randomized Evaluation of the 24-hour Coverage: Efficacy of Rotigotine; Clintrials.gov: NCT00474058) study demonstrated significant improvements in early-morning motor function (UPDRS III) and sleep disturbances (PDSS-2) with rotigotine transdermal system. Improvements were also reported on a Likert pain scale (measuring any type of pain). This post hoc analysis of RECOVER further evaluates the effect of rotigotine on pain, and whether improvements in pain may be attributable to benefits in motor function or sleep disturbance. PD patients with unsatisfactory early-morning motor impairment were randomized to optimal-dose (up to 16 mg/24 h) rotigotine or placebo, maintained for 4 weeks. Pain was assessed in the early-morning using an 11-point Likert pain scale (rated average severity of pain (of any type) over the preceding 12 hours from 0 [no pain] to 10 [worst pain ever experienced]). Post hoc analyses for patients reporting 'any' pain (pain score ≥1) at baseline, and subgroups reporting 'mild' (score 1-3), and 'moderate-to-severe' pain (score ≥4) were performed. Likert pain scale change from baseline in rotigotine-treated patients was further analyzed based on a UPDRS III/PDSS-2 responder analysis (a responder defined as showing a ≥30% reduction in early morning UPDRS III total score or PDSS-2 total score). As post hoc analyses, all p values presented are exploratory. Of 267 patients with Likert pain data (178 rotigotine, 89 placebo), 187 (70%) reported 'any' pain; of these 87 (33%) reported 'mild', and 100 (37%) 'moderate-to-severe' pain. Change from baseline pain scores decreased with rotigotine compared with placebo in patients with 'any' pain (-0.88 [95% CI: -1.56, -0.19], p = 0.013), and in the subgroup with 'moderate-to-severe' pain (-1.38 [-2.44, -0.31], p = 0.012). UPDRS III or PDSS-2 responders showed greater improvement in pain than non-responders. The results from this post hoc analysis of the RECOVER study suggest that pain was improved in patients with PD treated with rotigotine; this may be partly attributable to benefits in motor function and sleep disturbances. Prospective studies are warranted to investigate this potential benefit and the clinical relevance of these findings.

New frontiers in the pharmacological management of Parkinson's disease.

PubMed

Gottwald, Mildred D; Aminoff, Michael J

2008-07-01

Rasagiline, a selective COMT inhibitor, and rotigotine, a transdermal dopamine (D2) agonist, are two new agents that have been approved in the U.S. and Europe for the treatment of Parkinson's disease. Rasagiline is approved in the U.S. for both monotherapy and as an adjunct to levodopa. Its role in preventing disease progression has yet to be proven, but a large-scale study (ADAGIO) is under way. Rotigotine is approved for early-stage disease in Europe and the U.S. but is only approved in Europe for late-stage disease. It has recently been recalled due to the formation of insoluble crystals that interfere with absorption and may reduce its efficacy. Measures are being taken by the manufacturer to solve this problem. Istradefylline, and adenosine receptor antagonist, showed early promise but efficacy has not been demonstrated consistently, possibly due to higher than expected placebo effect. This has resulted in a nonapprovable letter from the FDA. With regard to perampanel, additional studies are needed to demonstrate safety and efficacy. Sanifamide and pardoprunox are agents that target multiple receptors that may modulate dyskinesia and other nonmotor symptoms in addition to motor symptoms, but phase III data are not yet available. Lusuride is an older dopamine agonist that has been reformulated as a transdermal patch and as a subcutaneous injection and may offer advantages in refractory patients with motor fluctuations. Sphermaine is a novel cell therapy designed to provide a localized source of levodopa directly to the brain. Gene therapies including AAV-GAD, AAV-AADC and AAV2-neurturin are in early stages of development in patients with advanced-stage disease but early safety data are promising. Copyright 2008 Prous Science, S.A.U. or its licensors. All rights reserved.

Preparation and characterization of sustained-release rotigotine film-forming gel.

PubMed

Li, Xiang; Zhang, Renyu; Liang, Rongcai; Liu, Wei; Wang, Chenhui; Su, Zhengxing; Sun, Fengying; Li, Youxin

2014-01-02

The aim of this study was to develop a film-forming gel formulation of rotigotine with hydroxypropyl cellulose (HPC) and Carbomer 934. To optimize this formulation, we applied the Response Surface Analysis technique and evaluated the gel's pharmacokinetic properties. The factors chosen for factorial design were the concentration of rotigotine, the proportion of HPC and Carbomer 934, and the concentration of ST-Elastomer 10. Each factor was varied over three levels: low, medium and high. The gel formulation was evaluated and optimized according to its accumulated permeation rate (Flux) through Franz-type diffusion. A pharmacokinetic study of rotigotine gel was performed with rabbits. The Flux of the optimized formulation reached the maximum (199.17 μg/cm(2)), which was 3% rotigotine and 7% ST-Elastomer 10 with optimal composition of HPC: Carbomer 934 (5:1). The bioavailability of the optimized formulation compared with intravenous administration was approximately 20%. A film-forming gel of rotigotine was successfully developed using the response surface analysis technique. The results of this study may be helpful in finding an optimum formulation for transdermal delivery of a drug. The product may improve patients' compliance and provide better efficacy. Copyright © 2013 Elsevier B.V. All rights reserved.

Rotigotine transdermal system and evaluation of pain in patients with Parkinson’s disease: a post hoc analysis of the RECOVER study

PubMed Central

2014-01-01

Background Pain is a troublesome non-motor symptom of Parkinson’s disease (PD). The RECOVER (Randomized Evaluation of the 24-hour Coverage: Efficacy of Rotigotine; Clintrials.gov: NCT00474058) study demonstrated significant improvements in early-morning motor function (UPDRS III) and sleep disturbances (PDSS-2) with rotigotine transdermal system. Improvements were also reported on a Likert pain scale (measuring any type of pain). This post hoc analysis of RECOVER further evaluates the effect of rotigotine on pain, and whether improvements in pain may be attributable to benefits in motor function or sleep disturbance. Methods PD patients with unsatisfactory early-morning motor impairment were randomized to optimal-dose (up to 16 mg/24 h) rotigotine or placebo, maintained for 4 weeks. Pain was assessed in the early-morning using an 11-point Likert pain scale (rated average severity of pain (of any type) over the preceding 12 hours from 0 [no pain] to 10 [worst pain ever experienced]). Post hoc analyses for patients reporting ‘any’ pain (pain score ≥1) at baseline, and subgroups reporting ‘mild’ (score 1–3), and ‘moderate-to-severe’ pain (score ≥4) were performed. Likert pain scale change from baseline in rotigotine-treated patients was further analyzed based on a UPDRS III/PDSS-2 responder analysis (a responder defined as showing a ≥30% reduction in early morning UPDRS III total score or PDSS-2 total score). As post hoc analyses, all p values presented are exploratory. Results Of 267 patients with Likert pain data (178 rotigotine, 89 placebo), 187 (70%) reported ‘any’ pain; of these 87 (33%) reported ‘mild’, and 100 (37%) ‘moderate-to-severe’ pain. Change from baseline pain scores decreased with rotigotine compared with placebo in patients with ‘any’ pain (-0.88 [95% CI: -1.56, -0.19], p = 0.013), and in the subgroup with ‘moderate-to-severe’ pain (-1.38 [-2.44, -0.31], p = 0.012). UPDRS III or PDSS-2 responders showed greater improvement in pain than non-responders. Conclusions The results from this post hoc analysis of the RECOVER study suggest that pain was improved in patients with PD treated with rotigotine; this may be partly attributable to benefits in motor function and sleep disturbances. Prospective studies are warranted to investigate this potential benefit and the clinical relevance of these findings. PMID:24602411

Outcomes from switching from rotigotine patch to alternate therapies in Parkinson's disease.

PubMed

Chitnis, Shilpa; Jaffery, Manall; Dewey, Richard B

2012-01-01

When rotigotine patch was withdrawn from the US market, we prospectively gathered data on efficacy, side effects, and daytime sedation on patients while taking rotigotine and following the switch to alternate therapies. Patients rated the efficacy of rotigotine on a scale of 0-5 (ineffective to extremely effective) and completed the Epworth Sleepiness Scale. At a follow-up visit a mean of 3 months later, patients rated their change in efficacy and side effects on a scale of -3 to +3 (much worse to much better) and again completed the Epworth Sleepiness Scale. Thirty-three patients were switched to a single alternate treatment. On rotigotine, the average efficacy score was 3.5, and after switching, the average change in efficacy was -0.67 (worsening). Average change scores for efficacy and adverse effects were 0.25 and 0.38 for levodopa, -0.88 and -0.25 for ropinirole IR, -1.2 and -0.83 for ropinirole XL, -0.80 and 1.0 for pramipexole, and -1.0 and 0.50 for rasagiline, respectively. Average change in Epworth score on each alternate agent was -3.9, -2.3, 1.3, 3.0, and 1. Rotigotine was an effective treatment with all groups deteriorating after switch except for the levodopa group. Fifty-eight percent of patients preferred rotigotine versus 36% preferring the alternate treatment.

Rotigotine vs ropinirole in advanced stage Parkinson's disease: a double-blind study.

PubMed

Mizuno, Yoshikuni; Nomoto, Masahiro; Hasegawa, Kazuko; Hattori, Nobutaka; Kondo, Tomoyoshi; Murata, Miho; Takeuchi, Masahiro; Takahashi, Masayoshi; Tomida, Takayuki

2014-12-01

To confirm the superiority of transdermal rotigotine up to 16 mg/24 h over placebo, and non-inferiority to ropinirole, in Japanese Parkinson's disease (PD) patients on concomitant levodopa therapy. This trial was a randomized, double-blind, double-dummy, three-arm parallel group placebo- and ropinirole-controlled trial. Four-hundred and twenty PD patients whose motor symptoms were not well controlled by levodopa treatment were randomized 2:2:1 to receive rotigotine, ropinirole (up to 15 mg/day) or placebo during a 16-week treatment period followed by a 4-week taper period. The primary variable was change in the Unified Parkinson's Disease Rating Scale (UPDRS) Part III (ON state) sum score from baseline to the end of the treatment period. The difference in the change in the UPDRS Part III (ON state) sum score from baseline to the end of treatment between rotigotine and placebo groups was -6.4 ± 1.2 (95% CI: -8.7 to -4.1; p < 0.001), indicating superiority of rotigotine over placebo. The difference between rotigotine and ropinirole groups was -1.4 ± 1.0 (95% CI: -3.2 to 0.5), below the non-inferiority margin, indicating the non-inferiority of rotigotine to ropinirole. Application site reaction was seen in 57.7% of the patients in the rotigotine group and in 18.6% in the ropinirole group (P < 0.001). No other safety issue was noted. Rotigotine was well tolerated at doses up to 16 mg/24 h and showed similar efficacy to ropinirole except that the application site reaction was much higher in the rotigotine group. Copyright © 2014. Published by Elsevier Ltd.

Rotigotine may control drooling in patients with Parkinson's Disease: Preliminary findings.

PubMed

Schirinzi, Tommaso; Imbriani, Paola; D'Elia, Alessio; Di Lazzaro, Giulia; Mercuri, Nicola Biagio; Pisani, Antonio

2017-05-01

To evaluate the efficacy of rotigotine in controlling the drooling of Parkinson's Disease (PD) patients. We assessed 7 PD patients (Hoehn and Yahr scale >2.5) with three different clinical scores (Drooling Severity and Frequency Scale - DSFS, Drooling Rating Scale - DRS and Sialorrhea Clinical Scale for PD - SCS) before and after 4 weeks of therapy. Statistical differences were analyzed with Wilcoxon signed-rank test. We observed that rotigotine significantly improves drooling as measured by the lowering of the three scores (p<0.05). Among non-motor symptoms of PD, drooling is one of the most embarrassing and disabling for patients. Current treatments are unsatisfactory and novel approaches are thus desirable. In this open-label pilot study we demonstrated on a small sample of patients that up to 4mg/24h of rotigotine, a non-ergolinic dopamine agonist with continuous transdermal delivery, may be helpful in the management of drooling in advanced PD. Copyright © 2017 Elsevier B.V. All rights reserved.

Taro corms mucilage/HPMC based transdermal patch: an efficient device for delivery of diltiazem hydrochloride.

PubMed

Sarkar, Gunjan; Saha, Nayan Ranjan; Roy, Indranil; Bhattacharyya, Amartya; Bose, Madhura; Mishra, Roshnara; Rana, Dipak; Bhattacharjee, Debashis; Chattopadhyay, Dipankar

2014-05-01

The aim of this work is to examine the effectiveness of mucilage/hydroxypropylmethylcellulose (HPMC) based transdermal patch (matrix type) as a drug delivery device. We have successfully extracted mucilage from Colocasia esculenta (Taro) corms and prepared diltiazem hydrochloride incorporated mucilage/HPMC based transdermal patches using various wt% of mucilage by the solvent evaporation technique. Characterization of both mucilage and transdermal patches has been done by several techniques such as Molisch's test, organoleptic evaluation of mucilage, mechanical, morphological and thermal analysis of transdermal patches. Skin irritation test is studied on hairless Albino rat skin showing that transdermal patches are apparently free of potentially hazardous skin irritation. Fourier transform infrared analysis shows that there is no interaction between drug, mucilage and HPMC while scanning electron microscopy shows the surface morphology of transdermal patches. In vitro drug release time of mucilage-HPMC based transdermal patches is prolonged with increasing mucilage concentration in the formulation. Copyright © 2014 Elsevier B.V. All rights reserved.

Transdermal patches: history, development and pharmacology

PubMed Central

Pastore, Michael N; Kalia, Yogeshvar N; Horstmann, Michael; Roberts, Michael S

2015-01-01

Transdermal patches are now widely used as cosmetic, topical and transdermal delivery systems. These patches represent a key outcome from the growth in skin science, technology and expertise developed through trial and error, clinical observation and evidence-based studies that date back to the first existing human records. This review begins with the earliest topical therapies and traces topical delivery to the present-day transdermal patches, describing along the way the initial trials, devices and drug delivery systems that underpin current transdermal patches and their actives. This is followed by consideration of the evolution in the various patch designs and their limitations as well as requirements for actives to be used for transdermal delivery. The properties of and issues associated with the use of currently marketed products, such as variability, safety and regulatory aspects, are then described. The review concludes by examining future prospects for transdermal patches and drug delivery systems, such as the combination of active delivery systems with patches, minimally invasive microneedle patches and cutaneous solutions, including metered-dose systems. PMID:25560046

Transdermal patches: history, development and pharmacology.

PubMed

Pastore, Michael N; Kalia, Yogeshvar N; Horstmann, Michael; Roberts, Michael S

2015-05-01

Transdermal patches are now widely used as cosmetic, topical and transdermal delivery systems. These patches represent a key outcome from the growth in skin science, technology and expertise developed through trial and error, clinical observation and evidence-based studies that date back to the first existing human records. This review begins with the earliest topical therapies and traces topical delivery to the present-day transdermal patches, describing along the way the initial trials, devices and drug delivery systems that underpin current transdermal patches and their actives. This is followed by consideration of the evolution in the various patch designs and their limitations as well as requirements for actives to be used for transdermal delivery. The properties of and issues associated with the use of currently marketed products, such as variability, safety and regulatory aspects, are then described. The review concludes by examining future prospects for transdermal patches and drug delivery systems, such as the combination of active delivery systems with patches, minimally invasive microneedle patches and cutaneous solutions, including metered-dose systems. © 2015 The British Pharmacological Society.

Estradiol Transdermal Patch

MedlinePlus

Most brands of estradiol transdermal patches are used to treat hot flushes (hot flashes; sudden strong feelings of heat ... different medication that does not contain estrogen. Most brands of estradiol transdermal patches are also sometimes used ...

Efficacy and safety of rotigotine in elderly patients with Parkinson's disease in comparison with the non-elderly: a post hoc analysis of randomized, double-blind, placebo-controlled trials.

PubMed

Nomoto, Masahiro; Iwaki, Hirotaka; Kondo, Hiroyuki; Sakurai, Masaya

2018-02-01

Rotigotine-a non-ergot dopamine agonist-has two advantages; it can stimulate all dopamine receptors (D1-D5) like innate dopamine, and its transdermal administration provides continuous dopaminergic stimulation. The age of the patient impacts the effect and adverse events of anti-parkinsonian treatment. We conducted a post hoc analysis on three randomized, double-blind, placebo-controlled trials performed in Japan to clarify the difference of anti-parkinsonian treatment in elderly and non-elderly patients. Data from two combination therapy trials (with levodopa) in advanced stage Parkinson's disease patients and one monotherapy trial in early stage patients were pooled and grouped by age (non-elderly aged < 70, elderly aged 70 +). In each age group, efficacy of rotigotine was compared to placebo. In the combination therapy, total Unified Parkinson's Disease Rating Scale Part III scores and some subtotal scores, including those for tremor, akinesia and gait disturbance, significantly improved in both elderly and non-elderly patients. Regarding safety, the incidence of total adverse event tended to be lower in elderly patients than non-elderly patients, although it was not significant. No difference was observed in maintenance dosage of rotigotine between the two groups. In conclusion, the improvement in motor symptoms and frequency of adverse events were shown to be similar in elderly and non-elderly patients with rotigotine-levodopa combination therapy. Further, there was no major difference in maintenance dosage of rotigotine between the age groups. These results suggest good tolerability of rotigotine among elderly patients.

Efficacy and safety of rotigotine in Japanese patients with restless legs syndrome: a phase 3, multicenter, randomized, placebo-controlled, double-blind, parallel-group study.

PubMed

Inoue, Yuichi; Shimizu, Tetsuo; Hirata, Koichi; Uchimura, Naohisa; Ishigooka, Jun; Oka, Yasunori; Ikeda, Junji; Tomida, Takayuki; Hattori, Nobutaka

2013-11-01

We aimed to ascertain the efficacy and safety of transdermal rotigotine (2 and 3mg/24h) in Japanese patients with restless legs syndrome (RLS). In our double-blind placebo-controlled study, 284 Japanese patients with idiopathic RLS were randomly assigned to receive rotigotine 2mg/24h or 3mg/24h, or placebo, for 13 weeks. The primary endpoint was the change in International Restless Legs Syndrome Study Group rating scale (IRLS) total score. The placebo-subtracted decreases in IRLS total score for rotigotine 2 mg/24 h and 3 mg/24 h were -2.8±1.3 and -3.1±1.3, respectively, which were significant (P<0.05). The interaction between baseline Pittsburgh Sleep Quality Index (PSQI) and treatment group for the change in IRLS total score was significant, indicating greater improvements in IRLS total score in patients with severe insomnia. Overall, 80.0%, 86.2%, and 51.6% of patients in the rotigotine 2 mg/24 h, 3 mg/24 h, and placebo groups, respectively, experienced adverse events (AEs) including application site reactions in 42.1%, 50.0%, and 7.4% of patients, respectively. None of the AEs were severe. Our results showed that rotigotine was effective without major safety concerns at doses of up to 3 mg/24 h in Japanese patients with RLS. Copyright © 2013 Elsevier B.V. All rights reserved.

A randomized study of rotigotine dose response on 'off' time in advanced Parkinson's disease.

PubMed

Nicholas, Anthony P; Borgohain, Rupam; Chaná, Pedro; Surmann, Erwin; Thompson, Emily L; Bauer, Lars; Whitesides, John; Elmer, Lawrence W

2014-01-01

Previous phase III studies in patients with advanced Parkinson's disease (PD) not adequately controlled on levodopa demonstrated significant reduction of 'off' time with rotigotine transdermal system up to 16 mg/24 h. However, the minimal effective dose has not been established. This international, randomized, double-blind, placebo-controlled study (SP921; NCT00522379) investigated rotigotine dose response up to 8 mg/24 h. Patients with advanced idiopathic PD (≥2.5 h of daily 'off' time on stable doses of levodopa) were randomized 1:1:1:1:1 to receive rotigotine 2, 4, 6, or 8 mg/24 h or placebo, titrated over 4 weeks and maintained for 12 weeks. The primary efficacy variable was change from baseline to end of maintenance in absolute time spent 'off'. 409/514 (80%) randomized patients completed maintenance. Mean (±SD) baseline daily 'off' times (h/day) were placebo: 6.4 (±2.5), rotigotine 2-8 mg/24 h: 6.4 (±2.6). Rotigotine 8 mg/24 h was the minimal dose to significantly reduce 'off' time versus placebo. LS mean (±SE) absolute change in daily 'off' time (h/day) from baseline was -2.4 (±0.28) with rotigotine 8 mg/24 h, and -1.5 (±0.26) with placebo; absolute change in 'off' time in the 8 mg/24 h group compared with placebo was -0.85 h/day (95% CI -1.59, -0.11; p = 0.024). There was an apparent dose-dependent trend. Adverse events (AEs) reported at a higher incidence in the rotigotine 8 mg/24 h group versus placebo included application site reactions, nausea, dry mouth, and dyskinesia; there was no worsening of insomnia, somnolence, orthostatic hypotension, confusional state or hallucinations, even in patients ≥75 years of age. The minimal statistically significant effective dose of rotigotine to reduce absolute 'off' time was 8 mg/24 h. The AE profile was similar to previous studies.

Rotigotine Effects on Early Morning Motor Function and Sleep in Parkinson's Disease: A Double-Blind, Randomized, pLacebo-Controlled Study (RECOVER)

PubMed Central

Trenkwalder, Claudia; Kies, Bryan; Rudzinska, Monika; Fine, Jennifer; Nikl, Janos; Honczarenko, Krystyna; Dioszeghy, Peter; Hill, Dennis; Anderson, Tim; Myllyla, Vilho; Kassubek, Jan; Steiger, Malcolm; Zucconi, Marco; Tolosa, Eduardo; Poewe, Werner; Surmann, Erwin; Whitesides, John; Boroojerdi, Babak; Chaudhuri, Kallol Ray

2011-01-01

In a multinational, double-blind, placebo-controlled trial (NCT00474058), 287 subjects with Parkinson's disease (PD) and unsatisfactory early-morning motor symptom control were randomized 2:1 to receive rotigotine (2–16 mg/24 hr [n = 190]) or placebo (n = 97). Treatment was titrated to optimal dose over 1–8 weeks with subsequent dose maintenance for 4 weeks. Early-morning motor function and nocturnal sleep disturbance were assessed as coprimary efficacy endpoints using the Unified Parkinson's Disease Rating Scale (UPDRS) Part III (Motor Examination) measured in the early morning prior to any medication intake and the modified Parkinson's Disease Sleep Scale (PDSS-2) (mean change from baseline to end of maintenance [EOM], last observation carried forward). At EOM, mean UPDRS Part III score had decreased by −7.0 points with rotigotine (from a baseline of 29.6 [standard deviation (SD) 12.3] and by −3.9 points with placebo (baseline 32.0 [13.3]). Mean PDSS-2 total score had decreased by −5.9 points with rotigotine (from a baseline of 19.3 [SD 9.3]) and by −1.9 points with placebo (baseline 20.5 [10.4]). This represented a significantly greater improvement with rotigotine compared with placebo on both the UPDRS Part III (treatment difference: −3.55 [95% confidence interval (CI) −5.37, −1.73]; P = 0.0002) and PDSS-2 (treatment difference: −4.26 [95% CI −6.08, −2.45]; P < 0.0001). The most frequently reported adverse events were nausea (placebo, 9%; rotigotine, 21%), application site reactions (placebo, 4%; rotigotine, 15%), and dizziness (placebo, 6%; rotigotine 10%). Twenty-four-hour transdermal delivery of rotigotine to PD patients with early-morning motor dysfunction resulted in significant benefits in control of both motor function and nocturnal sleep disturbances. © 2010 Movement Disorder Society PMID:21322021

Transdermal nicotine patches for eosinophilic pustular folliculitis.

PubMed

Yoshifuku, Asuka; Higashi, Yuko; Matsushita, Shigeto; Kawai, Kazuhiro; Kanekura, Takuro

2013-09-01

We previously reported the clinical effectiveness of transdermal nicotine patches for the treatment of skin disorders with eosinophilic infiltration such as Kimura's disease, erythema nodosum and eosinophilic pustular folliculitis (EPF). We assessed the efficacy and safety of transdermal nicotine patches for EPF. We treated eight patients with EPF with transdermal nicotine patches and evaluated the treatment response by performing overall lesional assessment. Excellent 77and good responses were obtained in five and one patient(s), respectively. In the other two patients, the lesions remained unchanged. No severe adverse effects were observed. Our results suggest that transdermal nicotine patches may be useful and safe in the treatment of EPF. © 2013 Japanese Dermatological Association.

The effects of the dopamine agonist rotigotine on hemispatial neglect following stroke.

PubMed

Gorgoraptis, Nikos; Mah, Yee-Haur; Machner, Bjoern; Singh-Curry, Victoria; Malhotra, Paresh; Hadji-Michael, Maria; Cohen, David; Simister, Robert; Nair, Ajoy; Kulinskaya, Elena; Ward, Nick; Greenwood, Richard; Husain, Masud

2012-08-01

Hemispatial neglect following right-hemisphere stroke is a common and disabling disorder, for which there is currently no effective pharmacological treatment. Dopamine agonists have been shown to play a role in selective attention and working memory, two core cognitive components of neglect. Here, we investigated whether the dopamine agonist rotigotine would have a beneficial effect on hemispatial neglect in stroke patients. A double-blind, randomized, placebo-controlled ABA design was used, in which each patient was assessed for 20 testing sessions, in three phases: pretreatment (Phase A1), on transdermal rotigotine for 7-11 days (Phase B) and post-treatment (Phase A2), with the exact duration of each phase randomized within limits. Outcome measures included performance on cancellation (visual search), line bisection, visual working memory, selective attention and sustained attention tasks, as well as measures of motor control. Sixteen right-hemisphere stroke patients were recruited, all of whom completed the trial. Performance on the Mesulam shape cancellation task improved significantly while on rotigotine, with the number of targets found on the left side increasing by 12.8% (P = 0.012) on treatment and spatial bias reducing by 8.1% (P = 0.016). This improvement in visual search was associated with an enhancement in selective attention but not on our measures of working memory or sustained attention. The positive effect of rotigotine on visual search was not associated with the degree of preservation of prefrontal cortex and occurred even in patients with significant prefrontal involvement. Rotigotine was not associated with any significant improvement in motor performance. This proof-of-concept study suggests a beneficial role of dopaminergic modulation on visual search and selective attention in patients with hemispatial neglect following stroke.

The effects of the dopamine agonist rotigotine on hemispatial neglect following stroke

PubMed Central

Gorgoraptis, Nikos; Mah, Yee-Haur; Machner, Bjoern; Singh-Curry, Victoria; Malhotra, Paresh; Hadji-Michael, Maria; Cohen, David; Simister, Robert; Nair, Ajoy; Kulinskaya, Elena; Ward, Nick; Greenwood, Richard

2012-01-01

Hemispatial neglect following right-hemisphere stroke is a common and disabling disorder, for which there is currently no effective pharmacological treatment. Dopamine agonists have been shown to play a role in selective attention and working memory, two core cognitive components of neglect. Here, we investigated whether the dopamine agonist rotigotine would have a beneficial effect on hemispatial neglect in stroke patients. A double-blind, randomized, placebo-controlled ABA design was used, in which each patient was assessed for 20 testing sessions, in three phases: pretreatment (Phase A1), on transdermal rotigotine for 7–11 days (Phase B) and post-treatment (Phase A2), with the exact duration of each phase randomized within limits. Outcome measures included performance on cancellation (visual search), line bisection, visual working memory, selective attention and sustained attention tasks, as well as measures of motor control. Sixteen right-hemisphere stroke patients were recruited, all of whom completed the trial. Performance on the Mesulam shape cancellation task improved significantly while on rotigotine, with the number of targets found on the left side increasing by 12.8% (P = 0.012) on treatment and spatial bias reducing by 8.1% (P = 0.016). This improvement in visual search was associated with an enhancement in selective attention but not on our measures of working memory or sustained attention. The positive effect of rotigotine on visual search was not associated with the degree of preservation of prefrontal cortex and occurred even in patients with significant prefrontal involvement. Rotigotine was not associated with any significant improvement in motor performance. This proof-of-concept study suggests a beneficial role of dopaminergic modulation on visual search and selective attention in patients with hemispatial neglect following stroke. PMID:22761293

Comparison of estrus synchronization by controlled internal drug release device (CIDR) and adhesive transdermal progestin patch in postpartum beef cows.

PubMed

Kajaysri, Jatuporn; Chumchoung, Chaiwat; Wutthiwitthayaphong, Supphathat; Suthikrai, Wanvipa; Sangkamanee, Praphai

2017-09-15

Estrous synchronization with progesterone based protocols has been essentially used in cattle industry. Although intravaginal devices have been commonly used, this technique may induce vaginitis. This study aimed at examining the efficiency of novel transdermal progestin patch on follicle development and comparing the progestin patch versus CIDR device on estrous synchronization, complication at treated site and pregnancy in beef cattle. In experiment 1, seven beef cows were treated with an adhesive transdermal progestin patch on the ventral surface of the proximal part of the tail for 7 days. The cows were daily examined the follicular development using ultrasonography starting on Day 0 till 3 days after hormone removal. Experiment 2, forty beef cows were divided into two equal groups (20 cows per group). The cows randomly allocated to received either vaginal insertion of CIDR (n = 20) or treated with an adhesive transdermal progestin patch (n = 20). The levels of plasma progesterone during the experiment and the numbers of standing estrous cows were recorded. Timed artificial inseminated (TAI) was performed at 60 h after CIDR or patch termination. Pregnancy rates were determined at 60 days after TAI. Experiment 1 revealed that the novel transdermal progestin patch could efficiently control follicular growth. All the seven treated cows had dominant follicle upon dermal patch removal indicating the effectiveness of the progestin patch. In experiment 2, the percentages of cows exhibited standing estrus were similar between transdermal patch (72.22%) and CIDR (70.00%). The levels of plasma progesterone during CIDR treatment were significantly higher (4.06 ± 1.65 ng/mL on Day 1 and 3.62 ± 1.60 ng/mL on Day 7) compared with transdermal patch (2.60 ± 1.43 ng/mL on Day 1 and 1.81 ± 1.57 ng/mL on Day 7). Three cows treated with CIDR (15%) developed vaginitis while none of cows had physically dermal reaction at adhesive site. Cows synchronized with these two protocols had similar pregnancy rates (50.00%) following fixed time artificial insemination. It is concluded that transdermal progestin patch was equally effective in estrus synchronization as compared with traditional CIDR. However, the transdermal patch demonstrated less complication. This device should therefore be considered as an alternative method for estrus synchronization in postpartum beef cattle. Copyright © 2017 Elsevier Inc. All rights reserved.

Conductive polymer nanotube patch for fast and controlled ex vivo transdermal drug delivery.

PubMed

Nguyen, Thao M; Lee, Sebin; Lee, Sang Bok

2014-10-01

To uptake and release hydrophilic model drugs and insulin in a novel conductive polymer (CP) nanotube transdermal patch. The externally controlled transdermal delivery of model drugs and insulin were tested ex vivo and results were compared with CP films. The unique intrinsic properties of CPs provide electrostatic interaction between the model drugs and polymer backbone. When a pulsed potential was applied, the drug delivery release profile mimics that of injection delivery. With a constant potential applied, the release rate constants of the patch system were up to three-times faster than the control (0 V) and released approximately 80% more drug molecules over 24 h. The CP nanotube transdermal patch represents a new and promising drug method, specifically for hydrophilic molecules, which have been a large obstacle for conventional transdermal drug delivery systems.

Current and emerging formulation strategies for the effective transdermal delivery of HIV inhibitors.

PubMed

Ham, Anthony S; Buckheit, Robert W

2015-02-01

Current and emerging formulation strategies for skin permeation are poised to open the transdermal drug delivery to a broader range of small molecule compounds that do not fit the traditional requirements for successful transdermal drug delivery, allowing the development of new patch technologies to deliver antiretroviral drugs that were previously incapable of being delivered through transdermal means. Transdermal drug delivery offers several distinct advantages over traditional dosage forms. Current antiretroviral drugs used for the treatment of HIV infection include a variety of highly active small molecule compounds with significantly limited skin permeability, and thus new and novel means of enhancing transport through the skin are needed. Current and emerging formulation strategies are poised to open the transdermal drug delivery to a broader range of compounds that do not fit the traditional requirements for successful transdermal drug delivery, allowing the development of new patch technologies to deliver antiretroviral drugs that were previously incapable of being delivered through transdermal means. Thus, with continuing research into skin permeability and patch formulation strategies, there is a large potential for antiretroviral transdermal drug delivery.

Current and emerging formulation strategies for the effective transdermal delivery of HIV inhibitors

PubMed Central

Ham, Anthony S; Buckheit, Robert W

2015-01-01

Current and emerging formulation strategies for skin permeation are poised to open the transdermal drug delivery to a broader range of small molecule compounds that do not fit the traditional requirements for successful transdermal drug delivery, allowing the development of new patch technologies to deliver antiretroviral drugs that were previously incapable of being delivered through transdermal means. Transdermal drug delivery offers several distinct advantages over traditional dosage forms. Current antiretroviral drugs used for the treatment of HIV infection include a variety of highly active small molecule compounds with significantly limited skin permeability, and thus new and novel means of enhancing transport through the skin are needed. Current and emerging formulation strategies are poised to open the transdermal drug delivery to a broader range of compounds that do not fit the traditional requirements for successful transdermal drug delivery, allowing the development of new patch technologies to deliver antiretroviral drugs that were previously incapable of being delivered through transdermal means. Thus, with continuing research into skin permeability and patch formulation strategies, there is a large potential for antiretroviral transdermal drug delivery. PMID:25690088

Rotigotine may improve sleep architecture in Parkinson's disease: a double-blind, randomized, placebo-controlled polysomnographic study.

PubMed

Pierantozzi, Mariangela; Placidi, Fabio; Liguori, Claudio; Albanese, Maria; Imbriani, Paola; Marciani, Maria Grazia; Mercuri, Nicola Biagio; Stanzione, Paolo; Stefani, Alessandro

2016-05-01

Growing evidence demonstrates that in Parkinson's Disease (PD) sleep disturbances are frequent and difficult to treat. Since the efficacy of rotigotine on sleep is corroborated by studies lacking polysomnography (PSG), this study explores the possible rotigotine-mediated impact on PSG parameters in PD patients. This is a randomized, double-blind, placebo-controlled, parallel-group study to determine the efficacy of rotigotine vs placebo on PSG parameters in moderately advanced PD patients. An unusual protocol was utilized, since patches were maintained from 18:00 h to awakening, minimizing the possible diurnal impact on motor symptoms. All participants underwent sleep PSG recordings, subjective sleep questionnaires (Parkinson Disease Sleep Scale [PDSS], Pittsburgh Sleep Quality Index [PSQI]), and the assessment of early-morning motor disability. We evaluated 42 PD patients (Hoehn & Yahr stages 2 and 3) with sleep impairment randomly assigned to active branch (N =21) or placebo (N = 21). Rotigotine significantly increased sleep efficiency and reduced both wakefulness after sleep onset and sleep latency compared to placebo. Moreover, the mean change in REM sleep quantity was significantly higher in the rotigotine than placebo group. The improvement of PSG parameters corresponded to the amelioration of PDSS and PSQI scores together with the improvement of patient morning motor symptoms. This study demonstrated the significant effect of rotigotine on sleep quality and continuity in PD patients by promoting sleep stability and increasing REM. The effectiveness of rotigotine on sleep may be ascribed to its pharmacokinetic/pharmacodynamic profile directly on both D1 and D2 receptors. Copyright © 2016 Elsevier B.V. All rights reserved.

Application of a buprenorphine transdermal patch for the perioperative analgesia in patients who underwent simple lumbar discectomy

PubMed Central

Tang, Jian; Fan, Jin; Yao, Yilun; Cai, Weihua; Yin, Guoyong; Zhou, Wei

2017-01-01

Abstract This study aimed to investigate the perioperative analgesic effect of a buprenorphine transdermal patch in patients who underwent simple lumbar discectomy. In total, 96 patients were randomly divided into parecoxib intravenous injection (Group A), oral celecoxib (Group B), and buprenorphine transdermal patch groups (Group C). The pain status, degree of satisfaction, adverse effects, and condition in which the patient received tramadol hydrochloride for uncontrolled pain were recorded on the night before surgery, postoperative day 1, postoperative day 3, and postoperative day 5. The degree of patient satisfaction in Group C was higher than that in Groups A and B, with minimal adverse effects. The buprenorphine transdermal patch had a better perioperative analgesic effect in patients who underwent simple lumbar discectomy. PMID:28514299

Converting from Transdermal to Buccal Formulations of Buprenorphine: A Pharmacokinetic Meta-Model Simulation in Healthy Volunteers.

PubMed

Priestley, Tony; Chappa, Arvind K; Mould, Diane R; Upton, Richard N; Shusterman, Neil; Passik, Steven; Tormo, Vicente J; Camper, Stephen

2017-09-29

 To develop a model to predict buprenorphine plasma concentrations during transition from transdermal to buccal administration.  Population pharmacokinetic model-based meta-analysis of published data.  A model-based meta-analysis of available buprenorphine pharmacokinetic data in healthy adults, extracted as aggregate (mean) data from published literature, was performed to explore potential conversion from transdermal to buccal buprenorphine. The time course of mean buprenorphine plasma concentrations following application of transdermal patch or buccal film was digitized from available literature, and a meta-model was developed using specific pharmacokinetic parameters (e.g., absorption rate, apparent clearance, and volumes of distribution) derived from analysis of pharmacokinetic data for intravenously, transdermally, and buccally administered buprenorphine.  Data from six studies were included in this analysis. The final transdermal absorption model employed a zero-order input rate that was scaled to reflect a nominal patch delivery rate and time after patch application (with decline in rate over time). The transdermal absorption rate constant became zero following patch removal. Buccal absorption was a first-order process with a time lag and bioavailability term. Simulations of conversion from transdermal 20 mcg/h and 10 mcg/h to buccal administration suggest that transition can be made rapidly (beginning 12 hours after patch removal) using the recommended buccal formulation titration increments (75-150 mcg) and schedule (every four days) described in the product labeling.  Computer modeling and simulations using a meta-model built from data extracted from publications suggest that rapid and straightforward conversion from transdermal to buccal buprenorphine is feasible. © 2017 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Design, development, physicochemical, and in vitro and in vivo evaluation of transdermal patches containing diclofenac diethylammonium salt.

PubMed

Arora, Priyanka; Mukherjee, Biswajit

2002-09-01

In this study, matrix-type transdermal patches containing diclofenac diethylamine were prepared using different ratios of polyvinylpyrrolidone (PVP) and ethylcellulose (EC) by solvent evaporation technique. The drug matrix film of PVP and EC was casted on a polyvinylalcohol backing membrane. All the prepared formulations were subjected to physical studies (moisture content, moisture uptake, and flatness), in vitro release studies and in vitro skin permeation studies. In vitro permeation studies were performed across cadaver skin using a modified diffusion cell. Variations in drug release profiles among the formulations studied were observed. Based on a physicochemical and in vitro skin permeation study, formulation PA4 (PVP/EC, 1:2) and PA5 (PVP/EC, 1:5) were chosen for further in vivo experiments. The antiinflammatory effect and a sustaining action of diclofenac diethylamine from the two transdermal patches selected were studied by inducing paw edema in rats with 1% w/v carrageenan solution. When the patches were applied half an hour before the subplantar injection of carrageenan in the hind paw of male Wistar rats, it was observed that formulation PA4 produced 100% inhibition of paw edema in rats 12 h after carrageenan insult, whereas in the case of formulation PA5, 4% mean paw edema was obtained half an hour after the carrageenan injection and the value became 19.23% 12 h after the carrageenan insult. The efficacy of transdermal patches was also compared with the marketed Voveran gel and it was found that PA4 transdermal patches produced a better result as compared with the Voveran gel. Hence, it can be reasonably concluded that diclofenac diethylamine can be formulated into the transdermal matrix type patches to sustain its release characteristics and the polymeric composition (PVP/EC, 1:2) was found to be the best choice for manufacturing transdermal patches of diclofenac diethylamine among the formulations studied. Copyright 2002 Wiley-Liss, Inc.

Transdermal rivastigmine: management of cutaneous adverse events and review of the literature.

PubMed

Greenspoon, Jill; Herrmann, Nathan; Adam, David N

2011-07-01

Alzheimer's disease is a chronic neurodegenerative disorder resulting in part from the degeneration of cholinergic neurons in the brain. Rivastigmine, a cholinesterase inhibitor, is commonly used as a treatment for dementia due to its ability to moderate cholinergic neurotransmission; however, treatment with oral rivastigmine can lead to gastrointestinal adverse effects such as nausea and vomiting. Transdermal administration of rivastigmine can minimize these adverse effects by providing continuous delivery of the medication, while maintaining the effectiveness of the oral treatment. While the transdermal form of rivastigmine has been found to have fewer systemic adverse effects compared with the oral form, cutaneous reactions, such as contact dermatitis, can lead to discontinuation of the drug in its transdermal form. Lack of patient compliance with regard to applying the patch to the designated site, applying the patch for the correct length of time or rotating patch application sites increases the risk of cutaneous adverse reactions. This article outlines the diagnosis and management of irritant contact dermatitis and allergic contact dermatitis secondary to transdermal rivastigmine. The large majority of reactions to transdermal patches are of an irritant type, which can be diagnosed clinically by the presence of a pruritic, erythematous, eczematous plaque strictly confined to the borders of the patch. In contrast, an allergic reaction can be differentiated by the presence of vesicles and/or oedema, erythema beyond the boundaries of the transdermal patch and lack of improvement of the lesion 48 hours after removal of the offending treatment. By encouraging the patient to follow a regular rotation schedule for the patch, and using lipid-based emollients for irritant dermatitis and pre- and post-treatment topical corticosteroids for allergic dermatitis, cutaneous reactions can often be alleviated and patients can continue with their medication regimen. Other simple changes to a patient's treatment routine, including minimizing the use of harsh soaps, avoiding recently shaven or damaged areas of skin and carefully removing the patch after use, can help to further decrease the risk of dermatitis development.

Formulation, in vitro and in vivo evaluation of transdermal patches containing risperidone.

PubMed

Aggarwal, Geeta; Dhawan, Sanju; Hari Kumar, S L

2013-01-01

The efficacy of oral risperidone treatment in prevention of schizophrenia is well known. However, oral side effects and patient compliance is always a problem for schizophrenics. In this study, risperidone was formulated into matrix transdermal patches to overcome these problems. The formulation factors for such patches, including eudragit RL 100 and eudragit RS 100 as matrix forming polymers, olive oil, groundnut oil and jojoba oil in different concentrations as enhancers and amount of drug loaded were investigated. The transdermal patches containing risperidone were prepared by solvent casting method and characterized for physicochemical and in vitro permeation studies through excised rat skin. Among the tested preparations, formulations with 20% risperidone, 3:2 ERL 100 and ERS 100 as polymers, mixture of olive oil and jojoba oil as enhancer, exhibited greatest cumulative amount of drug permeated (1.87 ± 0.09 mg/cm(2)) in 72 h, so batch ROJ was concluded as optimized formulation and assessed for pharmacokinetic, pharmacodynamic and skin irritation potential. The pharmacokinetic characteristics of the optimized risperidone patch were determined using rabbits, while orally administered risperidone in solution was used for comparison. The calculated relative bioavailability of risperidone transdermal patch was 115.20% with prolonged release of drug. Neuroleptic efficacy of transdermal formulation was assessed by rota-rod and grip test in comparison with control and marketed oral formulations with no skin irritation. This suggests the transdermal application of risperidone holds promise for improved bioavailability and better management of schizophrenia in long-term basis.

[Post marketing surveillance study with an analgesic (transdermal buprenorphine patch) in patients with moderate to severe chronic pain].

PubMed

Tschirner, M; Ritzdorf, I; Brünjes, R

2008-09-18

To obtain information on the efficacy, tolerability and safetyofa transdermal buprenorphine patch (Transtec PRO) in patients with moderate to severe chronic pain. In addition it should be evaluated to what extent the two fixed patch change days per weekare simplifyingthe therapy. In this prospective multi-center post marketing surveillance study patients with chronic cancer and non-cancer pain were treated with transdermal buprenorphine for up to eight weeks. The evaluation included pain intensity, the dosage of the applied analgesics and additional therapies, the renal function (by serum creatinine) and adverse events. 3654 patients were treated for a mean of 50.4 days. Using the NRS-11 the mean pain intensity decreased from 6.3 at the time when patients were switched to the transdermal buprenorphine patch to 2.6 at the last treatment evaluation. The matrix patch was safe and well tolerated also in patients with advanced renal insufficiency. Adverse events were reported in 6.7% of the patients. 89.3% of the physicians quoted to prefer transdermal buprenorphine with the two fixed patch change days per week compared to the pre-treatment. The buprenorphine-containing matrix patch was effective and well tolerated in patients with moderate to severe chronic cancer and noncancer pain. From the physicians view the two fixed patch change days per week facilitate the guidance of therapy. In patients with advanced renal insufficiency a dose adjustment is not necessary.

The Efficacy and Tolerability of the Clonidine Transdermal Patch in the Treatment for Children with Tic Disorders: A Prospective, Open, Single-Group, Self-Controlled Study.

PubMed

Song, Pan-Pan; Jiang, Li; Li, Xiu-Juan; Hong, Si-Qi; Li, Shuang-Zi; Hu, Yue

2017-01-01

To evaluate the efficacy and tolerability of a clonidine transdermal patch in the treatment of children with tic disorders (TD) and to establish a predictive model for patients. Forty-one patients who met the inclusion criteria entered into 12 weeks of prospective, open, single-group, self-controlled treatment with a clonidine transdermal patch. The Yale Global Tic Severity Scale (YGTSS) was employed before therapy (baseline) and at 4, 8, and 12 weeks after therapy. (1) The total effect rates of treatment with a clonidine transdermal patch were 29.27, 53.66, and 63.41% at 4, 8, and 12 weeks, respectively. Compared with the baseline, the differences were significant at three different observation periods. (2) Compared to the level of 25% reduction, there were significant decreases in the score-reducing rate of motor tic and total tic severities at 12 weeks. (3) If the disease course was ≤24 months and the motor tic score was <16 at the baseline, there was an effective rate of 100% for treatment with the clonidine transdermal patch. If the disease course was ≤24 months and the motor tic score was >16, there was an effective rate of 57.1%. If the disease course was >24 months and the clinical classification was chronic TD, there was an effective rate of 62.5%. If the disease course was >24 months and the clinical classification was Tourette's syndrome, 90% of the patients were invalid. (4) The main adverse events were rash, slight dizziness, and headache. (1) When patients were pretreated with a D2-dopamine receptor antagonist that was ineffective or not tolerated well, switching to a clonidine transdermal patch treatment was effective and safe. (2) A clonidine transdermal patch could be a first-line medication for mild and moderate TD cases that are characterized by motor tics.

Microprocessor-controlled iontophoretic drug delivery of 5-fluorouracil: pharmacodynamic and pharmacokinetic study.

PubMed

Chandrashekar, N S; Shobha Rani, R H

2007-01-01

The purpose of this study was to fabricate monolithic 5-fluorouracil (5-FU) transdermal patch with microprocessor- controlled iontophoretic delivery, to evaluate the pharmacodynamic effects on Dalton's lymphoma ascites (DLA) induced in Balb/c mice, and to study pharmacokinetics in rabbits. The transdermal patches were prepared by solvent casting method; a reprogrammable microprocessor was developed and connected to the patches. DLA cells were injected to the hind limb of Balb/c mice (10 animals/group). In the first group of mice 5-FU was administered i.v. (12 mg/kg). In the second group of mice, transdermal patches (20 mg/patch/animal) were installed and kept for 10 consecutive days, while the third (control) group was kept without any treatment. The tumor diameter was measured every 5th day for 30 days, and the animal survival time and death pattern were studied. The electric current density protocol of 0.5 mA/cm(2) for 30 min was used in the pharmacokinetic study in rabbits. There was a significant reduction in tumor volume in the animals treated with monolithic matrix 5-FU transdermal patch compared to untreated controls and i.v. therapy. Tumor volume of the control animals was 5.8 cm(3) on the 30th day, while in 5-FU with transdermal patch delivery animals it was only 0.23 cm(3) (p <0.05). DLA cells tumor-bearing mice treated with 5-FU with transdermal patch had significantly increased lifespan (ILS). Control animals survived only 21+/-1 days after the tumor inoculation, while i.v. 5-FU and 5-FU patches animals survived 24+/-2.7 days and 39.5+/-1.87 days with ILS of 25.58% and 88.09%, respectively (p <0.01). There was significant sustained release of 5-FU through microprocessor-controlled patches and half-life was significantly higher (p <0.05) compared to the i.v. route. Cytotoxic concentration of 5-FU can be achieved through the transdermal drug delivery and effective therapeutic drug concentration can be maintained up to 24 h, with less toxicity. A new generation of transdermal drug delivery systems based on microprocessor-controlled iontophoresis is in the late stages of development and promises to enhance the treatment of local and systemic medical conditions. The incorporation of microprocessor into these systems has been an important advancement to ensure safe and efficient administration of a wide variety of drugs.

Comparison of transdermal diclofenac patch with oral diclofenac as an analgesic modality following multiple premolar extractions in orthodontic patients: A cross over efficacy trial

PubMed Central

Bhaskar, Hemant; Kapoor, Pranav; Ragini

2010-01-01

Aims: This study was performed to compare the degree of post operative analgesia, patient compliance, and frequency of adverse events with the use of oral diclofenac tablets and transdermal diclofenac patch following multiple premolar extractions in patients undergoing orthodontic treatment. Materials and Methods: Twenty young pre-orthodontic patients requiring bilateral maxillary and mandibular first premolar extractions were selected for the study. The right maxillary and mandibular first premolars were extracted first and 50 mg oral diclofenac sodium tablets were prescribed to be taken thrice a day for three days. In the next appointment, the contralateral first premolars were extracted and a 100 mg transdermal diclofenac patch was applied once a day for three days. Pain relief and pain intensity with both the diclofenac formulations was recorded for each of the three postoperative days using 5-point Verbal Pain Intensity and Pain Relief Score Charts. Results and Conclusions: Statistical analyses revealed that there was a gradual increase in pain relief scores and a gradual decrease in pain intensity scores with the use of oral diclofenac tablets as well as with the transdermal patch. However, subjects reported that they were more comfortable using the transdermal patch particularly due to the once-a-day application and lesser frequency of systemic adverse effects. Results of this study indicate that the transdermal diclofenac patch provides as potent analgesia as the oral diclofenac tablets with the added advantage of better patient compliance and may be used for routine post extraction analgesia. PMID:22114407

Population pharmacokinetic model of transdermal nicotine delivered from a matrix-type patch.

PubMed

Linakis, Matthew W; Rower, Joseph E; Roberts, Jessica K; Miller, Eleanor I; Wilkins, Diana G; Sherwin, Catherine M T

2017-12-01

Nicotine addiction is an issue faced by millions of individuals worldwide. As a result, nicotine replacement therapies, such as transdermal nicotine patches, have become widely distributed and used. While the pharmacokinetics of transdermal nicotine have been extensively described using noncompartmental methods, there are few data available describing the between-subject variability in transdermal nicotine pharmacokinetics. The aim of this investigation was to use population pharmacokinetic techniques to describe this variability, particularly as it pertains to the absorption of nicotine from the transdermal patch. A population pharmacokinetic parent-metabolite model was developed using plasma concentrations from 25 participants treated with transdermal nicotine. Covariates tested in this model included: body weight, body mass index, body surface area (calculated using the Mosteller equation) and sex. Nicotine pharmacokinetics were best described with a one-compartment model with absorption based on a Weibull distribution and first-order elimination and a single compartment for the major metabolite, cotinine. Body weight was a significant covariate on apparent volume of distribution of nicotine (exponential scaling factor 1.42). After the inclusion of body weight in the model, no other covariates were significant. This is the first population pharmacokinetic model to describe the absorption and disposition of transdermal nicotine and its metabolism to cotinine and the pharmacokinetic variability between individuals who were administered the patch. © 2017 The British Pharmacological Society.

A case of overdose via tattoo.

PubMed

Borg, Roberta; Ashton, Antony

2015-08-01

Transdermal fentanyl patches are used frequently for the management of both acute and chronic pain. Adverse events with their use, in particular overdose, are not uncommon. We describe a case of fentanyl overdose from transdermal patch placed over a five-day old tattoo. The report will review the pharmacology of transdermal fentanyl and the physiology of tattooing, as well as the potential link between the two, which may have lead to the overdose.

Non-oral dopaminergic therapies for Parkinson’s disease: current treatments and the future

PubMed Central

Ray Chaudhuri, K; Qamar, Mubasher A; Rajah, Thadshani; Loehrer, Philipp; Sauerbier, Anna; Odin, Per; Jenner, Peter

2016-01-01

Dysfunction of the gastrointestinal tract has now been recognized to affect all stages of Parkinson’s disease (PD). The consequences lead to problems with absorption of oral medication, erratic treatment response, as well as silent aspiration, which is one of the key risk factors in developing pneumonia. The issue is further complicated by other gut abnormalities, such as small intestinal bacterial overgrowth (SIBO) and an altered gut microbiota, which occur in PD with variable frequency. Clinically, these gastrointestinal abnormalities might be associated with symptoms such as nausea, early-morning “off”, and frequent motor and non-motor fluctuations. Therefore, non-oral therapies that avoid the gastrointestinal system seem a rational option to overcome the problems of oral therapies in PD. Hence, several non-oral strategies have now been actively investigated and developed. The transdermal rotigotine patch, infusion therapies with apomorphine, intrajejunal levodopa, and the apomorphine pen strategy are currently in clinical use with a few others in development. In this review, we discuss and summarize the most recent developments in this field with a focus on non-oral dopaminergic strategies (excluding surgical interventions such as deep brain stimulation) in development or to be licensed for management of PD. PMID:28725704

Magnetophoresis for enhancing transdermal drug delivery: Mechanistic studies and patch design

PubMed Central

Murthy, S. Narasimha; Sammeta, Srinivasa M.; Bower, C.

2017-01-01

Magnetophoresis is a method of enhancement of drug permeation across the biological barriers by application of magnetic field. The present study investigated the mechanistic aspects of magnetophoretic transdermal drug delivery and also assessed the feasibility of designing a magnetophoretic transdermal patch system for the delivery of lidocaine. In vitro drug permeation studies were carried out across the porcine epidermis at different magnetic field strengths. The magnetophoretic drug permeation “flux enhancement factor” was found to increase with the applied magnetic field strength. The mechanistic studies revealed that the magnetic field applied in this study did not modulate permeability of the stratum corneum barrier. The predominant mechanism responsible for magnetically mediated drug permeation enhancement was found to be “magnetokinesis”. The octanol/water partition coefficient of drugs was also found to increase when exposed to the magnetic field. A reservoir type transdermal patch system with a magnetic backing was designed for in vivo studies. The dermal bioavailability (AUC0–6 h) from the magnetophoretic patch system in vivo, in rats was significantly higher than the similarly designed nonmagnetic control patch. PMID:20728484

Drug crystallization - implications for topical and transdermal delivery.

PubMed

Hadgraft, Jonathan; Lane, Majella E

2016-06-01

Crystallization of actives in skin following topical application was suggested by studies in the 1950s and 1960s but is poorly understood. In contrast, the problem of crystallization of actives on skin and in transdermal formulations has been known for many years. With respect to crystallization in skin, this review describes early reports of a skin 'reservoir' and possible reasons underlying its genesis. Techniques to study crystallization on and in skin and in transdermal patches are outlined. The role of the vehicle in skin delivery is emphasised. Studies which have investigated permeation from crystalline particles are described. Approaches to limit crystallization of actives are discussed. Using supersaturation and antinuclean polymers, control of crystal size is possible; controlled release from crystals is also employed in transdermal patches. Drug crystallization has significant implications for topical and transdermal delivery. Approaches have been developed to counteract the issue for transdermal patches but crystallization in and on the skin for other formulations remains unresolved. Greater knowledge of residence time of excipients and their interaction with skin at the molecular level is critical in order to address the problem. This will lay the foundations for better design of topical/transdermal formulations.

Natural oils as skin permeation enhancers for transdermal delivery of olanzapine: in vitro and in vivo evaluation.

PubMed

Aggarwal, Geeta; Dhawan, Sanju; HariKumar, S L

2012-03-01

The feasibility of development of transdermal delivery system of olanzapine utilizing natural oils as permeation enhancers was investigated. Penetration enhancing potential of corn (maize) oil, groundnut oil and jojoba oil on in vitro permeation of olanzapine across rat skin was studied. The magnitude of flux enhancement factor with corn oil, groundnut oil and jojoba oil was 7.06, 5.31 and 1.9 respectively at 5mg/ml concentration in solvent system. On the basis of in vitro permeation studies, eudragit based matrix type transdermal patches of olanzapine were fabricated using optimized concentrations of natural oils as permeation enhancers. All transdermal patches were found to be uniform with respect to physical characteristics. The interaction studies carried out by comparing the results of ultraviolet, HPLC and FTIR analyses for the pure drug, polymers and mixture of drug and polymers indicated no chemical interaction between the drug and excipients. Corn oil containing unsaturated fatty acids was found to be promising natural permeation enhancer for transdermal delivery of olanzapine with greatest cumulative amount of drug permeated (1010.68 μg/cm²/h) up to 24 h and caused no skin irritation. The fabricated transdermal patches were found to be stable. The pharmacokinetic characteristics of the final optimized matrix patch (T2) were determined after transdermal application to rabbits. The calculated relative bioavailability of TDDS was 113.6 % as compared to oral administration of olanzapine. The therapeutic effectiveness of optimized transdermal system was confirmed by tranquillizing activity in rotarod and grip mice model.

Drug profile: transdermal rivastigmine patch in the treatment of Alzheimer disease.

PubMed

Emre, Murat; Bernabei, Roberto; Blesa, Rafael; Bullock, Roger; Cunha, Luis; Daniëls, Hugo; Dziadulewicz, Edward; Förstl, Hans; Frölich, Lutz; Gabryelewicz, Tomasz; Levin, Oleg; Lindesay, James; Martínez-Lage, Pablo; Monsch, Andreas; Tsolaki, Magda; van Laar, Teus

2010-08-01

Cholinesterase inhibitors constitute one of the mainstays of treatment of Alzheimer disease (AD). Gastrointestinal side effects, difficulty accessing therapeutic doses and poor patient compliance have been identified as barriers to effective treatment with these substances. The rivastigmine transdermal patch provides continuous delivery of drug through the skin into the bloodstream, avoiding the fluctuations in plasma concentration associated with oral administration. This pharmacokinetic profile is associated with reduced side effects, resulting in easier access to expected target doses. These benefits, along with other practical advantages of the transdermal patch, may contribute to enhanced patient compliance. Here, we present a review of the current literature on rivastigmine patch, and offer advice based on our own collective clinical experience. Rivastigmine patch provides an efficient option for managing patients with AD, to be considered among the first line therapies for the disease.

[Are there innovations in the treatment of Parkinson's disease?].

PubMed

Ludin, H P

2004-11-03

In the group of medication acting on the dopaminergic system the transdermal application of a dopamine agonist (Rotigotine) and a new MAO B inhibitor (Rasigiline) are receiving most attention. With some concern we had to learn that pergolide, a potent dopamine agonist, may be the cause of clinically relevant valvulopathies. Our possibilities to act on non-dopaminergic deficits is still very limited. The studies demonstrating a positive effect of cholinesterase inhibitors on cognitive decline are at least a positive signal.

Synthesis of conjugated chitosan and its effect on drug permeation from transdermal patches.

PubMed

Satheeshababu, B K; Shivakumar, K L

2013-03-01

The aim of this study was to synthesis the conjugated chitosan by covalent attachment of thiol moieties to the cationic polymer, mediated by a carbodiimide to improve permeation properties of chitosan. Thioglycolic acid was covalently attached to chitosan by the formation of amide bonds between the primary amino groups of the polymer and the carboxylic acid groups of thioglycolic acid. Hence, these polymers are called as thiomers or thiolated polymers. Conjugation of chitosan was confirmed by Fourier transform-infrared and differential scanning calorimetric analysis. Matrix type transdermal patches of carvedilol were prepared using the different proportions of chitosan and chitosan-thioglycolic acid conjugates (2:0, 1.7:0.3, 1.4:0.6, 1:1, 0.6:1.4 and 0.3:1.7) by solvent casting technique. Prepared matrix type patches were evaluated for their physicochemical characterization followed by in vitro evaluation. Selected formulations were subjected for their ex vivo studies on Wistar albino rat skin and human cadaver skin using the modified Franz diffusion cell. As the proportion of conjugated chitosan increased, the transdermal patches showed increased drug permeation. The mechanism of drug release was found to be nonFickian profiles. The present study concludes that the transdermal patches of carvedilol using conjugated chitosan with different proportions of chitosan were successfully developed to provide improved drug permeation. The transdermal patches can be a good approach to improve drug bioavailability by bypassing the extensive hepatic first-pass metabolism of the drug.

Efficacy and Safety of Oral Diclofenac Sustained release Versus Transdermal Diclofenac Patch in Chronic Musculoskeletal Pain: A Randomized, Open Label Trial.

PubMed

Shinde, Viraj Ashok; Kalikar, Mrunalini; Jagtap, Satyajeet; Dakhale, Ganesh N; Bankar, Mangesh; Bajait, Chaitali S; Motghare, Vijay M; Pashilkar, Ashlesha A; Raghute, Latesh B; Khamkar, Ajita D

2017-01-01

To compare the efficacy, safety, and tolerability of transdermal patches of diclofenac sodium with oral diclofenac sustained release (SR) in patients of chronic musculoskeletal MSK pain conditions. The eligible patients were given either transdermal diclofenac patch or tablet diclofenac SR. Pain was assessed at 2 and 4 weeks using a visual analog scale. Adverse events were recorded. Patients with 18-65 years old of either gender with score of ≥4 on a 11-item numeric rating scale-numeric version of visual analog scale for pain with diagnosis of primary osteoarthritis (OA) of the knee or hand of at least 3 months duration, with independent radiological confirmation of OA or having pain associated with other MSK conditions such as soft-tissue rheumatism, cervical and lumbar back pain, and fibromyalgia, of at least 3 months duration were included in this study. Transdermal diclofenac diethylamine patch and tablet diclofenac sodium sustained release (SR) do not significantly differ in the reduction of numerical rating scores at the end of 4 weeks (P = 0.8393). Transdermal diclofenac was equi-efficacious as tablet diclofenac sodium SR in reducing pain due to chronic MSK pain conditions.

PATIENTS' KNOWLEDGE OF MEDICAL PATCHES IN HUNGARY.

PubMed

Somogyi, Orsolya; Zelko, Romana

2016-11-01

Transdermal therapy with medical patches is a simple possibility in home medication. As the correct use of patches has a decisive impact from the point of its modulator effect.A questionnaire survey was developed to explore level of patients' knowledge of the correct use of transdermal patches. A survey was administered in thirteen Hungarian community pharmacies from October of 2012 to May of 2015. Most of the participants, men and women over 18 years of age (n = 233), used major analgesic patches (fentanyl); the remainder were given nitroglycerin, NSAID analgesics patches during the survey. For the hypothesis testing it was assumed that men were more likely to use a razor for skin depilation before patch application than women as their denser pelage hinders patch adhesion. The hypothesis testing showed no significant gender difference in razor use (X² = 0.201; p = 0.654). Pharmacists should direct patients to avoid using soap for skin cleansing before patch application because only 22 percent of the participants always avoided its use. Since only 9 tests were flawless from 233 completed questionnaires. Many patients do not understand how to correctly apply a transdermal dosage patch. Pharmacists should teach their correct application based on results.

A method to visualize transdermal nickel permeation in mouse skin using a nickel allergy patch

PubMed Central

Sugiyama, Tomoko; Uo, Motohiro; Wada, Takahiro; Hongo, Toshio; Omagari, Daisuke; Komiyama, Kazuo; Oikawa, Masakazu; Kusama, Mikio; Mori, Yoshiyuki

2015-01-01

Metal patch test is often used in clinical settings when metal-induced contact dermatitis is suspected. However, the transdermal permeation behavior of metal ions from the patch test remains unclear. Current patch tests using high concentrations of metal salt solutions have some side effects, e.g. acute skin reactions to high concentrations of metal salt. To resolve these, estimating metal ion transdermal permeation is wished. In this study, synchrotron radiation X-ray fluorescence (SR-XRF) and micro-focused particle-induced X-ray emission (micro-PIXE) were used to visualize the time-dependent Ni permeation in mouse skin. The cross-sectional diffusion of Ni was visualized in a time-dependent manner. Our results indicate that maximum Ni permeation occurs after 24 h of patch treatment, and the permeated Ni content was high in the epidermis and spread into the dermis beyond the basal layer. This method may be useful to determine the appropriate solution concentration and duration of administration for the patch test. PMID:26484550

Pharmacokinetics of 2 Formulations of Transdermal Fentanyl in Cynomolgus Macaques (Macaca fascicularis)

PubMed Central

Carlson, Amy M; Kelly, Richard; Fetterer, David P; Rico, Pedro J; Bailey, Emily J

2016-01-01

Fentanyl is a μ-opioid agonist that often is used as the analgesic component for balanced anesthesia in both human and veterinary patients. Minimal information has been published regarding appropriate dosing, and the pharmacokinetics of fentanyl are unknown in NHP. The pharmacokinetic properties of 2 transdermal fentanyl delivery methods, a solution (2.6 and 1.95 mg/kg) and a patch (25 µg/h), were determined when applied topically to the dorsal scapular area of cynomolgus macaques (Macaca fascicularis). Serum fentanyl concentrations were analyzed by using liquid chromatography–mass spectrometry. Compared with the patch, the transdermal fentanyl solution generated higher drug concentrations over longer time. Adverse reactions occurred in the macaques that received the transdermal fentanyl solution at 2.6 mg/kg. Both preparations showed significant interanimal variability in the maximal serum drug levels, time to achieve maximal fentanyl levels, elimination half-life, and AUC values. Both the maximal concentration and the time at which this concentration occurred were increased in macaques compared with most other species after application of the transdermal fentanyl patch and compared with dogs after application of the transdermal fentanyl solution. The pharmacokinetic properties of transdermal fentanyl in macaques are markedly different from those in other veterinary species and preclude its use as a long-acting analgesic drug in NHP. PMID:27423151

Rotigotine's effect on PLM-associated blood pressure elevations in restless legs syndrome

PubMed Central

Cassel, Werner; Benes, Heike; Kesper, Karl; Rye, David; Sica, Domenic; Winkelman, John W.; Bauer, Lars; Grieger, Frank; Joeres, Lars; Moran, Kimberly; Schollmayer, Erwin; Whitesides, John; Carney, Hannah C.; Walters, Arthur S.; Oertel, Wolfgang; Trenkwalder, Claudia

2016-01-01

Objective: This double-blind, placebo-controlled, interventional trial was conducted to investigate the effects of rotigotine patch on periodic limb movement (PLM)–associated nocturnal systolic blood pressure (SBP) elevations. Methods: Patients with moderate to severe restless legs syndrome (RLS) were randomized to rotigotine (optimal dose [1–3 mg/24 h]) or placebo. Continuous beat-to-beat blood pressure (BP) assessments were performed during polysomnography at baseline and at the end of 4-week maintenance. Primary outcome was change in number of PLM-associated SBP elevations (defined as slope of linear regression ≥2.5 mm Hg/beat-to-beat interval over 5 consecutive heartbeats [≥10 mm Hg]). Additional outcomes were total SBP elevations, PLM-associated and total diastolic BP (DBP) elevations, periodic limb movements index (PLMI), and PLM in sleep arousal index (PLMSAI). Results: Of 81 randomized patients, 66 (37 rotigotine, 29 placebo) were included in efficacy assessments. PLM-associated SBP elevations were significantly reduced with rotigotine vs placebo (least squares mean treatment difference [95% confidence interval (CI)] −160.34 [−213.23 to −107.45]; p < 0.0001). Rotigotine-treated patients also had greater reduction vs placebo in total SBP elevations (−161.13 [−264.47 to −57.79]; p = 0.0028), PLM-associated elevations (−88.45 [−126.12 to −50.78]; p < 0.0001), and total DBP elevations (−93.81 [−168.45 to −19.16]; p = 0.0146), PLMI (−32.77 [−44.73 to −20.80]; p < 0.0001), and PLMSAI (−7.10 [−11.93 to −2.26]; p = 0.0047). Adverse events included nausea (rotigotine 23%; placebo 8%), headache (18% each), nasopharyngitis (18%; 8%), and fatigue (13%; 15%). Conclusions: Further investigation is required to determine whether reductions in nocturnal BP elevations observed with rotigotine might modify cardiovascular risk. Classification of evidence: This study provides Class I evidence that for patients with moderate to severe RLS, rotigotine at optimal dose (1–3 mg/24 h) reduced PLM-associated nocturnal SBP elevations. PMID:27164714

A review of compliance to treatment in Alzheimer's disease: potential benefits of a transdermal patch.

PubMed

Small, Gary; Dubois, Bruno

2007-11-01

Following prescribed medication regimens is essential for the effective treatment of any medical condition. Unfortunately, patients often fail to follow recommendations, and treatment non-compliance represents a widespread, often underestimated problem, placing tremendous burden on the healthcare system. Compliance in Alzheimer's disease (AD), a chronic neurodegenerative disease typically afflicting older adults, is especially challenging. To review factors contributing to poor treatment compliance in AD, considering the prominent role care givers often play in treatment management; and acknowledging strategic approaches, particularly modern transdermal patches, to improve compliance in this particularly susceptible population. Articles were identified by searching MEDLINE in November 2006 (search limits: 1987-2007) using the terms: compliance; Alzheimer's; treatment; and transdermal. Additional resources included bibliographies of identified articles. Strategic approaches to improving treatment compliance include: simplifying treatment regimens, using reminder packaging, and developing more patient- or caregiver-friendly modes of administration. To date, AD therapies have been administered orally. However, recent developments in alternative modes of drug delivery, such as transdermal patches, may offer effective, well-tolerated treatment options with the potential to enhance compliance. A patch containing rivastigmine (Exelon), an established cholinesterase inhibitor, has been developed and demonstrated to have good efficacy and tolerability in patients with AD. In addition, initial caregiver experience suggests preference for the patch over oral administration. Transdermal patches may be an effective way to optimize treatment compliance for AD, as well as an increasing number of other chronic conditions that typically afflict the older population, offering the possibility of more sustained clinical benefits.

Efficacy and Safety of Oral Diclofenac Sustained release Versus Transdermal Diclofenac Patch in Chronic Musculoskeletal Pain: A Randomized, Open Label Trial

PubMed Central

Shinde, Viraj Ashok; Kalikar, Mrunalini; Jagtap, Satyajeet; Dakhale, Ganesh N.; Bankar, Mangesh; Bajait, Chaitali S.; Motghare, Vijay M.; Pashilkar, Ashlesha A.; Raghute, Latesh B.; Khamkar, Ajita D.

2017-01-01

Introduction: To compare the efficacy, safety, and tolerability of transdermal patches of diclofenac sodium with oral diclofenac sustained release (SR) in patients of chronic musculoskeletal MSK pain conditions. Materials and Methods: The eligible patients were given either transdermal diclofenac patch or tablet diclofenac SR. Pain was assessed at 2 and 4 weeks using a visual analog scale. Adverse events were recorded. Patients with 18–65 years old of either gender with score of ≥4 on a 11-item numeric rating scale-numeric version of visual analog scale for pain with diagnosis of primary osteoarthritis (OA) of the knee or hand of at least 3 months duration, with independent radiological confirmation of OA or having pain associated with other MSK conditions such as soft-tissue rheumatism, cervical and lumbar back pain, and fibromyalgia, of at least 3 months duration were included in this study. Results: Transdermal diclofenac diethylamine patch and tablet diclofenac sodium sustained release (SR) do not significantly differ in the reduction of numerical rating scores at the end of 4 weeks (P = 0.8393). Conclusion: Transdermal diclofenac was equi-efficacious as tablet diclofenac sodium SR in reducing pain due to chronic MSK pain conditions. PMID:29472748

Mechanisms of gastroprotection by transdermal nitroglycerin in the rat

PubMed Central

Calatayud, Sara; Sanz, María-Jesús; Canet, Amparo; Bello, Regina; de Rojas, Francisco Díaz; Esplugues, Juan V

1999-01-01

Nitric oxide (NO) donors prevent experimentally-induced gastric mucosal damage, but their clinical utility is limited by short duration of action or unsuitability of the pharmaceutical form employed. This study analyses the gastroprotection elicited by a clinically used mode of continuous administration of an NO donor, namely the nitroglycerin patch. Application to rats of a transdermal patch that releases doses of nitroglycerin comparable to those used in man (40, 80, 160 and 400 ng min−1 rat−1) reduced gastric damage induced by indomethacin (25 mg kg−1, p.o. or s.c.). The nitroglycerin patch (160 ng  min−1 rat−1) also diminished damage by oral administration (1 ml) of acidified bile salts (100 mg kg−1 taurocholic acid in 150 mM HCl) or 50% ethanol. Transdermal nitroglycerin (160 ng min−1 rat−1) did not influence basal gastric blood flow, as measured by lasser-doppler flowmetry, but prevented its reduction by indomethacin. Transdermal nitroglycerin (160 ng min−1 rat−1) prevented in vivo leukocyte rolling and adherence in the rat mesentery microvessels superfused with indomethacin, as evaluated by intravital microscopy. The transdermal nitroglycerin patch protects the gastric mucosa from damage by mechanisms that involve maintenance of mucosal blood flow and reduction of leukocyte-endothelial cell interaction. PMID:10455256

Use of rivastigmine transdermal patch in the treatment of Alzheimer's disease.

PubMed

Winblad, Bengt; Machado, João Carlos

2008-12-01

Cholinesterase inhibitors such as rivastigmine and donepezil exhibit a dose-response relationship, with higher doses of the drugs demonstrating greater efficacy. Transdermal patches provide smooth continuous drug delivery, with the potential to offer efficacious levels of drug exposure while avoiding the peaks and troughs associated with side effects. As a small, lipophilic and hydrophilic molecule, rivastigmine (C14H22N2O2) is chemically well-suited to transdermal delivery. The technology underlying the rivastigmine patch allows it to be discreetly small and thin. The target dose 9.5 mg/24 h rivastigmine patch has a diameter of just 3.5 cm and a surface area of 10 cm2. A large randomized controlled trial has demonstrated that the target dose 9.5 mg/24 h rivastigmine patch provided similar efficacy to the highest rivastigmine capsule doses, yet with three times fewer reports of nausea and vomiting. Thus, the rivastigmine patch enables quick and easy access to high dose efficacy. The skin tolerability profile is good, and the patch has demonstrated excellent adhesion. The apparent success of rivastigmine patch, in terms of clinical utility and patient acceptability, suggests that it may mark the next generation of dementia treatment.

From high doses of oral rivastigmine to transdermal rivastigmine patches: user experience and satisfaction among caregivers of patients with mild to moderate Alzheimer disease.

PubMed

Reñé, R; Ricart, J; Hernández, B

2014-03-01

Rivastigmine, a treatment for mild to moderate Alzheimer disease (AD), is the first cholinesterase inhibitor to be available in the transdermal format. We aim to describe user experience and satisfaction with the rivastigmine patch, as well as any clinical changes perceived in patients. Observational, cross-sectional, multicentre study with 239 investigators and 1851 informal caregivers of patients with mild to moderate AD. Patients were treated with transdermal rivastigmine patches for ≥ 6 months and had previously received high doses of oral rivastigmine. Mean caregiver age was 59.8±14.4 years and 70.9% were women. They spent 10.0±7.1hours per day providing care and 79.8% lived with the patient. Patch instructions were described as easy to follow by 97.1% of the caregivers and 92.1% of them rated patch application as easy or very easy. The most commonly cited disadvantage was adhesion problems (26.8%). Discontinuation of treatment was due to cutaneous reactions in most cases. Overall, 76.5% of the caregivers were satisfied or very satisfied with transdermal treatment and 77.4% considered that its interference with daily activities was minimal or null. The patch was preferred to oral treatment by 94.3% of caregivers. Clinical Global Impression of Change ratings improved according to 61.3% of the caregivers and 53% of the investigators. Few caregivers reported medication forgetfulness. Most caregivers of patients with mild to moderate AD preferred the transdermal format of rivastigmine to the oral format. Caregivers also reported overall satisfaction, ease of use, and reduced impact on daily activities for transdermal rivastigmine format, in addition to patient improvement compared to their condition under the previous treatment. Copyright © 2012 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.

Factors Associated with Greater Adherence to and Satisfaction with Transdermal Rivastigmine in Patients with Alzheimer's Disease and Their Caregivers.

PubMed

Riepe, Matthias; Weinman, John; Osae-Larbi, Judith; Mulick Cassidy, Amy; Knox, Sean; Chaves, Ricardo; Müller, Beate

2015-01-01

Adherence to cholinesterase inhibitors is important in order to maximise treatment efficacy. This study aimed to investigate patient and caregiver factors associated with adherence to and satisfaction with transdermal rivastigmine treatment. Sociodemographic, clinical and psychosocial data were collected from 127 patients and their caregivers during the first follow-up visit after prescription. At the second follow-up, data were collected on 110 of the dyads. Adherence to and satisfaction with the treatment were assessed using the Medication Adherence Report Scale and an adapted version of the Alzheimer's Disease Caregiver Preference Questionnaire. 66.2% of the caregivers reported being adherent to, and 77.0% were satisfied with, the patch at the second follow-up. Factors predicting higher adherence at the second follow-up were caregivers' greater frequency of contact with patients, greater satisfaction with the information received about the patch, better tolerability of the patch and living at home with their caregivers. Greater concerns of the caregivers about the patch and the patients' belief in 'other' causes of their Alzheimer's disease predicted a lower adherence at the second follow-up. Assessing and addressing caregivers' concerns about transdermal rivastigmine, improving doctor-patient/caregiver communication to increase caregiver satisfaction with information about the patch as well as providing education and support around patients' beliefs and tolerability of the patch could improve adherence to transdermal rivastigmine. © 2015 S. Karger AG, Basel.

Cost analysis of once-daily ISMN versus twice-daily ISMN or transdermal patch for nitrate prophylaxis.

PubMed

Brown, R E; Kendall, M J; Halpern, M T

1997-02-01

To compare the costs and outcomes of treating exercise-induced angina with once- or twice-daily isosorbide mononitrate (ISMN) or transdermal patch. A decision-analytic model was designed based on published literature showing compliance and increasing symptoms and estimates from physicians on treatment patterns and worsening symptoms. Data show that patients are more compliant with once-daily ISMN (Imdur, Astra Hässle, Mölndal, Sweden) and patch regimens than with twice-daily dose. Based upon the assumption that more compliant patients are better controlled, the model found that fewer medical care resources were consumed by patients treated with the once-daily and the patch regimens. The unit cost of the twice-daily ISMN regimen is 40% of the unit cost of the once-daily. Annual costs of treating an exercise-induced angina patient are 248 pounds for Imdur compared to 250 pounds for the twice-daily ISMN and 299 pounds for the transdermal patch. Unit prices alone are not good indicators for estimating medical management costs.

Synthesis and characterization of modified starch/polybutadiene as novel transdermal drug delivery system.

PubMed

Saboktakin, Mohammad Reza; Akhyari, Shahab; Nasirov, Fizuli A

2014-08-01

Transdermal drug delivery systems are topically administered medicaments in the form of patches that deliver drugs for systemic effects at a predetermined and controlled rate. It works very simply in which drug is applied inside the patch and it is worn on skin for long period of time. Polymer matrix, drug, permeation enhancers are the main components of transdermal drug delivery systems. The objective of the present study was to develop the modified starch and 1,4-cis polybutadiene nanoparticles as novel polymer matrix system. We have been studied the properties of a novel transdermal drug delivery system with clonidine as drug model. Copyright © 2014 Elsevier B.V. All rights reserved.

Scopolamine Transdermal Patch

MedlinePlus

... the adhesive surface of the patch, the clear plastic protective strip should be peeled off and discarded. ... needed, remove the patch and dispose of it. Wrap the patch in tissue or paper to avoid ...

Diclofenac Transdermal Patch

MedlinePlus

... will be applying the patch. Cut open the envelope containing the patches, cutting on the dotted line ... it. Pull apart the zipper seal on the envelope and remove one patch. Reseal the envelope by ...

Effects of Internet-Based Voucher Reinforcement and a Transdermal Nicotine Patch on Cigarette Smoking

ERIC Educational Resources Information Center

Glenn, Irene M.; Dallery, Jesse

2007-01-01

Nicotine replacement products are commonly used to promote smoking cessation, but alternative and complementary methods may increase cessation rates. The current experiment compared the short-term effects of a transdermal nicotine patch to voucher-based reinforcement of smoking abstinence on cigarette smoking. Fourteen heavy smokers (7 men and 7…

Ethinyl Estradiol and Norelgestromin Transdermal Patch

MedlinePlus

... the skin. One patch is applied once a week for 3 weeks, followed by a patch-free week. Follow the directions on your prescription label carefully, ... new patch on the same day of the week (the Patch Change Day). Apply a new patch ...

A comparison of a novel testosterone bioadhesive buccal system, striant, with a testosterone adhesive patch in hypogonadal males.

PubMed

Korbonits, Márta; Slawik, Marc; Cullen, Derek; Ross, Richard J; Stalla, Günter; Schneider, Harald; Reincke, Martin; Bouloux, Pierre M; Grossman, Ashley B

2004-05-01

A novel delivery system has been developed for testosterone replacement. This formulation, COL-1621 (Striant), a testosterone-containing buccal mucoadhesive system, has been shown in preliminary studies to replace testosterone at physiological levels when used twice daily. Therefore, the current study compared the steady-state pharmacokinetics and tolerability of the buccal system with a testosterone-containing skin patch (Andropatch or Androderm) in an international multicenter study of a group of hypogonadal men. Sixty-six patients were randomized into two groups; one applied the buccal system twice daily, whereas the other applied the transdermal patch daily, in each case for 7 d. Serum total testosterone and dihydrotestosterone concentrations were measured at d 1, 3 or 4, and 6, and serially over the last 24 h of the study. Pharmacokinetic parameters for each formulation were calculated, and the two groups were compared. The tolerability of both formulations was also evaluated. Thirty-three patients were treated with the buccal preparation, and 34 were treated with the transdermal patch. The average serum testosterone concentration over 24 h showed a mean of 18.74 nmol/liter (SD =; 5.90) in the buccal system group and 12.15 nmol/liter (SD =; 5.55) in the transdermal patch group (P < 0.01). Of the patients treated with the buccal system, 97% had average steady-state testosterone concentrations within the physiological range (10.41-36.44 nmol/liter), whereas only 56% of the transdermal patch patients achieved physiological total testosterone concentrations (P < 0.001 between groups). Testosterone concentrations were within the physiological range in the buccal system group for a significantly greater portion of the 24-h treatment period than in the transdermal patch group (mean, 84.9% vs. 54.9%; P < 0.001). Testosterone/dihydrotestosterone ratios were physiological and similar in both groups. Few patients experienced major adverse effects from either treatment. No significant local tolerability problems were noted with the buccal system, other than a single patient withdrawal. We conclude that this buccal system is superior to the transdermal patch in achieving testosterone concentrations within the normal range. It may, therefore, be a valuable addition to the range of choices for testosterone replacement therapy.

A clinical study of transdermal contraceptive patch in Thai adolescence women.

PubMed

Piyasirisilp, Rachatapon; Taneepanichskul, Surasak

2008-02-01

To study cycle control, compliance and safety of a transdermal contraceptive patch in adolescent Thai women. Fifty-eight healthy women were assigned to receive 3 cycles of contraceptive patch (ethinyl estradiol 20 microg and norelgestromin 150 microg/day). All participants aged 16-20 years were invited to participate from the family planning clinic at King Chulalongkorn Memorial Hospital. Data were collected on adverse effects, perceived advantages and disadvantages, body weight, blood pressure, patch detachments and compliance. Data were analyzed using mean, percentage and student's t-test. The participants' average age was 19.4 years, height 158.8 cm, weight 51.8 kg, BMI 20.8 Kg/m2. The most location of patch application was the abdomen and the most adverse event was breast tenderness (31.0%) followed by application site reaction, nausea vomiting and headache respectively. The breast symptom was mild in severity. The participants reported decrease in dysmenorrhea and shorter duration of bleeding. There were no significant changes in body weight and blood pressure. The improvement of their facial acne was reported. There were no pregnancies during use and the adhesion of the contraceptive patch is excellent. Partial patch detachment was reported in only 6.9%. No completed patch detachment was found. The present study found an overall positive impression of a new transdermal contraceptive patch. The good compliance and few side effects were demonstrated. The adhesive patch contraceptive was excellent.

Preliminary Experience with Transdermal Oxybutynin Patches for Hyperhidrosis.

PubMed

Bergón-Sendín, M; Pulido-Pérez, A; Sáez-Martín, L C; Suárez-Fernández, R

2016-12-01

Hyperhidrosis is very common and has a considerable impact on patients' quality of life. While oral oxybutynin is associated with good response rates, adverse effects are common and frequently cause patients to stop treatment. Following the recent launch of oxybutynin in a transdermal patch formulation in Spain, we undertook a preliminary study to assess treatment response and adverse effects in patients with hyperhidrosis. This prospective study of 25 patients treated twice weekly with transdermal oxybutynin patches over 10 weeks assessed treatment response on 2 subjective scales: the Hyperhidrosis Disease Severity Scale (HDSS) and a visual analog scale (VAS) for sweating. Sixty percent of patients showed an improvement in HDSS scores. VAS scores improved in all cases, and 68% of patients achieved a reduction of 3 points or more. Just 2 patients (8%) experienced treatment-related adverse effects (irritant dermatitis at the patch application site in both cases). Although our results are based on a small sample, they suggest that transdermal oxybutynin could be a useful option for the treatment of hyperhidrosis and that it has an excellent safety and tolerability profile. Copyright © 2016 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.

Fatal intravenous fentanyl abuse: four cases involving extraction of fentanyl from transdermal patches.

PubMed

Tharp, Amy M; Winecker, Ruth E; Winston, David C

2004-06-01

The transdermal fentanyl system delivers a specific dose at a constant rate. Even after the prescribed application time has elapsed, enough fentanyl remains within a patch to provide a potentially lethal dose. Death due to the intravenous injection of fentanyl extracted from transdermal patches has not been previously reported. We present 4 cases in which the source of fentanyl was transdermal patches and was injected. In all of these cases, the victim was a white male who died at home. Case 1 was a 35-year-old with no known history of drug use, who was found by his wife on the floor of his workshop. Police recovered a fentanyl patch, needle, and syringe at the scene. Case 2 was a 38-year-old with a known history of drug use whose family claimed that he was in a treatment program that used fentanyl patches for unknown reasons. His brother found him dead in bed, and law enforcement officers found a hypodermic needle beside the body; a ligature around his left hand, and apparent needle marks between his first and second digits were also noted. Case 3 was a 42-year-old with a recent attempted suicide via overdose who was found dead at his home. An empty box of fentanyl patches, Valium, Ritalin, and 2 syringes were found at the scene. Case 4 was a 39-year-old found by his mother, who admitted to removing a needle with attached syringe from the decedent's arm. Medications at the scene included hydrocodone, alprazolam, zolpidem, and fentanyl patches. All reported deaths were attributed to fentanyl intoxication, with blood concentrations ranging from 5 to 27 microg/L.

Pharmacodynamics of transdermal granisetron in women with nausea and vomiting of pregnancy.

PubMed

Caritis, Steve; Zhao, Yang; Chen, Hui-Jun; Venkataramanan, Raman

2016-07-01

Limited options exist for women with nausea and vomiting of pregnancy (NVP) who cannot tolerate oral intake. Transdermal delivery of granisetron, a 5-hydroxytryptamine-3 receptor antagonist, provides an effective alternative for such patients. The objective of this study was to evaluate the pharmacodynamics of granisetron administered intravenously (IV) and as a sustained release transdermal patch in women with NVP. We recruited 16 women with singleton gestation between 12 0/7-18 6/7 weeks who were receiving treatment for NVP and had a Pregnancy Unique Quantification of Emesis and Nausea (PUQE) score of ≥6. All consenting subjects received 1 mg of granisetron as an IV infusion over 5 minutes and blood was obtained prior to the infusion and at 10, 20, 30, and 60 minutes and at 2, 4, 6, 8, 12, and 24 hours after the start of the infusion. After a minimum washout of 48 hours after initiation of IV granisetron, a 52-cm(2) granisetron patch (34.3 mg) was placed on the upper arm of all subjects for 7 days. Blood was drawn prior to patch placement and daily thereafter for 9 days. The subjects were evaluated daily. The PUQE score was obtained from these subjects prior to the IV infusion and daily for 2 days after and again prior to and daily for 9 days after patch placement. Complete data were available in 15 women after IV administration and 13 women after patch placement. One woman stopped participation during the IV infusion while data were not available in 2 additional women after patch placement due to noncompliance. Peak plasma granisetron concentrations after IV and transdermal administration were similar (∼10 ng/mL). Prior to IV administration of granisetron, the PUQE score was 8.6 ± 1.8 (mean ± SD). The PUQE scores were significantly reduced for the ensuing 2 days (P < .01). The PUQE score prior to patch placement was 7.6 ± 2.4. Scores were significantly (P < .001) reduced within 1 day of patch placement and stayed significantly reduced during the ensuing 6 days of patch placement. The patch was removed on the seventh day and PUQE scores increased significantly on the third day after patch removal. No serious side effects were reported either during IV administration or patch placement. Granisetron significantly improved symptoms of nausea and vomiting as gauged by the PUQE score. After IV infusion the reduction in PUQE score was observed within 1 day. When granisetron was administered as a patch, benefit likewise was seen within 1 day suggesting rapid absorption of the medication transdermally. The beneficial effect of transdermal granisetron on the PUQE score persisted for the entire 7 days during which the patch was in place. In this small cohort, the granisetron patch appeared to be efficacious in reducing the symptoms of nausea and vomiting. The patch provides another option for treating this disorder and may be particularly useful in women who cannot tolerate oral medications. Copyright © 2016 Elsevier Inc. All rights reserved.

Granisetron Transdermal Patch

MedlinePlus

... patch. Each patch is stuck onto a thin plastic liner and a separate rigid plastic film. Do not open the pouch in advance, ... cut the patch into pieces. Peel the thin plastic liner off of the printed side of the ...

Lidocaine Transdermal Patch

MedlinePlus

... It works by stopping nerves from sending pain signals. ... time and the length of time you may wear the patches. Never apply more than three patches at one time, and never wear patches for more than 12 hours per day. ...

Complications of oral exposure to fentanyl transdermal delivery system patches.

PubMed

Prosser, Jane M; Jones, Brent E; Nelson, Lewis

2010-12-01

Fentanyl is a synthetic opioid available therapeutically as an intravenous, transbucal, or transdermal preparation. It is also used as a drug of abuse through a variety of different methods, including the oral abuse of transdermal fentanyl patches. This is a series of patients with oral fentanyl patch exposure reported to our center and represents the first series of oral fentanyl patch exposures collected outside of the postmortem setting. In this series, we examined the New York Poison Control Center database for all cases of oral abuse of fentanyl reported between January 2000 and April 2008. Twenty cases were reported, nine were asymptomatic or had symptoms of opioid withdrawal; 11 had symptoms of opioid intoxication. Eight patients were administered naloxone and all showed improvement in clinical status. Only one case resulted in a confirmed fatality-this patient had an orally adherent patch discovered at intubation. Oral exposure may result in life-threatening toxicity. Patients should be closely assessed and monitored for the opioid toxidrome, and if symptomatic, should be managed with opioid antagonists and ventilatory support.

Nicotine patches improve mood and response speed in a lexical decision task.

PubMed

Gentry, M V; Hammersley, J J; Hale, C R; Nuwer, P K; Meliska, C J

2000-01-01

The effects of smoking a cigarette or wearing a transdermal nicotine patch on mood and lexical decision-making were tested in eight smokers. Each participant was tested after 4 hours of smoking abstinence, under 4 conditions: placebo (very low nicotine) cigarette, nicotine cigarette, placebo patch, and nicotine patch. Relative to placebo, wearing the nicotine patch reduced Profile of Mood States (POMS) Total Mood Disturbance and Fatigue/Inertia scores, while increasing the speed of some types of lexical decisions. Smoking a nicotine cigarette did not affect reaction times, but unexpectedly decreased the accuracy of Word/ Nonword lexical decisions. Thus, transdermal nicotine may improve mood and facilitate longterm memory search and/or attentional processes in nicotine-deprived smokers.

Daytime symptoms of restless legs syndrome--clinical characteristics and rotigotine effectiveness.

PubMed

Takahashi, Masayoshi; Ikeda, Junji; Tomida, Takayuki; Hirata, Koichi; Hattori, Nobutaka; Inoue, Yuichi

2015-07-01

To elucidate the prevalence and clinical characteristics of daytime restless legs syndrome (RLS) among patients with idiopathic RLS and investigate the effectiveness of rotigotine for daytime RLS. In 256 enrolled RLS patients, we investigated factors associated with the presence of RLS symptoms throughout the day. We also assessed the duration of daytime RLS symptoms at hourly intervals, time of initial symptom onset during the day, and associations between duration of daytime and nighttime RLS symptoms. In addition, we compared changes in duration and frequency of RLS symptoms during daytime and nighttime after randomly assigning patients to a 13-week treatment with rotigotine, a dopamine agonist patch with 24-hour action, or placebo. Eighty-one (31.6%) patients had daytime RLS symptoms. Only the International Restless Legs Syndrome Study Group rating scale total score was significantly associated with the presence of daytime RLS symptoms (p < 0.01) on multiple logistic regression analysis. Daytime RLS symptom onset was at 6 a.m. in 44.4% of patients; symptom duration increased significantly toward nighttime. There was a significant positive association between duration of daytime and nighttime RLS symptoms (p < 0.0001) and a greater statistically significant reduction of daytime RLS symptom duration with rotigotine treatment than with placebo (p = 0.03). Daytime symptoms are frequent in patients with RLS and may be associated with increased severity of the disorder and prolonged nighttime RLS symptoms. Rotigotine could become an important treatment choice for daytime symptoms. Copyright © 2015 Elsevier B.V. All rights reserved.

Exposure to Fentanyl After Transdermal Patch Administration for Cancer Pain Management.

PubMed

Bista, Sudeep R; Haywood, Alison; Hardy, Janet; Norris, Ross; Hennig, Stefanie

2016-06-01

This study aimed to describe exposure after fentanyl transdermal patch administration in patients with advanced cancer to quantify variability around the exposure. Patients (n  =  56) with advanced cancer who received transdermal fentanyl (Durogesic®; median dose, 50 μg/h; range, 12-200 μg/h) provided venous blood samples (n  =  163) at various times (0.5-72 hours) during several patch application intervals. Plasma fentanyl concentration was determined (median, 0.9 μg/L; range, 0.04-9.7 μg/L) by high-performance liquid chromatography coupled to tandem mass spectrometry. Pharmacokinetic analysis was performed using nonlinear mixed-effects modeling with NONMEM. A 1-compartment distribution model with first-order absorption and elimination described fentanyl exposure after transdermal patch administration. Fentanyl apparent clearance (between-subject variability [BSV], %) was estimated at 122 L/h/70 kg and 38.5%, respectively. The absorption rate constant was 0.013 h(-1) . Between-occasion variability on apparent clearance was 22.0%, which was lower than BSV, suggesting predictable exposure within the same patient and justifying therapeutic drug monitoring. Except for weight-based dosing, no other patient characteristic could be identified to guide initial fentanyl dose selection in patients with advanced cancer. © 2015, The American College of Clinical Pharmacology.

Rivastigmine Transdermal Patch

MedlinePlus

... also used to treat dementia in people with Parkinson's disease (a brain system disease with symptoms of slowing ... cure Alzheimer's disease or dementia in people with Parkinson's disease. Continue to use transdermal rivastigmine even if you ...

Efficacy and safety of a transdermal contraceptive system.

PubMed

Smallwood, G H; Meador, M L; Lenihan, J P; Shangold, G A; Fisher, A C; Creasy, G W

2001-11-01

To evaluate the efficacy, cycle control, compliance, and safety of a transdermal contraceptive system that delivers norelgestromin 150 microg and ethinyl estradiol 20 microg daily. In this open-label, 73-center study, 1672 healthy, ovulatory, sexually active women received ORTHO EVRA/EVRA for six (n = 1171) or 13 cycles (n = 501). The treatment regimen for each cycle was three consecutive 7-day patches (21 days) followed by 1 patch-free week. The overall and method-failure probabilities of pregnancy through 13 cycles were 0.7% and 0.4%, respectively. The incidence of breakthrough bleeding was low throughout the study. Perfect compliance (21 consecutive days of dosing, followed by a 7-day drug-free interval; no patch could be worn for more than 7 days) was achieved in 90% of subject cycles; only 1.9% of patches detached completely. Adverse events were typical of hormonal contraception, and most were mild-to-moderate in severity and not treatment limiting. The most common adverse events resulting in discontinuation were application site reactions (1.9%), nausea (1.8%), emotional lability (1.5%), headache (1.1%), and breast discomfort (1.0%). The transdermal contraceptive patch provides effective contraception and cycle control, and is well tolerated. The weekly change schedule for the contraceptive patch is associated with excellent compliance and wearability characteristics.

The effect of transdermal nicotine patches on sleep and dreams.

PubMed

Page, F; Coleman, G; Conduit, R

2006-07-30

This study was undertaken to determine the effect of 24-h transdermal nicotine patches on sleep and dream mentation in 15 smokers aged 20 to 33. Utilising a repeated measures design, it was found that more time awake and more ASDA micro-arousals occurred while wearing the nicotine patch compared to placebo. Also, the percentage of REM sleep decreased, but REM latency and the proportion of time spent in NREM sleep stages did not change significantly. Dream reports containing visual imagery, visual imagery ratings and the number of visualizable nouns were significantly greater from REM compared to Stage 2 awakenings, regardless of patch condition. However, a general interaction effect was observed. Stage 2 dream variables remained equivalent across nicotine and placebo conditions. Within REM sleep, more dream reports containing visual imagery occurred while wearing the nicotine patch, and these were rated as more vivid. The greater frequency of visual imagery reports and higher imagery ratings specifically from REM sleep suggests that previously reported dreaming side effects from 24-h nicotine patches may be specific to REM sleep. Combined with previous animal studies showing that transdermally delivered nicotine blocks PGO activity in REM sleep, the current results do no appear consistent with PGO-based hypotheses of dreaming, such as the Activation-Synthesis (AS) or Activation, Input and Modulation (AIM) models.

Transdermal rivastigmine in the treatment of Alzheimer's disease: current and future directions.

PubMed

Amanatkar, Hamid Reza; Grossberg, George Thomas

2014-10-01

Despite the fact that the prevalence of Alzheimer's disease (AD) is exponentially increasing, we have not yet been able to develop a new treatment to modify the course of the disease. This vacuum makes the traditional cholinesterase inhibitors and N-methyl-D-aspartate receptor antagonist the only accessible pharmacotherapy options for the treatment of this disease. Among these medications, the only available transdermal patch at this time is the rivastigmine patch. This patch provides significantly lower gastrointestinal adverse effects. A higher tolerability rate provides the option for physicians to continue treatment with higher doses of rivastigmine in advanced stages of AD. Moreover, ease of use, easy-to-follow schedule, less administration time spent by the caregiver result in greater adherent to the treatment. This article aims to provide a comprehensive drug profile for transdermal rivastigmine, to review currently available treatment options, and to try to anticipate future treatment directions for AD.

Design, Development, and Optimization of Dexibuprofen Microemulsion Based Transdermal Reservoir Patches for Controlled Drug Delivery

PubMed Central

Ali, Fatima Ramzan; Yousuf, Rabia Ismail; Ali, Syed Abid; Imtiaz, Muhammad Suleman; Bashir, Lubna; Naz, Shazia

2017-01-01

The aim of the study was to develop a reservoir-type transdermal patch for a controlled delivery of dexibuprofen and to evaluate its in vivo anti-inflammatory activity in Albino Wistar rats. In order to develop these patches, six formulations of dexibuprofen microemulsion comprising ethyl oleate, Tween 80: PG (2 : 1), and water were prepared by simplex lattice design and characterized. The reservoir compartment was filled with these microemulsions and in vitro release and skin permeation were assessed. The optimized patch was obtained on the basis of the responses: Q24 and flux. The impact of drug loading, surface area, membrane thickness, adhesive, and agitation speed on drug release and permeation was also studied. The skin sensitivity reaction and in vivo anti-inflammatory activity of optimized patch were evaluated. Stability study at three different temperatures for three months was carried out. The result suggests that a membrane based patch with zero-order release rate, Q24 of 79.13 ± 3.08%, and maximum flux of 331.17 µg/cm2h can be obtained exhibiting suitable anti-inflammatory activity with no visible skin sensitivity reaction. The outcomes of stability study recommend storage of patches at 4°C having shelf-life of 6.14 months. The study demonstrates that the reservoir-type transdermal patch of dexibuprofen microemulsion has a potential of delivering drug across skin in controlled manner with required anti-inflammatory activity. PMID:29090219

Fatal overdose after ingestion of a transdermal fentanyl patch in two non-human primates.

PubMed

Deschamps, Jack-Yves; Gaulier, Jean-Michel; Podevin, Guillaume; Cherel, Yan; Ferry, Nicolas; Roux, Françoise A

2012-11-01

CASE HISTORY AND PRESENTATION: Two non-human primates (Macaca fascicularis), weight 3.5 kg, enrolled in an experimental protocol received a 25 μg hour(-1) transdermal fentanyl patch for postoperative analgesia. The following day both animals were clinically normal, but after a new induction of anaesthesia with ketamine, they developed severe and prolonged respiratory distress, profound coma and myosis. MANAGEMENT AND FOLLOW-UP: Attempted reversal with naloxone was ineffective. After several hours of ventilation, both primates eventually died, 7 and 15 hours after ketamine injection, respectively. In both cases, the patch was discovered in the animal's cheek pouch. Subsequent fentanyl serum concentration measurements (8.29 and 14.80 μg L(-1) ) confirmed fentanyl overdose. This report of two fatal intoxications in non-human primates secondary to ingestion of a transdermal fentanyl patch demonstrates that this method of analgesia is inappropriate for non-human primates, because of their tendency to chew almost anything they can reach. © 2012 The Authors. Veterinary Anaesthesia and Analgesia. © 2012 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesiologists.

Fatal fentanyl intoxication following excessive transdermal application.

PubMed

Edinboro, L E; Poklis, A; Trautman, D; Lowry, S; Backer, R; Harvey, C M

1997-07-01

The case history and toxicological findings of a fatal fentanyl intoxication due to the application of multiple transdermal patches are presented. An 83 year-old white female with terminal cancer was found dead with three 100 mg/h fentanyl patches on her chest. The autopsy and subsequent histological studies revealed extensive areas of gastric carcinoma, a large atrial tumor, ulceration of esophagus, metastasis of peripancreatic lymph nodes and a recent surgical removal of part of the lower lobe of the left lung. Toxicological analysis by GC/MS yielded fentanyl concentrations of blood, 25 ng/mL; brain, 54 ng/g; heart 94 ng/g; kidney 69 ng/g; and liver 104 ng/g. The cause of death was determined to be fentanyl overdose and the manner of death was ruled undetermined as the investigation was unable to conclusively establish whether this was an accidental overdose, a suicide, an assisted suicide, or possible a homicide. This case demonstrates the need for caution in self-administration of transdermal fentanyl patches, in particular, the dangers inherent in the application of multiple patches which can result in the release of potentially toxic or lethal doses.

Enhancement of skin permeation of flurbiprofen via its transdermal patches using isopulegol decanoate (ISO-C10) as an absorption enhancer: pharmacokinetic and pharmacodynamic evaluation.

PubMed

Chen, Yang; Quan, Peng; Liu, Xiaochang; Guo, Wenjia; Song, Wenting; Cun, Dongmei; Wang, Zhongyan; Fang, Liang

2015-09-01

The study aimed to prepare a transdermal patch for flurbiprofen using isopulegol decanoate (ISO-C10) as a permeation enhancer, and to evaluate the in-vitro and in-vivo percutaneous permeation of the drug, as well as the pharmacodynamic efficacy of the formulation. The permeation experiments were conducted on rabbit skin, and the pharmacokinetic profiles and synovial fluid drug concentration were measured after in-vivo transdermal administration. A deconvolution approach was employed to analyse the correlation between the in-vitro and in-vivo drug permeation. The anti-inflammatory and analgesic effects were, respectively, assessed using the adjuvant arthritis model and the acetic acid induced pain model. ISO-C10 could increase the in-vitro permeation of flurbiprofen from 46.22 ± 5.65 μg/cm(2) to 101.07 ± 10.85 μg/cm(2) . The in-vivo absorption of the drug was also improved by the enhancer, and a good linear correlation was observed between the in-vitro and in-vivo drug permeation. Meanwhile, the ISO-C10 contained patches increased the drug disposition in synovial fluid and enhanced the pharmacodynamic efficacy of the formulation. ISO-C10 would be a promising permeation enhancer for improving the in-vitro and in-vivo delivery of flurbiprofen from its transdermal patches. © 2015 Royal Pharmaceutical Society.

Human Growth Hormone Delivery with a Microneedle Transdermal System: Preclinical Formulation, Stability, Delivery and PK of Therapeutically Relevant Doses

PubMed Central

Ameri, Mahmoud; Kadkhodayan, Miryam; Nguyen, Joe; Bravo, Joseph A.; Su, Rebeca; Chan, Kenneth; Samiee, Ahmad; Daddona, Peter E.

2014-01-01

This study evaluated the feasibility of coating formulated recombinant human growth hormone (rhGH) on a titanium microneedle transdermal delivery system, Zosano Pharma (ZP)-hGH, and assessed preclinical patch delivery performance. Formulation rheology and surface activity were assessed by viscometry and contact angle measurement. rhGH liquid formulation was coated onto titanium microneedles by dip-coating and drying. The stability of coated rhGH was determined by size exclusion chromatography-high performance liquid chromatography (SEC-HPLC). Preclinical delivery and pharmacokinetic studies were conducted in female hairless guinea pigs (HGP) using rhGH coated microneedle patches at 0.5 and 1 mg doses and compared to Norditropin® a commercially approved rhGH subcutaneous injection. Studies demonstrated successful rhGH formulation development and coating on microneedle arrays. The ZP-hGH patches remained stable at 40 °C for six months with no significant change in % aggregates. Pharmacokinetic studies showed that the rhGH-coated microneedle patches, delivered with high efficiency and the doses delivered indicated linearity with average Tmax of 30 min. The absolute bioavailability of the microneedle rhGH patches was similar to subcutaneous Norditropin® injections. These results suggest that ZP-transdermal microneedle patch delivery of rhGH is feasible and may offer an effective and patient-friendly alternative to currently marketed rhGH injectables. PMID:24838219

Efficacy of rivastigmine tartrate, transdermal system, in Alzheimer's disease.

PubMed

Nieto, Rachel A; Deardorff, William James; Grossberg, George T

2016-01-01

As the most common major neurocognitive disorder, Alzheimer's disease (AD) will play an increasingly important role both socially and financially as the population ages. Approved treatments for AD are symptomatic in nature and show modest improvements in cognition and global functioning among patients with AD. This article focuses on the pharmacokinetics, pharmacodynamics, efficacy, and safety of the transdermal patch form of the cholinesterase inhibitor rivastigmine. The rivastigmine transdermal system is approved for the treatment of patients with mild, moderate, and severe AD. Three randomized trials have shown the rivastigmine patch to be efficacious and tolerable across all stages of AD. The rivastigmine patch offers several advantages over the capsule form, including decreased peak to trough plasma fluctuations, reduced rates of nausea and vomiting, better treatment adherence, higher probability of reaching the target dose, ease of administration, and greater satisfaction among caregivers. These factors may be especially important in patients with severe AD, in which patients are more vulnerable to adverse side effects from higher doses. While the patch is more expensive than generic therapies, patient populations that may benefit from the patch include those that are particularly sensitive to GI side effects, have chronic gastrointestinal problems, have difficulty swallowing medications, or have failed to respond with high doses of other generic options.

Pharmacokinetics, safety and tolerability of a novel tocopheryl phosphate mixture/oxycodone transdermal patch system: a Phase I study.

PubMed

Gavin, Paul D; Simon, Lee S; Schlagheck, Thomas; Smith, Alisha J; Shakib, Sepehr

2017-07-01

To characterize the pharmacokinetic profile and evaluate the safety and tolerability of a transdermal oxycodone patch containing tocopheryl phosphate mixture (TPM). Eleven healthy subjects received a single application of three TPM/oxycodone patches applied to the torso for 72 h. Oxycodone was detected 8.0 ± 2.7-h postpatch administration, reaching a mean maximum plasma concentration of 3.41 ± 1.34 ng/ml at 49.3 ± 21.2 h. The safety profile was consistent with the application method and known side-effect profile of oxycodone and naltrexone. No treatment-limiting skin irritation was observed. A 3-day application of the TPM/oxycodone patch demonstrated an acceptable safety profile and was well tolerated by healthy subjects, with limited dermal irritation following application.

Fentanyl Transdermal Patch

MedlinePlus

Fentanyl patches are used to relieve severe pain in people who are expected to need pain medication ... and who cannot be treated with other medications. Fentanyl is in a class of medications called opiate ( ...

Selegiline Transdermal Patch

MedlinePlus

... patch from direct heat such as heating pads, electric blankets, heat lamps, saunas, hot tubs, and heated ... may make you drowsy. Do not drive a car or operate machinery until you know how this ...

Nicotine Transdermal Patch

MedlinePlus

... patches are used to help people stop smoking cigarettes. They provide a source of nicotine that reduces ... cause harm to the fetus.do not smoke cigarettes or use other nicotine products while using nicotine ...

Testosterone Transdermal Patch

MedlinePlus

... one else can use it accidentally or on purpose. Keep track of how many patches are left ... to your pharmacist or contact your local garbage/recycling department to learn about take-back programs in ...

Nitroglycerin Transdermal Patch

MedlinePlus

... vasodilators. It works by relaxing the blood vessels so that the heart does not need to work ... patches may be applied in slightly different ways, so be sure to follow the directions included with ...

Optimization and charaterization of repaglinide biodegradable polymeric nanoparticle loaded transdermal patchs: in vitro and in vivo studies.

PubMed

Vijayan, V; Reddy, K Ravindra; Sakthivel, S; Swetha, C

2013-11-01

Biodegradable polymeric nanoparticles loaded Repaglinide were prepared by solvent extraction method. In this method chitosan, PLA and PCL were employed to prepare Repaglinide polymeric nanoparticles. Some of the formulation parameters were optimized to obtain high quality nanoparticles. The particles were spherical shape with sizes of 108.6 ± 3.4 nm to 220.6 ± 1.2 nm and the poly dispersity indexes were in the range of 0.06 to 0.44. The zeta potential was in the range between - 16.48 ± 2.02 and 30.52 ± 3.20 mV. The percentage entrapment efficiency (EE%) was 81.4 ± 1.8% to 92.7 ± 1.4%. The drug release behavior was studied by externally sink method and the release pattern of drug was found to follow zero order, Higuchi and Peppas equations. The optimized PLA-Repaglinide nanoparticles were loaded in Methocel transdermal patches. These transdermal patches were evaluated by physiochemical parameters, in vitro, ex vivo and in vivo studies. Based on in vivo hypoglycemic results, bioavailability parameters like AUC, AUMC, Cmax, Tmax, MRT, t1/2 and relative bioavailability were found to be 2218.88 μIU/mL/h, 381630.3 μIU/mL/h, 41.88 μIU/mL, 36 h, 83.24h, and 52.79 h respectively. The transdermal patch containing Repaglinide nanoparticles showed 76 fold effective than conventional oral administrations. Copyright © 2013 Elsevier B.V. All rights reserved.

Fractional derivatives in the diffusion process in heterogeneous systems: The case of transdermal patches.

PubMed

Caputo, Michele; Cametti, Cesare

2017-09-01

In this note, we present a simple mathematical model of drug delivery through transdermal patches by introducing a memory formalism in the classical Fick diffusion equation based on the fractional derivative. This approach is developed in the case of a medicated adhesive patch placed on the skin to deliver a time released dose of medication through the skin towards the bloodstream.The main resistance to drug transport across the skin resides in the diffusion through its outermost layer (the stratum corneum). Due to the complicated architecture of this region, a model based on a constant diffusivity in a steady-state condition results in too simplistic assumptions and more refined models are required.The introduction of a memory formalism in the diffusion process, where diffusion parameters depend at a certain time or position on what happens at preceeding times, meets this requirement and allows a significantly better description of the experimental results.The present model may be useful not only for analyzing the rate of skin permeation but also for predicting the drug concentration after transdermal drug delivery depending on the diffusion characteristics of the patch (its thickness and pseudo-diffusion coefficient). Copyright © 2017 Elsevier Inc. All rights reserved.

Patterns of use of a free nicotine patch program for Medicaid and uninsured patients.

PubMed Central

Jaén, C. R.; Cummings, K. M.; Shah, D.; Aungst, W.

1997-01-01

This study assessed the use and effectiveness of a free nicotine patch program among Medicaid and uninsured smokers. Patterns of patch use, associated behaviors with quit attempt, side effects, and self-reported abstinence from smoking for 6 months were evaluated prospectively among patients from five urban family practice offices and a nicotine dependence clinic located in a comprehensive cancer center in Western New York. Results indicated that the majority of participants used the program as intended, and 90% of the participants found the patch useful in their quit attempt. Fourteen percent of participants were abstinent for 6 months or more. We found no support for inappropriate use of transdermal nicotine patches among patients with no health insurance or those on Medicaid. Transdermal nicotine patches are an effective cessation aid for smokers. Given the tall of the consequences of smoking on health costs, barriers to access to effective treatment for smoking cessation among individuals covered by Medicaid for health insurance need to be eliminated. PMID:9170833

A novel male contraceptive pill-patch combination: oral desogestrel and transdermal testosterone in the suppression of spermatogenesis in normal men.

PubMed

Hair, W M; Kitteridge, K; O'Connor, D B; Wu, F C

2001-11-01

This study investigated the effect of transdermal T and oral desogestrel on the reproductive axis of healthy men. Twenty-three men were randomized to 1 of 3 treatment groups and received a daily transdermal T patch plus oral desogestrel at a dose of 75, 150, or 300 microg/d for 24 wk. Baseline blood and semen samples were obtained and then every 4 wk thereafter for 32 wk. The outcome measures were sperm density and plasma levels of FSH, LH, total and free T. The results show a dose-dependent suppression of spermatogenesis and gonadotropins. Seven of the 17 subjects became azoospermic. Desogestrel (300 microg daily) in combination with 5 mg daily transdermal T was the most effective (57% azoospermic), whereas a dose of 75 microg was ineffective (0% azoospermic). Total and free plasma T were reduced by approximately 30%. High density lipoprotein cholesterol was significantly reduced. No serious side-effects were encountered. We conclude that daily self-administered desogestrel with transdermal T is capable of suppressing the male reproductive axis, although the efficacy was less marked and less consistent than injectable regimens. The lower efficacy is likely to be due to failure of the transdermal T system to maintain circulating T levels consistently in the required range.

Enhancement of transdermal protein delivery by photothermal effect of gold nanorods coated on polysaccharide-based hydrogel.

PubMed

Haine, Aung Thu; Koga, Yuki; Hashimoto, Yuta; Higashi, Taishi; Motoyama, Keiichi; Arima, Hidetoshi; Niidome, Takuro

2017-10-01

Transdermal protein delivery is a useful and attractive method for protein therapy and dermal vaccination. However, this delivery method is restricted by the low permeability of the stratum corneum. The purpose of this study was to develop a transdermal delivery system for enhancement of protein permeability into the skin. First, we prepared a transparent gel patch made of polysaccharides with gold nanorods on the gel surface and fluorescein isothiocyanate-modified ovalbumin (FITC-OVA) inside. Next, the gel patch was placed on mouse skin to allow contact with the coated gold nanorods, and irradiated by a continuous-wave laser. The laser irradiation heated the gold nanorods and the skin temperature increased to 43°C, resulting in enhanced translocation of FITC-OVA into the skin. These results confirmed the capability of the transdermal protein delivery system to perforate the stratum corneum and thus facilitate the passage of proteins across the skin. Copyright © 2017 Elsevier B.V. All rights reserved.

Pharmacokinetics of a novel transdermal rivastigmine patch for the treatment of Alzheimer’s disease: a review

PubMed Central

Kurz, A; Farlow, M; Lefèvre, G

2009-01-01

Background: Cholinesterase inhibitors have all been available in oral formulations, but a rivastigmine transdermal patch has now been developed and is approved in many countries worldwide for the treatment of mild-to-moderate Alzheimer’s disease (AD) (including the USA, Latin America, Europe and Asia). Objectives: To review the available pharmacokinetic data that supported the rationale behind the development of the rivastigmine transdermal patch and its clinical effects in dementia therapy. This article will also discuss how the patch may alter the treatment paradigm for patients with AD. Results: The 9.5 mg/24 h rivastigmine patch was shown to provide comparable exposure to the highest recommended doses of capsules (12 mg/day) with significantly lower maximum plasma concentration (Cmax 8.7 vs. 21.6 ng/ml) and slower absorption rate (tmax 8.1 vs. 1.4 h). In a clinical trial of 1195 AD patients, this translated into similar efficacy with three times fewer reports of nausea and vomiting (7.2% vs. 23.1%, and 6.2% vs. 17.0% respectively). Consequently, more patients in the 9.5 mg/24 h patch group achieved their target therapeutic dose at the end of the study, compared with those in the 12 mg/day capsule group (95.9% vs. 64.4%). Conclusion: The rivastigmine patch provides continuous drug delivery over 24 h and similar efficacy to the highest recommended dose of oral rivastigmine with improved tolerability. This may allow patients to achieve optimal therapeutic doses and to benefit from a longer duration of treatment. PMID:19392927

An open-label, two-period comparative study on pharmacokinetics and safety of a combined ethinylestradiol/gestodene transdermal contraceptive patch.

PubMed

Zhang, Chao; Li, Haiyan; Xiong, Xin; Zhai, Suodi; Wei, Yudong; Zhang, Shuang; Zhang, Yuanyuan; Xu, Lin; Liu, Li

2017-01-01

We investigated the pharmacokinetics and safety profiles of a newly developed combined ethinylestradiol (EE)/gestodene (GSD) transdermal contraceptive patch after a single-dose administration and compared with the market available tablet formulation in healthy adult subjects. An open-label, two-period comparative study was conducted in 12 healthy women volunteers. A single dose of the study combined EE/GE transdermal contraceptive patch and oral tablet (Milunet ® ) were administered. Blood samples at different time points after dose were collected, and concentrations were analyzed. A reliable, highly sensitive and accurate high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC/MS/MS) assay method was developed in this study to determine the plasma concentrations of EE and GSD. Compared to the tablet, the study patch had a significantly decreased maximum plasma concentration ( C max ), extended time to reach the C max and half-life, as well as increased clearance and apparent volume of distribution. The half-lives of EE and GSD of the patch were 3.3 and 2.2 times, respectively, than the half-life of the tablet. The areas under the plasma concentration-time curve (AUCs) of EE and GSD of the patch were 8.0 and 16.2 times, respectively, than the AUC of the tablet. No severe adverse event was observed during the whole study, and the general safety was acceptable. In conclusion, compared to the oral tablet Milunet, the study contraceptive patch was well tolerated and showed potent drug exposure, significant extended half-life and stable drug concentrations.

Investigation of the hemostatic effect of a transdermal patch containing 0.55 mg ethinyl estradiol and 2.1 mg gestodene compared with a monophasic oral contraceptive containing 0.03 mg ethinyl estradiol and 0.15 mg levonorgestrel: an open-label, randomized, crossover study.

PubMed

Junge, Wolfgang; Heger-Mahn, Doris; Trummer, Dietmar; Merz, Martin

2013-09-01

Transdermal delivery of contraceptives offers several advantages over combined oral contraceptives (COCs), including effective absorption and the provision of relatively constant serum concentrations. Ethinyl estradiol (EE) and the progestin gestodene are well-absorbed through the skin and, therefore, well-suited for use in a transdermal contraceptive patch. The objective of this study was to investigate the impact of a once-weekly transparent, transdermal patch delivering low doses of EE and gestodene equivalent to a COC containing 0.02 mg EE and 0.06 mg gestodene on hemostasis parameters compared with a monophasic COC containing 0.03 mg EE and 0.15 mg levonorgestrel. In this single-center, open-label, randomized, crossover study, 30 women (aged 18-35 years) received three cycles of each treatment, separated by a two-cycle washout period. The primary outcome measure was the absolute change from baseline in prothrombin fragments 1 + 2 and D-dimer. For both treatments, prothrombin fragments 1 + 2 remained stable during the first treatment period, and increased only slightly in the second period (mean absolute change 0.025 and 0.028 nmol/L in the novel Bayer patch and COC groups, respectively). Increases in D-dimer were observed in both periods (mean absolute change 107.0 ± 147.2 ng/L for the novel Bayer patch and 113.7 ± 159.0 ng/L for the COC). There were no statistically significant treatment differences in prothrombin 1 + 2 or D-dimer (p = 0.667 and p = 0.884, respectively) and no statistically significant treatment sequence or period effects. A COC containing 0.03 mg EE and 0.15 mg levonorgestrel and the novel Bayer patch have comparable influence on hemostatic endpoints. Both treatments were well-tolerated by subjects.

Response to rivastigmine transdermal patch or memantine plus rivastigmine patch is affected by apolipoprotein E genotype in Alzheimer patients.

PubMed

Han, Hyun Jeong; Kim, Byeong C; Lee, Jun-Young; Ryu, Seung-Ho; Na, Hae Ri; Yoon, Soo Jin; Park, Hyun Young; Shin, Joon Hyun; Cho, Soo-Jin; Yi, Hyon-Ah; Choi, Mun Seong; Heo, Jae-Hyeok; Park, Kyung Won; Kim, Kwang K; Choi, Seong Hye

2012-01-01

The apolipoprotein E (APOE) genotype in response to pharmacological treatments in patients with Alzheimer's disease (AD) remains a matter of controversy. This analysis investigated the effect of the APOE genotype on the clinical response to rivastigmine transdermal patch monotherapy or memantine plus rivastigmine patch in patients with mild to moderate AD. Two hundred and six (n = 206) patients with probable AD and Mini-Mental State Examination (MMSE) scores of 10-20 were randomized to rivastigmine patch monotherapy or memantine plus rivastigmine patch for 24 weeks. Of the 206 patients with probable AD, 146 patients who consented to genetic testing for APOE were included and assessed for this subgroup study. There were no significant differences on MMSE, NPI, ADAS-cog, ADCS-ADL, CDR-SB, NPI and FAB between rivastigmine patch monotherapy and memantine plus rivastigmine patch according to the APOE genotype. However, patients with moderately severe AD (MMSE ≤15) who were APOE ε4 carriers showed higher responder rates on ADCS-ADL with memantine plus rivastigmine patch compared to rivastigmine patch monotherapy. Moderately severe AD patients with the APOE ε4 allele may respond more favorably to memantine plus rivastigmine patch than ε4 noncarriers. Copyright © 2012 S. Karger AG, Basel.

HPLC detection of plasma concentrations of diclofenac in human volunteers administered with povidone-ethylcellulose-based experimental transdermal matrix-type patches.

PubMed

Mukherjee, B; Mahapatra, S; Das, S; Roy, G; Dey, S

2006-06-01

By developing a high-performance liquid chromatography (HPLC) method, we estimated the blood concentrations of diclofenac in human volunteers administered with the transdermal patches prepared with povidone-ethylcellulose and oral diclofenac tablets. Drug-excipient interaction studies were done using the FTIR technique. The external morphology of the prepared patch before and after application to human skin was analyzed with scanning electron microscopy. FTIR studies revealed that there was no predominant interaction between the drug and polymers. In vivo studies revealed that the average concentrations of drug in plasma were 376, 1562, 2953, 2902, 2864, and 2948 ng/ml after 2, 4, 8, 24, 30, and 48 h from patches each containing 50 mg of diclofenac diethylamine, respectively, and the mean concentrations of drug in plasma after the oral administration of marketed tablet containing 50 mg diclofenac sodium were 383.7, 2569, 3693.5, 162.5, and 55.3 ng/ml at 2, 4, 8, 24, and 30 h after oral administration. Values of Cmax were 3693.5 after oral administration and 2953.8 ng/ml in the case of transdermal application. From this study, we have achieved the sustained blood level of diclofenac from the experimental patches along with an analytical method based on HPLC to determine the diclofenac blood level. Copyright 2006 Prous Science.

Improvement in bioavailability of transdermally applied flurbiprofen using tulsi (Ocimum sanctum) and turpentine oil.

PubMed

Charoo, Naseem Ahmad; Shamsher, Areeg Anwer Ali; Kohli, Kanchan; Pillai, Krishna; Rahman, Ziyaur

2008-09-01

Penetration enhancing potential of tulsi and turpentine oil on transdermal delivery of flurbiprofen, a potent non-steroidal anti-inflammatory agent, was investigated. The transdermal permeation rate of flurbiprofen across the rat abdominal skin from binary solvent mixture composition of propylene glycol (PG):isopropyl alcohol (IPA) (30:70%, v/v) was 98.88 microg/cm(2)/h, significantly higher than other binary solvent mixtures. The corresponding steady state plasma concentration, 0.71 microg/ml, was much lower than required steady state plasma concentration of 3-5 microg/ml. Hence influence of tulsi and turpentine oil in the optimized binary solvent mixture along with the increased drug load on the flurbiprofen permeation was evaluated. The magnitude of the flux enhancement factor with turpentine oil and tulsi oil was 2.4 and 2.0 respectively at 5% (v/v) concentration beyond which there was no significant increase in the flux. Addition of 2% (w/v) hydroxypropyl methylcellulose (HPMC), as a thickening agent, resulted in desired consistency for the fabrication of patch with insignificant effect on permeation rate of flurbiprofen. The reservoir type of transdermal patch formulation, fabricated by encapsulating the flurbiprofen reservoir solution within a shallow compartment moulded from polyester backing film and microporous ethyl vinyl acetate membrane, did not modulate the skin permeation of flurbiprofen through rat skin in case of turpentine formulations whereas flux of formulations with tulsi oil was significantly altered. The influence of penetration enhancer and solvents on the anatomical structure of the rat skin was studied. Enhancement properties exhibited by turpentine oil and tulsi oil in optimized binary solvent mixture were superior as compared to solvent treated and normal control groups with negligible skin irritation. The fabricated transdermal patches were found to be stable. The bioavailability of flurbiprofen with reference to orally administered flurbiprofen in albino rats was found to increase by 2.97, 3.80 and 5.56 times with transdermal patch formulation without enhancer, tulsi and turpentine oil formulations, respectively. The results were confirmed by pharmacodynamic studies in rat edema inflammation model.

Not so patchy story of attempted suicide…leading to 24 hours of deep sleep and survival!

PubMed

Trist, Adam Joseph; Sahota, Hardeep; Williams, Lucy

2017-01-17

Here, we present a somewhat unusual suicide attempt where, despite an unbelievable overdose with transdermal fentanyl patches, the patient survived. The patient-a woman aged 70 years, who has suffered from chronic back pain despite starting transdermal fentanyl patches in 2007. The unconventional method of attempted suicide was based on online research into deaths from fentanyl patch toxicity. She had gradually accumulated 100 µg fentanyl patches from repeat prescriptions, applying 14 patches with fatal intent, alongside 2 45 mg mirtazapine tablets, and concurrent therapeutic doses of tramadol and morphine sulfate oral solution. However, after 24 hours, she awoke from a deep sleep to the sound of the telephone ringing, somewhat amazed her drastic efforts had failed. During admission to Great Western hospital, she was seen by liaison psychiatry and subsequently transferred to the care of the pain management team, to which she had already been referred. 2017 BMJ Publishing Group Ltd.

Polymer microneedles fabricated from alginate and hyaluronate for transdermal delivery of insulin.

PubMed

Yu, Weijiang; Jiang, Guohua; Zhang, Yang; Liu, Depeng; Xu, Bin; Zhou, Junyi

2017-11-01

To reduce the inconvenient and painful of subcutaneous needle injection, the polymer microneedle patches that fabricated from modified alginate and hyaluronate were prepared for transdermal delivery of insulin. The as-prepared microneedles (MNs) exhibited excellent mechanical strength to penetrate the skin and good degradability to release loaded insulin. In vitro skin insertion capability was determined by staining with tissue-marking dye after insertion, and the real-time penetration depth was monitored using optical coherence tomography. Confocal microscopy images revealed that the rhodamine B and fluorescein isothiocyanate-labeled insulin (FITC-insulin) can gradually diffuse from the puncture sites to deeper tissue. In vivo and pharmacodynamic studies were then conducted to estimate the feasibility of the administration of insulin-loaded microneedle patches on diabetic mice for glucose regulation. The relative pharmacologic availability (RPA) and relative bioavailability (RBA) of insulin from microneedle patches were 90.5±6.8% and 92.9±7%, respectively. These results suggests the MNs developed in this study have a promising application in diabetes treatment via transdermal delivery. Copyright © 2017 Elsevier B.V. All rights reserved.

The transdermal formulation of rivastigmine improves caregiver burden and treatment adherence of patients with Alzheimer's disease under daily practice conditions

PubMed Central

Adler, G; Mueller, B; Articus, K

2014-01-01

Background Rivastigmine is the only cholinesterase inhibitor (ChEI) available as transdermal patch. The patch was developed to improve gastrointestinal tolerability and treatment adherence to higher dosages as compared with oral medication. Preferences of patients and caregivers for the patch were reported; however, neither patient compliance nor caregiver burden has yet been measured under routine practice conditions. Methods This was a prospective, multi-centre, observational study in patients with Alzheimer's disease treated with rivastigmine patch in Germany. To compare the transdermal with oral dosage forms, physicians were asked to enrol patients who recently switched from oral to transdermal medication. Beyond effectiveness and tolerability, outcome measures were drug adherence evaluated by the Morisky questionnaire, and caregiver burden, measured as the daily time expenditure for dressing the patient, controlling appearance and administration of medication. Results In total, 1104 outpatients (57.5% female gender; mean age 77 ± 7 years) were enrolled in 220 sites. After 6 months of treatment, 67.5% of patients had an improved Clinical Global Impression and the Mini-Mental State Examination score increased from 19.0 ± 5.1 to 20.0 ± 5.2 (p < 0.001); 84.1% of patients were still on treatment, 64.6% on the target dose of 9.5 mg/day. Compliance and patient satisfaction with therapy continuously increased over the study period and average time savings of caregivers added up to 20 min/day. In general, tolerability was deemed good and there were no unexpected adverse events. Conclusions Transdermal rivastigmine is an effective treatment alternative, which may improve adherence and treatment satisfaction of the patient and relieve the caregiver. Controlled parallel-group trials are warranted. Clinical trials registration: none (observational study). PMID:24588972

The transdermal formulation of rivastigmine improves caregiver burden and treatment adherence of patients with Alzheimer's disease under daily practice conditions.

PubMed

Adler, G; Mueller, B; Articus, K

2014-04-01

Rivastigmine is the only cholinesterase inhibitor (ChEI) available as transdermal patch. The patch was developed to improve gastrointestinal tolerability and treatment adherence to higher dosages as compared with oral medication. Preferences of patients and caregivers for the patch were reported; however, neither patient compliance nor caregiver burden has yet been measured under routine practice conditions. This was a prospective, multi-centre, observational study in patients with Alzheimer's disease treated with rivastigmine patch in Germany. To compare the transdermal with oral dosage forms, physicians were asked to enrol patients who recently switched from oral to transdermal medication. Beyond effectiveness and tolerability, outcome measures were drug adherence evaluated by the Morisky questionnaire, and caregiver burden, measured as the daily time expenditure for dressing the patient, controlling appearance and administration of medication. In total, 1104 outpatients (57.5% female gender; mean age 77 ± 7 years) were enrolled in 220 sites. After 6 months of treatment, 67.5% of patients had an improved Clinical Global Impression and the Mini-Mental State Examination score increased from 19.0 ± 5.1 to 20.0 ± 5.2 (p < 0.001); 84.1% of patients were still on treatment, 64.6% on the target dose of 9.5 mg/day. Compliance and patient satisfaction with therapy continuously increased over the study period and average time savings of caregivers added up to 20 min/day. In general, tolerability was deemed good and there were no unexpected adverse events. Transdermal rivastigmine is an effective treatment alternative, which may improve adherence and treatment satisfaction of the patient and relieve the caregiver. Controlled parallel-group trials are warranted. none (observational study). © 2014 Novartis Pharma GmbH. International Journal of Clinical Practice published by John Wiley & Sons Ltd.

Management of an oral ingestion of transdermal fentanyl patches: a case report and literature review.

PubMed

Faust, Andrew C; Terpolilli, Ralph; Hughes, Darrel W

2011-01-01

Purpose. Fentanyl is available as a transdermal system for the treatment of chronic pain in opioid-tolerant patients; however, it carries a black box warning due to both the potency of the product and the potential for abuse. In this report, we describe a case of transbuccal and gastrointestinal ingestion of fentanyl patches and the management of such ingestion. Summary. A 32-year-old man was brought to the emergency department (ED) via emergency medical services for toxic ingestion and suicide attempt. The patient chewed and ingested two illegally purchased transdermal fentanyl patches. In the ED, the patient was obtunded, dizzy and drowsy. Initial vital signs showed the patient to be afebrile and normotensive with a heart rate of 63, respiratory rate of 16, and oxygen saturation of 100% on 2 liters nasal cannula after administration of 2 milligrams of intravenous naloxone. The patient was treated with whole bowel irrigation and continuous intravenous naloxone infusion for approximately 48 hours without complications. Conclusion. Despite numerous case reports describing oral ingestion of fentanyl patches, information on the management of such intoxication is lacking. We report successful management of such a case utilizing whole bowel irrigation along with intravenous push and continuous infusion naloxone.

Management of an Oral Ingestion of Transdermal Fentanyl Patches: A Case Report and Literature Review

PubMed Central

Faust, Andrew C.; Terpolilli, Ralph; Hughes, Darrel W.

2011-01-01

Purpose. Fentanyl is available as a transdermal system for the treatment of chronic pain in opioid-tolerant patients; however, it carries a black box warning due to both the potency of the product and the potential for abuse. In this report, we describe a case of transbuccal and gastrointestinal ingestion of fentanyl patches and the management of such ingestion. Summary. A 32-year-old man was brought to the emergency department (ED) via emergency medical services for toxic ingestion and suicide attempt. The patient chewed and ingested two illegally purchased transdermal fentanyl patches. In the ED, the patient was obtunded, dizzy and drowsy. Initial vital signs showed the patient to be afebrile and normotensive with a heart rate of 63, respiratory rate of 16, and oxygen saturation of 100% on 2 liters nasal cannula after administration of 2 milligrams of intravenous naloxone. The patient was treated with whole bowel irrigation and continuous intravenous naloxone infusion for approximately 48 hours without complications. Conclusion. Despite numerous case reports describing oral ingestion of fentanyl patches, information on the management of such intoxication is lacking. We report successful management of such a case utilizing whole bowel irrigation along with intravenous push and continuous infusion naloxone. PMID:21629807

Polyurethanes as self adhesive matrix for the transdermal drug delivery of testosterone.

PubMed

Gansen, P; Dittgen, M

2012-05-01

The new technology to manufacture transdermal active patches without solvents or increased temperatures described here is based on polyol and isocyanate reacting to polyurethane (PU) in the presence of the drug. The technology was proven using testosterone (T) as the drug and N,N-Diethyl-m-toluamide (DEET) and Limonene (L) as enhancers for skin permeation. The experimental patches varied in drug content and enhancer concentration. The patches were evaluated regarding adhesion to stainless steel or leather, in vitro drug release and T permeation across human cadaver skin using Franz cell. Comparing the results with those of a parallel investigation of the commercial product, Testopatch(®), adhesion to leather and in vitro drug release of the experimental patches were found to be higher. The steady-state flux (J(SS)) of T from the experimental patches was found lower than Testopatch(®). The flux of the experimental patch P3, which had the highest concentration of DEET and a low concentration of L was comparable to J(SS) of the commercial product, Testopatch(®).

Design and characterization of an adhesive matrix based on a poly(ethyl acrylate, methyl methacrylate).

PubMed

Cilurzo, Francesco; Minghetti, Paola; Pagani, Stefania; Casiraghi, Antonella; Montanari, Luisa

2008-01-01

The main issue in the development of transdermal patches made of poly(ethyl acrylate, methyl methacrylate) (Eudragit NE 40D, PMM) is the shrinkage phenomenon during the spreading of the latex onto the release liner. To solve this problem, the latex is usually freeze-dried and then re-dissolved in an organic solvent (method 1). To simplify the production process, we prepared an adhesive matrix by adding to the commercial PMM latex a plasticizer and an additive (anti-shrinkage agent) that avoids the shrinkage of the water dispersion spread onto the release liner (method 2). In some cases the active ingredient itself, such as potassium diclofenac (DK) and nicotine (NT), works as anti-shrinkage agent. In this work, the effects of the preparation method, types and concentrations of the plasticizer (triacetin and tributyl citrate) on the adhesive properties of the transdermal patches were investigated. The adhesive properties of the prepared patch were determined by texture analysis, peel adhesion test and shear adhesion. The PMM/plasticizer interactions were evaluated by ATR-FTIR spectroscopy. Furthermore, the in vitro skin permeation profiles of DK and NT released from the patch were determined by Franz cell method. Generally speaking, the variables that mainly modify the adhesive properties are the concentration and type of the plasticizer. The skin permeation profiles of DK and NT from the patch prepared by method 2 overlapped with those obtained with the commercial products. The results underline that the PMM latex can be used conveniently in the development of transdermal patches.

Lidocaine self-sacrificially improves the skin permeation of the acidic and poorly water-soluble drug etodolac via its transformation into an ionic liquid.

PubMed

Miwa, Yasushi; Hamamoto, Hidetoshi; Ishida, Tatsuhiro

2016-05-01

Poor transdermal penetration of active pharmaceutical ingredients (APIs) impairs both bioavailability and therapeutic benefits and is a major challenge in the development of transdermal drug delivery systems. Here, we transformed a poorly water-soluble drug, etodolac, into an ionic liquid in order to improve its hydrophobicity, hydrophilicity and skin permeability. The ionic liquid was prepared by mixing etodolac with lidocaine (1:1, mol/mol). Both the free drug and the transformed ionic liquid were characterized by differential scanning colorimetry (DSC), infrared spectroscopy (IR), and saturation concentration measurements. In addition, in vitro skin-permeation testing was carried out via an ionic liquid-containing patch (Etoreat patch). The lidocaine and etodolac in ionic liquid form led to a relatively lower melting point than either lidocaine or etodolac alone, and this improved the lipophilicity/hydrophilicity of etodolac. In vitro skin-permeation testing demonstrated that the Etoreat patch significantly increased the skin permeation of etodolac (9.3-fold) compared with an etodolac alone patch, although an Etoreat patch did not increase the skin permeation of lidocaine, which was consistent with the results when using a lidocaine alone patch. Lidocaine appeared to self-sacrificially improve the skin permeation of etodolac via its transformation into an ionic liquid. The data suggest that ionic liquids composed of approved drugs may substantially expand the formulation preparation method to meet the challenges of drugs which are characterized by poor rates of transdermal absorption. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Preparation and Characterization of Rivastigmine Transdermal Patch Based on Chitosan Microparticles.

PubMed

Sadeghi, Mohsen; Ganji, Fariba; Taghizadeh, Seyyed Mojtaba; Daraei, Bahram

2016-01-01

Here we report a novel approach for preparation of a 6-day transdermal drug delivery system (TDDS) as treatment for mild to moderate Alzheimer's disease. The spray drying method was used to prepare microparticles containing the anti-Alzheimer drug, Rivastigmine, in combination with the natural polymer, chitosan, for transdermal drug delivery applications. The content of the drug was determined by High Performance Liquid Chromatography (HPLC) method which was validated as per FDA guidelines. The morphology and size range of the microparticles were determined; and the effect of drug concentration in the solution injected into the spray dryer on the particles characterizations was studied. The stability of Rivastigmine at high temperature was confirmed using FTIR analysis as well as a validate HPLC assay. The obtained results show that the drug was stable at high temperatures with 7 to 42% loading in the microparticles, and the higher drug concentrations of the solution injected into the spray dryer resulted in increase of the drug loading, surface drug and microparticles distortion. The TDDS containing the microparticles was also prepared with microparticle to dry adhesive ratios of 5, 10 and 15% using acrylic adhesive. Based on adhesion properties of the patches, gained from the probe tack and the peel adhesion 180° tests, and the 15% patch by having more drug content per unit area of the patch, and still having similar adhesion properties was compared to the microparticles-free patch of 5.1% Rivastigmine salt (equivalent to the drug content of the 15% patch) from the permeation point of view by using Franz cell diffusion over 6 days. The drug permeation rate from the microparticle-free patch was slower than the 15% microparticles patch, which is the result of crystallization of Rivastigmine salt in the acrylic adhesive. The 6-day-prepared TDDS can be considered as an alternative for one-week application of 6 Exelon patches.

Effect of isopropyl myristate on the viscoelasticity and drug release of a drug-in-adhesive transdermal patch containing blonanserinEffect of isopropyl myristate on the viscoelasticity and drug release of a drug-in-adhesive transdermal patch containing blonanserinretain-->.

PubMed

Zhao, Chunyi; Quan, Peng; Liu, Chao; Li, Qiaoyun; Fang, Liang

2016-11-01

The purpose of this study was to investigate the effect of isopropyl myristate (IPM), a penetration enhancer, on the viscoelasticity and drug release of a drug-in-adhesive transdermal patch containing blonanserin. The patches were prepared with DURO-TAK ® 87-2287 as a pressure-sensitive adhesive (PSA) containing 5% ( w / w ) of blonanserin and different concentrations of IPM. An in vitro release experiment was performed and the adhesive performance of the drug-in-adhesive patches with different concentrations of IPM was evaluated by a rolling ball tack test and a shear-adhesion test. The glass transition temperature ( T g ) and rheological parameters of the drug-in-adhesive layers were determined to study the effect of IPM on the mechanical properties of the PSA. The results of the in vitro release experiment showed that the release rate of blonanserin increased with an increasing concentration of IPM. The rolling ball tack test and shear-adhesion test showed decreasing values with increasing IPM concentration. The results were interpreted on the basis of the IPM-induced plasticization of the PSA, as evidenced by a depression of the glass transition temperature and a decrease in the elastic modulus. In conclusion, IPM acted as a plasticizer on DURO-TAK ® 87-2287, and it increased the release of blonanserin and affected the adhesive properties of the PSA.

Design of a Drug-in-Adhesive Transdermal Patch for Risperidone: Effect of Drug-Additive Interactions on the Crystallization Inhibition and In Vitro/In Vivo Correlation Study.

PubMed

Weng, Wei; Quan, Peng; Liu, Chao; Zhao, Hanqing; Fang, Liang

2016-10-01

The purpose of this work was to develop and design an appropriate drug-in-adhesive patch for transdermal delivery of risperidone (RISP). Various formulation factors were investigated by in vitro permeation study using excised rabbit skin. Increasing the drug concentration in the pressure sensitive adhesive (PSA) was used to enhance the drug permeation. To overcome the high crystallization tendency of the patch, several crystallization inhibitors such as PVP, PEG, and surfactants and fatty acids were evaluated by microscopy study. The mechanism of crystallization inhibition was investigated by differential scanning calorimetry, nuclear magnetic resonance spectrometer, and FT-IR studies. RISP and its active metabolite were determined after topical application of the optimized transdermal patch, and the in vivo pharmacokinetic parameters were compared with the intravenous administration group. The microscopy study indicated that fatty acid greatly inhibited the crystallization of RISP in PSA. The inhibition was attributed to the drug-additive interaction between amino group of RISP and the carboxyl group of fatty acid which was further confirmed by (1)H-NMR and FT-IR studies. The optimal permeation profile was obtained with the patches containing 5% RISP and 5% oleic acid in Duro-Tak(®) 87-2287. The in vivo pharmacokinetic study exhibited a sustained absorption and metabolism profile and well correlated with the in vitro permeation data. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Impact of 6-month earlier versus postponed initiation of rotigotine on long-term outcome: post hoc analysis of patients with early Parkinson's disease with mild symptom severity.

PubMed

Timmermann, Lars; Asgharnejad, Mahnaz; Boroojerdi, Babak; Dohin, Elisabeth; Woltering, Franz; Elmer, Lawrence W

2015-01-01

Investigate impact of 6-month earlier versus postponed initiation of rotigotine in patients with early Parkinson's disease (PD) with mild symptom severity. Long-term benefit of rotigotine in early-PD has been demonstrated: SP702 (NCT00594165) and SP716 (NCT00599196) were long-term, open-label extensions of double-blind, placebo-controlled studies of 6-month maintenance; rotigotine was well tolerated for up to 6 years, and demonstrated efficacy (Unified Parkinson's Disease Rating Scale [UPDRS] II + III below baseline) for ∼ 2 years (SP702) and ∼ 4 years (SP716). Post hoc analysis of patients at Hoehn and Yahr 1-2; groups defined by treatment received in 6-month double-blind studies: 'Rotigotine-Rotigotine' received rotigotine (n = 221), 'Placebo-Rotigotine' received placebo (n = 125). At the start of open-label rotigotine maintenance, UPDRS II + III mean ± SD change from double-blind baseline was: -8.5 ± 10.6 'Rotigotine-Rotigotine', -7.7 ± 9.0 'Placebo-Rotigotine.' After this initial improvement scores gradually increased: It took ∼ 45 months for mean scores to cross baseline in 'Rotigotine-Rotigotine', and ∼ 21 months in 'Placebo-Rotigotine.' At the time mean UPDRS II + III had crossed baseline in 'Placebo-Rotigotine' (open-label week 84; ∼ 21 months), treatment difference (LS-mean) to 'Rotigotine-Rotigotine' change from baseline was -3.89 (95% CI -6.94, -0.84); p = 0.013. In this post hoc analysis, 6-month earlier initiation of rotigotine resulted in slower return to baseline mean UPDRS II + III; initiation of rotigotine in patients with minimal/no functional disability or impairment may lead to an extended benefit.

In vivo immunomodulatory, cumulative skin irritation, sensitization and effect of d-limonene on permeation of 6-mercaptopurine through transdermal drug delivery.

PubMed

Chandrashekar, N S; Hiremath, Shobha Rani Rajeev

2008-04-01

Using skin as a port for systemic drug administration, transdermal drug delivery has expanded greatly over the last two decades. Our aim was to formulate the single layer drug-in-adhesive transdermal patch for 6-mercaptopurine (6-MP). In vitro permeation study was carried out using modified Franz diffusion cell with and without of different concentration of d-limonene in human cadaver skin. In vivo immunomodulatory was carried out in mice, cumulative skin irritation, sensitization and patch adherence study was done in both mice and human subjects. 6-MP flux increased from 43+/-12.2 microg/cm2h (control) to 162.8+/-32.2 microg/cm2h (6% w/v d-limonene) data was significant (p<0.05), with decrease in the lag time to 35+/-9.3 min compared to control of 90 +/-15.3 min. In vivo immunomodulatory effect was shown in the Balb/c mice with 100 mumol/kg/body wt of animal for 5d (one dose/d) of d-limonene. WBC count of 13469 cells/mm peak was observed on 12th day, bone marrow cells of 26.3 x 10(6) cells/femur and alpha-esterase positive cells of 1259+/-328.4 cells/4000 bone marrow cells. Cumulative skin irritation, sensitisation and patch adherence in animals and human subjects showed no skin irritation and sensitization. Patch adhesion was greater than 90.0% respectively in both human subjects and mice. The percentage of human subjects with adhesive residue was significantly less with scores of zero. d-Limonene proved as good chemical enhancer by increasing in the skin permeability with shortened the lag time. It proved that therapeutic amount of 6-MP can be delivered through transdermal drug delivery.

Buprenorphine: revisiting the efficacy of transdermal delivery system.

PubMed

Kitzmiller, Joseph P; Barnett, Christopher J; Steiner, Nathan S; Stoicea, Nicoleta; Kamar, Nawal; Luzum, Jasmine A; Mikulik, Eduard; Bergese, Sergio D

2015-01-01

Buprenorphine is a lipid-soluble pharmaceutic used in the management of chronic pain. It is a partial agonist at μ-opioid receptors, an antagonist at κ-opioid receptors, an agonist at δ-opioid receptors and a partial agonist at ORL-1 (nociceptin) receptors. An extensive literature search, including Google Scholar and Pubmed database, was conducted. Terms including and associated to 'efficacy of transdermal buprenorphine' were utilized to procure contemporary research articles in order to evaluate and compare the transdermal buprenorphine patch to commonly used traditional pain management medications. Transdermal buprenorphine has demonstrated better efficacy than conventional pain management pharmacotherapies. Side effects were similar to those associated with other opioids and included headache, dizziness, somnolence, constipation, dry mouth, nausea, vomiting, pruritus and erythema. Similar to transdermal delivery systems used with other medication, transdermal buprenorphine was associated with application-site pruritus and application-site reactions. Transdermal buprenorphine has significant potential for managing chronic pain. In addition to increased convenience and efficacy, advantages of transdermal buprenorphine include decreased tolerance and decreased withdrawal.

Rivastigmine From Capsules to Patch: Therapeutic Advances in the Management of Alzheimer’s Disease and Parkinson’s Disease Dementia

PubMed Central

Micca, Joseph L.; Grossberg, George T.; Velting, Drew M.

2014-01-01

Objective: To discuss the pharmacology, mechanism of action, and chemical properties of the cholinesterase inhibitor (ChEI) rivastigmine; to provide a rationale for transdermal delivery and supportive clinical data, along with practical guidance on rivastigmine patch use in Alzheimer’s disease and Parkinson’s disease dementia. Data Sources: Pivotal studies of rivastigmine capsules and patch were identified using PubMed and the rivastigmine US prescribing information. PubMed searches were performed in 2013 using rivastigmine as a keyword. Study Selection: English-language articles related to rivastigmine considered of relevance to primary care physicians were included. Data Synthesis: Pharmacologic differences exist between rivastigmine and ChEIs. Clinical studies demonstrate symptomatic efficacy of oral rivastigmine across all stages of Alzheimer’s disease and mild-to-moderate Parkinson’s disease dementia. However, gastrointestinal adverse events limit access to optimal therapeutic doses. Strategies that lower maximum plasma concentrations (Cmax) and prolong time to Cmax, ie, transdermal delivery, may improve tolerability. Clinical registration studies have demonstrated improved tolerability of rivastigmine 9.5-mg/24-h patch versus 6-mg twice-daily capsules in mild-to-moderate Alzheimer’s disease, and a positive benefit-risk profile of 13.3-mg/24-h versus 9.5-mg/24-h patch in patients needing enhanced efficacy. Clinical data comparing 13.3-mg/24-h versus 4.6-mg/24-h patch in severe Alzheimer’s disease demonstrated efficacy on cognition and activities of daily living. These data led to approval of rivastigmine patch in severe Alzheimer’s disease. Transdermal delivery also has practical advantages, including simple, once-daily administration and a visual indicator of compliance. Potential application site reactions can be minimized and need not be a barrier to treatment. Conclusions: In addition to practical advantages, rivastigmine patch may improve clinical outcomes throughout the course of Alzheimer’s disease by providing access to high-dose efficacy without compromising tolerability. PMID:25667813

Single- and multiple-dose pharmacokinetics of a novel tetramethylpyrazine reservoir-type transdermal patch versus tetramethylpyrazine phosphate oral tablets in healthy normal volunteers, and in vitro/in vivo correlation.

PubMed

Shen, Teng; Xu, Huinan; Weng, Weiyu; Zhang, Jianfang

2013-01-01

A novel reservoir-type transdermal system of 2,3,5,6-tetramethylpyrazine (TMP) was developed containing eucalyptus oil as a penetration enhancer. The single and multiple-dose pharmacokinetic profiles of TMP administrated by TMP transdermal patch were characterized in healthy volunteers using an in vivo, randomized, open-label, two-way crossover design. 2,3,5,6-Tetramethylpyrazine phosphate (TMPP) oral tablets were chosen as reference. Following single/multiple oral administration of 200/100 mg TMPP tablets, a TMP C(max) of 1284/613.5 ng/mL was observed within 0.75 h. Single/multiple applications of the TMP patch yielded mean C(max) of 309/325 ng/mL at a median T(max) of 5/4 h, with steady state achieved at second application. The mean C(min) of the patch was 131±30.38 ng/mL, contrasting to nearly zero for the tablet. Multiple applications of patch produced an accumulative effect over single application. At steady state 250 mg/20 cm(2) TMP patch given daily provided comparable exposure to 100 mg TMPP tablets three times daily (3753.91 versus 3563.67 ng·h/mL). TMP tablets and patch yielded similar steady-state plasma concentrations: C(av) (148.48±51.27, 156.41±40.31 ng/mL). The results demonstrated that TMP patch can achieve a therapeutic effect that is comparable to oral administration, exhibited prolonged and sustained plasma levels, fewer drug fluctuations, lower adverse effects, more convenience, and improved patient compliance. In-vitro permeation through human skin demonstrated zero-order kinetics with the flux of 364 µg/cm(2)/h. The predicted C(av) (163.9 ng/mL) was in agreement with the observed C(av) (156.4 ng/mL).

Effects of Transdermal Tulobuterol in Pediatric Asthma Patients on Long-Term Leukotriene Receptor Antagonist Therapy: Results of a Randomized, Open-Label, Multicenter Clinical Trial in Japanese Children Aged 4-12 Years.

PubMed

Katsunuma, Toshio; Fujisawa, Takao; Mizuho, Nagao; Akira, Akasawa; Nomura, Ichiro; Yamaoka, Akiko; Kondo, Hisashi; Masuda, Kei; Yamaguchi, Koichi; Terada, Akihiko; Ikeda, Masanori; Nishioka, Kenji; Adachi, Yuichi; Kurihara, Kazuyuki

2013-01-01

Few studies have examined the efficacy or safety of a transdermal β2 agonist as add-on medicationto long-term leukotriene receptor antagonist (LTRA) therapy in pediatric asthma patients. In this randomized, open-label, multicenter clinical trial, children aged 4-12 years on long-term LTRA therapy were treated with tulobuterol patches (1-2 mg daily) or oral sustained-release theophylline (usual dose, 4-5 mg_kg daily) for 4 weeks. LTRAs were continued throughout the trial. Outcomes included volume peak expiratory flow (% PEF), fractional exhaled nitric oxide (FeNO), clinical symptoms and adverse events. Thirty-three and 31 patients were treated with tulobuterol patches and theophylline, respectively. % PEF measured in the morning and before bedtime was significantly higher at all times in the treatment period compared with baseline in the tulobuterol patch group (p < 0.001), and was significantly higher in the tulobuterol patch group compared with the theophylline group. FeNO was similar and unchanged from baseline in both groups. There were no drug-related adverse events in either group. These results suggest that short-term use of a transdermal β2 agonist is an effective therapy for pediatric asthma without inducing airway inflammation in children on long-term LTRA therapy. © 2013 Japanese Society of Allergology.

Use of transdermal nicotine in a state-level prescription plan for the elderly. A first look at 'real-world' patch users.

PubMed

Orleans, C T; Resch, N; Noll, E; Keintz, M K; Rimer, B K; Brown, T V; Snedden, T M

1994-02-23

To assess transdermal nicotine use patterns and outcomes in a population of low-income older smokers. A 6-month telephone follow-up survey of smokers filling prescriptions for transdermal nicotine in the first 3 months of 1992. Pennsylvania's Pharmaceutical Assistance Plan for the Elderly, the nation's largest state-level prescription plan for the elderly. A total of 1070 noninstitutionalized male and female smokers aged 65 through 74 years. Self-reported physician/pharmacist advice and adjunctive treatments, concomitant smoking, and 6-month smoking abstinence. Respondents were predominantly long-term heavy smokers. They used nicotine patches for an average of 5 weeks, with few reporting use beyond 3 months or recalling bothersome side effects. Most of those with previous quit attempts rated quitting with the patch "easier." The 29% self-reported 6-month quit rate observed is encouraging. However, compliance with patch use guidelines was far from ideal in this high-risk population: only 54% of respondents received any initial advice or materials from their physicians or pharmacists, fewer than 2% took part in a formal clinic or one-to-one treatment program, and almost half (47%) smoked while using the patch, including 20% who smoked every day. Concomitant smoking was strongly associated with failure to achieve abstinence (P < .001). More frequent contact with physicians and/or pharmacists was associated with less concomitant smoking (P < .001) and higher quit rates (P = .005). This survey offers an important first look at problems and prospects for nicotine patch therapy in older adults, with implications for other groups as well. Prospective studies are needed to clarify optimal treatment regimens and adjuncts.

Acute cholinergic syndrome in a patient with mild Alzheimer's type dementia who had applied a large number of rivastigmine transdermal patches on her body.

PubMed

Suzuki, Yoshiki; Kamijo, Yoshito; Yoshizawa, Tomohiro; Fujita, Yuji; Usui, Kiyotaka; Kishino, Tohru

2017-11-01

A 91-year-old woman was transferred to our Emergency Medical Center and Poison Center with somnolence, hypertension (186/61 mm Hg), and repeated vomiting. Three hours later, 10 transdermal patches, each containing 18 mg of rivastigmine (9.5 mg/24 h), were found on her lower back and both thighs, when miosis, facial and trunk sweating, enhanced bowel sound, hypertension, and sinus tachycardia were noted. She was diagnosed with acute cholinergic syndrome due to rivastigmine poisoning. Her hypertension and sinus tachycardia peaked 8 and 5 h after all the patches were removed, respectively. Her symptoms subsided spontaneously after 17 h. In the present case, our patient was presented with acute cholinergic syndrome due to carbamate intoxication after massive transdermal exposure to rivastigmine. Toxicological analysis revealed a remarkably high estimated serum rivastigmine concentration (150.6 ng/ml) and notably low serum butyrylcholinesterase activity (35 IU/l) on admission, with a markedly prolonged calculated elimination half-life of 6.5 h. Emergency physicians should consider acetylcholinesterase inhibitor exposure (e.g., rivastigmine) when patients are present with acute cholinergic syndrome.

EFFECT OF HYDROPHILIC AND HYDROPHOBIC POLYMER ON IN VITRO DISSOLUTION AND PERMEATION OF BISOPROLOL FUMARATE THROUGH TRANSDERMAL PATCH.

PubMed

Shabbir, Maryam; Ali, Sajid; Raza, Moosa; Sharif, Ali; Akhtar, Furoan Muhammad; Manan, Abdul; Fazli, Ali Raza; Younas, Neelofar; Manzoor, Iqra

2017-01-01

A matrix transdermal patch of bisoprolol fumarate was formulated with different concentrations of Eudragit RS 100 and Methocel E5 with PEG 400 as plasticizer by solvent evaporation technique. Tween 80 was added to the optimized patch to evaluate the effect of permeation enhancer at different concentration through the excised rabbit's skin. The patches were analyzed for weight variation, drug content, swelling index, erosion studies, moisture content, moisture uptake, water vapor transmission rate (WVTR) and water vapor permeability (WVP). In vitro dissolution test was carried out in USP dissolution apparatus V to select the optimized formulation. In vitr skin permeation studies were done in Franz diffusion cell using rabbit skin as a model membrane. The cumulative drug release and flux were determined to compare the result of test patches with a control patch. The greatest enhancement ratio (ER) was obtained in F03-PE with 30% Tween 80. F03-PE seemed to follow zero order kinetics with super case II mechanism of drug release. Statistical ANOVA suggested that there was a significant difference in formulations, steady flux and cumulative permeation rate at different Tween 80 concentrations.

A comparative multicenter study of two transdermal estradiol replacement therapies in the treatment of postmenopausal symptoms.

PubMed

Van Leusden, H A; Albertyn, G; Verlaine, C; Van Ruymbeke, J

1993-01-01

Comparison of the effects of treatment of two transdermal therapeutic systems for estrogen replacement therapy with regard to efficacy, tolerability, and acceptance. Open randomized. Multicenter. A study population of 104 postmenopausal women was randomized on a 1:1 basis to treatment with one of two estradiol patches, System (Cilag) and Estraderm (Ciba-Geigy). Systolic and diastolic BP, hot flushes, night sweating, fatigue, insomnia, depression, nervousness, headache, vaginal discomfort (efficacy variables); bleeding, dermatological symptoms, comfort and adhesiveness of patch, and other possible causes of discontinuation (tolerability); general evaluation by patient (acceptance). Considering all efficacy variables, 53% of Systen and 46% of Estraderm patients found the therapy satisfactory. Tolerability was somewhat higher in the Systen group. Adhesiveness of the patch was significantly better for Systen. Overall, 79% of Systen patients and 62% of Estraderm patients evaluated treatment as "good" or "very good." The majority of patients in both groups found the patch very comfortable or only slightly obtrusive.

Engineering approaches to transdermal drug delivery: a tribute to contributions of prof. Robert Langer.

PubMed

Mitragotri, S

2013-01-01

Transdermal drug delivery continues to provide an advantageous route of drug administration over injections. While the number of drugs delivered by passive transdermal patches has increased over the years, no macromolecule is currently delivered by the transdermal route. Substantial research efforts have been dedicated by a large number of researchers representing varied disciplines including biology, chemistry, pharmaceutics and engineering to understand, model and overcome the skin's barrier properties. This article focuses on engineering contributions to the field of transdermal drug delivery. The article pays tribute to Prof. Robert Langer, who pioneered the engineering approach towards transdermal drug delivery. Over a period spanning nearly 25 years since his first publication in the field of transdermal drug delivery, Bob Langer has deeply impacted the field by quantitative analysis and innovative engineering. At the same time, he has inspired several generations of engineers by collaborations and mentorship. His scientific insights, innovative technologies, translational efforts and dedicated mentorship have transformed the field. © 2013 S. Karger AG, Basel.

A Randomized, Double-Blind, Placebo-Controlled, Laboratory Classroom Assessment of Methylphenidate Transdermal System in Children with ADHD

ERIC Educational Resources Information Center

McGough, James J.; Wigal, Sharon B.; Abikoff, Howard; Turnbow, John M.; Posner, Kelly; Moon, Eliot

2006-01-01

Objective: This study evaluates the efficacy, duration of action, and tolerability of methylphenidate transdermal system (MTS) in children with ADHD. Method: Participants were dose optimized over 5 weeks utilizing patch doses of 10, 16, 20, and 27 mg applied in the morning and worn for 9 hours. Following optimization, 80 participants were…

Transdermal skin patch based on reduced graphene oxide: A new approach for photothermal triggered permeation of ondansetron across porcine skin.

PubMed

Teodorescu, Florina; Quéniat, Gurvan; Foulon, Catherine; Lecoeur, Marie; Barras, Alexandre; Boulahneche, Samia; Medjram, Mohmaed Salah; Hubert, Thomas; Abderrahmani, Amar; Boukherroub, Rabah; Szunerits, Sabine

2017-01-10

The development of a skin-mounted patch capable of controlled transcutaneous delivery of therapeutics through thermal activation provides a unique solution for the controlled release of active principles over long-term periods. Here, we report on a flexible transdermal patch for photothermal triggered release of ondansetron (ODS), a commonly used drug for the treatment of chemotherapy-induced nausea and vomiting and used as model compound here. To achieve this, a dispersion of ODS-loaded reduced graphene oxide (rGO-ODS) nanosheets were deposited onto Kapton to produce a flexible polyimide-based patch. It is demonstrated that ODS loaded Kapton/rGO patches have a high drug delivery performance upon irradiation with a continuous laser beam at 980nm for 10min due to an induced photothermal heating effect. The ability of ODS impregnated Kapton/rGO patches as transdermal delivery scaffolds for ODS across the skin is in addition investigated using porcine ear skin as a model. We show that the cumulative quantity and flux of ODS passing the skin are highly depending on the laser power density used. At 5Wcm -2 irradiation, the ODS flux across pig skin was determined to be 1.6μgcm -2 h -1 comparable to other approaches. The use of tween 20 as skin enhancer could significantly increase the ODS flux to 13.2μgcm -2 h -1 . While the skin penetration enhancement is comparable to that obtained using other well-known permeation enhancers, the actual superiority and interest of the proposed approach is that the Kapton/rGO photoactivatable skin patch can be loaded with any drugs and therapeutics of interest, making the approach extremely versatile. The on demand delivery of drugs upon local laser irradiation and the possibility to reload the interface with the drug makes this new drug administration route very appealing. Copyright © 2016 Elsevier B.V. All rights reserved.

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

PubMed

Urdl, Wolfgang; Apter, Dan; Alperstein, Alan; Koll, Peter; Schönian, Siegfried; Bringer, Jacques; Fisher, Alan C; Preik, Michael

2005-08-01

To investigate contraceptive efficacy, compliance and user's satisfaction with transdermal versus oral contraception (OC). 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. 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). 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.

Nanocrystal cellulose as drug excipient in transdermal patch for wound healing: an overview

NASA Astrophysics Data System (ADS)

Zuki, S. A. Mohd; Rahman, N. Abd; Abu Bakar, N. F.

2018-03-01

Wound must be carefully treated to avoid serious infection that needs costly treatment. Method to enhance the recovery of the wound is crucial to have effective wound treatment. One of the technologies in wound treatment is transdermal patch that has the benefits of being non-invasive, easy to handle and permits constant drug dosage. In order to obtain a good controlled drug release, drug excipient needs to be investigated. Recently, natural Nanocrystal Cellulose (NCC) which can be synthesized from animal, algae, microorganism or plant has been actively used in drug delivery system as excipient. The application of NCC is advantageous due to its large surface area, biodegradable, non-toxic and abundance source.

Hydrogel-Forming Microneedle Arrays for Enhanced Transdermal Drug Delivery

PubMed Central

Donnelly, Ryan F; Singh, Thakur Raghu Raj; Garland, Martin J; Migalska, Katarzyna; Majithiya, Rita; McCrudden, Cian M; Kole, Prashant Laxman; Mahmood, Tuan Mazlelaa Tuan; McCarthy, Helen O; Woolfson, A David

2012-01-01

Unique microneedle arrays prepared from crosslinked polymers, which contain no drug themselves, are described. They rapidly take up skin interstitial fluid upon skin insertion to form continuous, unblockable, hydrogel conduits from attached patch-type drug reservoirs to the dermal microcirculation. Importantly, such microneedles, which can be fabricated in a wide range of patch sizes and microneedle geometries, can be easily sterilized, resist hole closure while in place, and are removed completely intact from the skin. Delivery of macromolecules is no longer limited to what can be loaded into the microneedles themselves and transdermal drug delivery is now controlled by the crosslink density of the hydrogel system rather than the stratum corneum, while electrically modulated delivery is also a unique feature. This technology has the potential to overcome the limitations of conventional microneedle designs and greatly increase the range of the type of drug that is deliverable transdermally, with ensuing benefits for industry, healthcare providers and, ultimately, patients. PMID:23606824

Weight Change After Smoking Cessation Using Variable Doses of Transdermal Nicotine Replacement

PubMed Central

Dale, Lowell C; Schroeder, Darrell R; Wolter, Troy D; Croghan, Ivana T; Hurt, Richard D; Offord, Kenneth P

1998-01-01

OBJECTIVE Examine weight change in subjects receiving variable doses of transdermal nicotine replacement for smoking cessation. DESIGN Randomized, double-blind clinical trial. SETTING One-week inpatient treatment with outpatient follow-up through 1 year. INTERVENTION This report examines weight change after smoking cessation for 70 subjects randomized to placebo or to 11, 22, or 44 mg/d doses of transdermal nicotine. The study included 1 week of intensive inpatient treatment for nicotine dependence with active patch therapy continuing for another 7 weeks. Counseling sessions were provided weekly for the 8 weeks of patch therapy and with long-term follow-up visits at 3, 6, 9, and 12 months. MEASUREMENTS AND MAIN RESULTS Forty-two subjects were confirmed biochemically (i.e., by expired carbon monoxide) to be nonsmokers at all weekly visits during patch therapy. Their 8-week weight change from baseline was 3.0 ±2.0 kg. For these subjects, 8-week weight change was found to be negatively correlated with percentage of cotinine replacement (r=−.38, p=.012) and positively correlated with baseline weight (r=.48, p=.001), and age (r=.35, p=.025). Men had higher (p=.003) 8-week weight gain (4.0 ±1.8 kg) than women (2.1 ±1.7 kg). Of the 21 subjects who abstained continuously for the entire year, 20 had their weight measured at 1-year follow-up. Among these 20 subjects, 1-year weight change was not found to be associated with gender, baseline weight, baseline smoking rate, total dose of transdermal nicotine, or average percentage of cotinine replacement during the 8 weeks of patch therapy. CONCLUSIONS This study suggests that higher replacement levels of nicotine may delay postcessation weight gain. This effect is consistent for both men and women. We could not identify any factors that predict weight change with long-term abstinence from smoking. PMID:9462489

Patient-controlled analgesia: therapeutic interventions using transdermal electro-activated and electro-modulated drug delivery.

PubMed

Indermun, Sunaina; Choonara, Yahya E; Kumar, Pradeep; Du Toit, Lisa C; Modi, Girish; Luttge, Regina; Pillay, Viness

2014-02-01

Chronic pain poses a major concern to modern medicine and is frequently undertreated, causing suffering and disability. Patient-controlled analgesia, although successful, does have limitations. Transdermal delivery is the pivot to which analgesic research in drug delivery has centralized, especially with the confines of needle phobias and associated pain related to traditional injections, and the existing limitations associated with oral drug delivery. Highlighted within is the possibility of further developing transdermal drug delivery for chronic pain treatment using iontophoresis-based microneedle array patches. A concerted effort was made to review critically all available therapies designed for the treatment of chronic pain. The drug delivery systems developed for this purpose and nondrug routes are elaborated on, in a systematic manner. Recent developments and future goals in transdermal delivery as a means to overcome the individual limitations of the aforementioned delivery routes are represented as well. The approval of patch-like devices that contain both the microelectronic-processing mechanism and the active medicament in a small portable device is still awaited by the pharmaceutical industry. This anticipated platform may provide transdermal electro-activated and electro-modulated drug delivery systems a feasible attempt in chronic pain treatment. Iontophoresis has been proven an effective mode used to administer ionized drugs in physiotherapeutic, diagnostic, and dermatological applications and may be an encouraging probability for the development of devices and aids in the treatment of chronic pain. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association.

Prevention of peripheral side-effects of transdermal hyoscine by adjunctive therapy with low dosage of pyridostigmine.

PubMed Central

Ziv, I; Versano, D; Ruach, M; Izraeli, S; Almog, S; Alhalel, A; Alkalay, M; Menahem, S; Tochner, Z

1992-01-01

1. The value of low dosage of pyridostigmine (30 mg three times daily) in preventing peripheral anti-muscarinic side effects of a transdermal controlled-release formulation of hyoscine, was tested in a double-blind placebo-controlled study, involving 47 healthy subjects. 2. Salivary excretion was repeatedly measured during 48 h of combined therapy of two transdermal hyoscine patches with pyridostigmine and 14 h after its cessation. Blood acetylcholinesterase activity was also measured, serving as an index of pyridostigmine bioavailability. 3. The adjunctive therapy with pyridostigmine was highly effective in preventing the substantial impairment in salivary flow caused by the transdermal formulation. An associated 23% inhibition of blood acetylcholinesterase activity was observed. 4. Small doses of pyridostigmine may therefore have a role in increasing the tolerability of transdermal hyoscine therapy. In some patients this drug combination might also allow some increment of the hyoscine dose. PMID:1524963

Alzheimer’s Disease and Its Treatment With a Novel Transdermal Patch Therapy: Survey of Caregiver Experiences

PubMed Central

Pepp, Mike

2012-01-01

Objective: To investigate experiences and perceptions of caregivers of patients with Alzheimer’s disease using transdermal patch therapy. Method: Assessment methods for the pilot study comprised an interview between the caregiver and a moderator, an interview between 1 moderator and 2 caregivers, or a video diary. The subsequent quantitative study involved a 45-minute telephone questionnaire. For both studies, participants were required to be the principal caregiver of a patient with Alzheimer’s disease who had been receiving transdermal patch therapy for at least 3 months. Their responses were grouped into the following 6 themes: interpersonal relationships, impact on caregivers, from symptoms to treatment, help and support for caregivers, daily routine, and caregiver experience with the patch. Results: Overall, 206 caregivers were enrolled from France, Germany, Greece, Spain, and the United States between July 2009 and January 2011 (pilot study: N = 56; quantitative study: N = 150). The studies revealed that caregivers of patients with Alzheimer’s disease experienced emotional and practical impacts, and many felt that they had not received sufficient information from health care providers about Alzheimer’s disease, treatment options, or available support. In the quantitative study, 47% of caregivers who had been caring for the patient prior to diagnosis (61% of total respondents) felt that there had been a delay in seeking medical advice, frequently due to slow onset of symptoms of Alzheimer’s disease. In both studies, patch therapy was considered more convenient and easier to administer than oral treatments. The practical and efficacy advantages of the patch often translated into emotional benefits. Conclusions: With recent data highlighting the importance of early initiation of symptomatic Alzheimer’s disease therapy and the importance of reaching an optimal therapeutic dose, reasons for delay in treatment initiation need to be explored. Information that patients and caregivers receive at the time of diagnosis may aid therapeutic decisions. PMID:23251856

The pros and cons of transdermal nicotine therapy.

PubMed

Gourlay, S

1994-02-07

To review current knowledge of the efficacy, safety and cost of transdermal nicotine therapy for smoking cessation. 1. Published and unpublished reports of randomised, double-blind trials of at least 12 weeks' duration, in smokers motivated to cease smoking, identified by a search of the MEDLINE database, article and book bibliographies, Current contents, and by a request to the Medical Department of Ciba-Geigy (Australia) Ltd. 2. A clinical trial of 1500 smokers using transdermal nicotine (S Gourlay, unpublished data). Transdermal nicotine more than doubles the success rates of smoking cessation attempts in motivated subjects who smoke at least 10-15 cigarettes per day (odds ratio 12 months after quitting, 2.3; 95% confidence interval, 1.6-3.4). Application site reactions are not uncommon (erythema or burning < or = 16%, transient itch < or = 50%) and cause discontinuation of therapy in up to 10% of subjects. Sleep disturbance due to nocturnal nicotine absorption occurs in up to 13% of subjects when patches are worn overnight. Smoking or nicotine chewing gum used concurrently with transdermal nicotine could raise peak nicotine levels but is unlikely to adversely affect individuals with established tolerance to nicotine. Smoking and (theoretically) nicotine replacement therapies should be avoided in pregnancy or patients with unstable coronary artery disease. In such patients, the risk-benefit ratio of nicotine replacement therapies may be favourable for nicotine-dependent smokers unable to cease smoking by alternative methods. Transdermal nicotine is an effective smoking cessation therapy for motivated, nicotine-dependent smokers. As most smokers can cease smoking on their own, and the patches are costly, they should be recommended only for smokers who are unable to quit by simpler means and those likely to suffer severe nicotine withdrawal symptoms.

Rotigotine Improves Abnormal Circadian Rhythm of Blood Pressure in Parkinson's Disease.

PubMed

Oka, Hisayoshi; Nakahara, Atuso; Umehara, Tadashi

2018-05-15

Cardiovascular autonomic failure is commonly associated with Parkinson's disease (PD), affecting the daily lives of patients. Rotigotine was recently reported not to influence cardiovascular autonomic responses in contrast to other dopaminergic drugs. The effect of rotigotine on daily blood pressure (BP) fluctuations might reflect autonomic failure in patients with PD. Twenty-five PD patients who were receiving rotigotine and 12 patients not receiving rotigotine were recruited. Systolic BP during the daytime and nighttime was measured by 24-h BP monitoring at an interval of 2 years. The patients were divided into 3 groups according to the BP fluctuation type: dippers (nocturnal fall in BP ≥10%), non-dippers (0-10%), and risers (< 0%). The time course of BP was compared between the patients given rotigotine and those not given rotigotine. Among the 25 patients who received rotigotine, the BP type worsened in 2 patients, was unchanged in 16 patients, and improved in 7 patients. Among the 12 patients who were not receiving rotigotine, the BP type worsened in 5 patients, was unchanged in 4 patients, and improved only in 3 patients (p = 0.042). Rotigotine improves the abnormal circadian rhythm of BP in patients with PD. Rotigotine was suggested to have favorable effects on cardiovascular autonomic responses and circadian rhythm in patients with PD. © 2018 S. Karger AG, Basel.

Identification of the Human SULT Enzymes Involved in the Metabolism of Rotigotine.

PubMed

Jia, Chaojun; Luo, Lijun; Kurogi, Katsuhisa; Yu, Juming; Zhou, Chunyang; Liu, Ming-Cheh

2016-06-01

Sulfation has been reported to be a major pathway for the metabolism and inactivation of rotigotine in vivo. The current study aimed to identify the human cytosolic sulfotransferase (SULT) enzyme(s) capable of mediating the sulfation of rotigotine. Of the 13 known human SULTs examined, 6 of them (SULT1A1, 1A2, 1A3, 1B1, 1C4, 1E1) displayed significant sulfating activities toward rotigotine. pH dependence and kinetic parameters of the sulfation of rotigotine by relevant human SULTs were determined. Of the 6 human organ samples tested, small intestine and liver cytosols displayed considerably higher rotigotine-sulfating activity than did brain, lung, and kidney. Moreover, sulfation of rotigotine was shown to occur in HepG2 human hepatoma cells and Caco-2 human colon adenocarcinoma cells under metabolic conditions. Collectively, the results obtained provided a molecular basis underlying the previous finding of the excretion of sulfated rotigotine by patients undergoing treatment with rotigotine. © 2015, The American College of Clinical Pharmacology.

Attitudes Towards the Vaginal Ring and Transdermal Patch Among Adolescents and Young Women

PubMed Central

Raine, Tina R.; Epstein, Laura B.; Harper, Cynthia C.; Brown, Beth A.; Boyer, Cherrie B.

2009-01-01

Purpose The vaginal ring and the transdermal patch offer important contraceptive options for women at high risk of unintended pregnancy. Little is known about what adolescents and young women think about these methods and why use of the ring has been relatively low compared to the patch. We sought to examine young women’s attitudes and perceptions about the ring and the patch to better understand the relationship between perceptions of these methods and decisions to use them. Methods Sixteen focus groups of young women aged 15–26 years (n=113) from family planning clinics in the San Francisco Bay Area were convened. Data from the focus groups were analyzed using standard content analysis. Results While young women expressed apprehension and doubt about both methods, for the most part women expressed more positive attitudes about the patch. Two related themes for the ring and the patch were identified: “lack of trust in effectiveness,” and “method use concerns. Two themes unique to the ring: “concerns regarding vaginal insertion” and “sexual partner perceptions” and three themes unique to the patch: “ease of remembering”, “visibility issues”, and “perceived health risk” were identified. Conclusions Increased provider education about apprehensions related to the ring and the patch may lead to increased use of the ring and counter recent declines in use of the patch. It would be unfortunate if these safe and effective options for young women are underutilized because negative attitudes and perceptions about these methods act as barriers to adoption. PMID:19699422

Transdermal Scopolamine and Acute Postoperative Urinary Retention in Pelvic Reconstructive Surgery.

PubMed

Propst, Katie; OʼSullivan, David M; Tulikangas, Paul K

2016-01-01

To evaluate the relationship between perioperative use of transdermal scopolamine and the rate of urinary retention after stress urinary incontinence and pelvic organ prolapse procedures in women. This is a retrospective, cohort study; the primary outcome is the rate of acute postoperative urinary retention. Study candidates were adult female patients who underwent pelvic reconstructive surgery at a tertiary care center. Subjects were excluded if preoperative postvoid residual urine volume was greater than 150 mL, preoperative urodynamic testing was not performed, or if a postoperative trial of void was not performed. Subjects were grouped based on preoperative use of transdermal scopolamine. Patients were selected consecutively until 138 subjects per group was reached. Differences in rates of acute postoperative urinary retention were evaluated using a chi-square test. Group demographics were evaluated using t tests and χ tests. Two hundred seventy-six subjects were included in the analysis, 138 received a transdermal scopolamine patch in the perioperative period and 138 did not. The overall rate of acute postoperative urinary retention was 25.3%. There was no significant difference in the rate of acute postoperative urinary retention between the study groups (scopolamine, 26.8%; no scopolamine, 23.9%; P = 0.580). Demographics of the 2 groups were compared; patients who received scopolamine patch were younger (P = 0.001), received a greater amount of intravenous fluids (P = 0.007), and underwent a greater percentage of incontinence procedures (P = 0.048). Otherwise, there were no differences between the groups. Transdermal scopolamine is not a risk factor for acute postoperative urinary retention after pelvic reconstructive procedures.

Repeated applications of a transdermal patch: analytical solution and optimal control of the delivery rate.

PubMed

Simon, L

2007-10-01

The integral transform technique was implemented to solve a mathematical model developed for percutaneous drug absorption. The model included repeated application and removal of a patch from the skin. Fick's second law of diffusion was used to study the transport of a medicinal agent through the vehicle and subsequent penetration into the stratum corneum. Eigenmodes and eigenvalues were computed and introduced into an inversion formula to estimate the delivery rate and the amount of drug in the vehicle and the skin. A dynamic programming algorithm calculated the optimal doses necessary to achieve a desired transdermal flux. The analytical method predicted profiles that were in close agreement with published numerical solutions and provided an automated strategy to perform therapeutic drug monitoring and control.

Role of pressure-sensitive adhesives in transdermal drug delivery systems.

PubMed

Lobo, Shabbir; Sachdeva, Sameer; Goswami, Tarun

2016-01-01

Transdermal drug delivery systems (TDDS) are employed for the delivery of drugs across skin into the systemic circulation. Pressure-sensitive adhesive (PSA) is one of the most critical components used in a TDDS. The primary function of PSA is to help in adhesion of patch to skin, but more importantly it acts as a matrix for the drug and other excipients. Hence, apart from adhesion of the patch, PSA also affects other critical quality attributes of the TDDS such as drug delivery, flux through skin and physical and chemical stability of the finished product. This review article provides a summary of the adhesives used in various types of TDDS. In particular, this review will cover the design types of TDDS, categories of PSAs and their evaluation and regulatory aspects.

Spray-on transdermal drug delivery systems.

PubMed

Ibrahim, Sarah A

2015-02-01

Transdermal drug delivery possesses superior advantages over other routes of administration, particularly minimizing first-pass metabolism. Transdermal drug delivery is challenged by the barrier nature of skin. Numerous technologies have been developed to overcome the relatively low skin permeability, including spray-on transdermal systems. A transdermal spray-on system (TSS) usually consists of a solution containing the drug, a volatile solvent and in many cases a chemical penetration enhancer. TSS promotes drug delivery via the complex interplay between solvent evaporation and drug-solvent drag into skin. The volatile solvent carries the drug into the upper layers of the stratum corneum, and as the volatile solvent evaporates, an increase in the thermodynamic activity of the drug occurs resulting in an increased drug loading in skin. TSS is easily applied, delivering flexible drug dosage and associated with lower incidence of skin irritation. TSS provides a fast-drying product where the volatile solvent enables uniform drug distribution with minimal vehicle deposition on skin. TSS ensures precise dose administration that is aesthetically appealing and eliminates concerns of residual drug associated with transdermal patches. Furthermore, it provides a better alternative to traditional transdermal products due to ease of product development and manufacturing.

Neuroprotective effect of rotigotine against complex I inhibitors, MPP⁺ and rotenone, in primary mesencephalic cell culture.

PubMed

Radad, Khaled; Scheller, Dieter; Rausch, Wolf-Dieter; Reichmann, Heinz; Gille, Gabrielle

2014-01-01

Dopamine agonists are suggested to be more efficacious in treating Parkinson's disease (PD) as they have neuroprotective properties in addition to their receptor-related actions. The present study was designed to investigate the neuroprotective effects of rotigotine, a D3/D2/D1 dopamine receptor agonist, against the two powerful complex I inhibitors, 1-methyl-4-phenylpyridinium (MPP+) and rotenone, in primary mesencephalic cell culture relevant to PD. Primary mesencephalic cell cultures were prepared from embryonic mouse mesencephala at gestation day 14. Three sets of cultures were treated with rotigotine alone, rotigotine and MPP⁺, and rotigotine and rotenone to investigate the effect of rotigotine on the survival of dopaminergic neurons against age-, MPP⁺- and rotenone-induced cell death. At the end of each treatment, cultures were fixed and stained immunohistochemically against tyrosine hydroxylase (TH). The effect of rotigotine against rotenone-induced reactive oxygen species (ROS) production was measured using CH-H2DCFDA fluorescence dye. Rotigotine alone did not influence the survival of tyrosine hydroxylase immunoreactive (THir) neurons except at 10 µM, it significantly decreased the number of THir neurons by 40% compared to untreated controls. Treatment of cultures with 0.01 µM rotigotine rescued 10% of THir neurons against MPP⁺-induced cell death. Rotigotine was also found to significantly rescue 20% of THir neurons at 0.01 µM of rotenone-treated cultures. Using of CH-H2DCFDA fluorescence dye, it was found that rotigotine significantly attenuated ROS production compared to rotenone-treated cultures. Rotigotine provides minor protection against MPP⁺ and rescues a significant number of THir neurons against rotenone in primary mesencephalic cell cultures relevant to PD.

Behavior Therapy and the Transdermal Nicotine Patch: Effects on Cessation Outcome, Affect, and Coping.

ERIC Educational Resources Information Center

Cinciripini, Paul M.; And Others

1996-01-01

Process and outcome of a smoking cessation program using behavior therapy along (BT) or behavior therapy plus the nicotine patch (BTP) was studied in 64 participants. Abstinence was significantly higher for the BTP group from the end of behavioral treatment (79% vs. 63%) through the three-month follow-up, with the effects weakening at the six- and…

Buprenorphine Transdermal Patch

MedlinePlus

... it to direct heat such as heating pads, electric blankets, heat lamps, saunas, hot tubs, and heated ... may make you drowsy. Do not drive a car, operate machinery, or do other possibly dangerous activities ...

Methylphenidate Transdermal Patch

MedlinePlus

... of heat such as hair dryers, heating pads, electric blankets, and heated waterbeds.Be careful not to ... or operate dangerous machinery. Do not drive a car or operate machinery until you know how this ...

Oxybutynin Transdermal Patch

MedlinePlus

... can use baby oil or a medical adhesive removal pad to remove residue that will not come ... room temperature and away from excess heat and moisture (not in the bathroom).Unneeded medications should be ...

Report of a patient chewing fentanyl patches who was titrated onto methadone

PubMed Central

Dale, Eric; Ashby, Fleur; Seelam, Kalyan

2009-01-01

This case report discusses the clinical presentation and management of a patient presenting to substance misuse services reporting chewing fentanyl patches in addition to wearing them transdermally. The patient was successfully titrated onto methadone 30 mg. Only one previously reported case of an individual chewing fentanyl patches was found in the literature; no case reports were found where treatment involved titrating the patient onto methadone. The pharmacology and illicit use of fentanyl are also considered. PMID:22114625

PREPARATION, IN VITRO AND IN VIVO CHARACTERIZATION OF HYDROPHOBIC PATCHES OF A HIGHLY WATER SOLUBLE DRUG FOR PROLONGED PLASMA HALF LIFE: EFFECT OF PERMEATION ENHANCERS.

PubMed

Yaqoob, Ayesha; Ahmad, Mahmood; Mahmood, Asif; Sarfraz, Rai Muhammad

2016-11-01

Aim of present study was to develop metoprolol matrix patches using different enhancers. Combination of two hydrophobic polymers, ethyl cellulose and eudragit RL 100 (8 : 2) were used for preparation of unilaminated matrix patch. 10% w/w of isopropyl myristate (IPM), dimethyl sulfoxide (DMSO), span (20 (S20), Tween 20 (T20) and eucalyptus oil as enhancers and 40% of dibutyl phthalate as plasticizer were used. Prepared patches were evaluated for physical appearance, weight uniformity and thickness. FTIR studies were performed to assess compatibility among ingredients and developed formulation. Dissolution and permeation studies were performed to compare effects of enhancers. Surface morphology after release was examined by scanning electron microscopy. Selected formulation was subjected to in vivo studies by randomized crossover design in rabbits (n = 6) for pharmacokinetic comparison with oral solution administration. Physical evaluation revealed that translucent, flexible, non brittle patches of uniform weight and thickness were prepared. Release from patches followed Higuchi model. Mechanism of release was Fickian. Formulation containing IPM showed that release was by anomalous transport. Highest permeation flux was observed for formulation containing IPM with 2-fold enhancement in permeation. Permeation flux for patches was in order of formulation with no enhancer > IPM > T20 > S20 > DMSO = eucalyptus oil. Plasma concentration from in vivo studies exhibited sustained plasma levels of metoprolol after transdermal patch application in comparison to oral solution administration. Pharmacokinetic analysis of in vivo data elucidated that half life was increased 8 times when compared to oral administration, due to controlled release of drug for longer period of time. These findings suggested that hydrophobic transdermal patches of highly water soluble drug metoprolol were successfully prepared with 10% of IPM for sustained systemic delivery for prolonged half life.

Pharmacokinetics of a granisetron transdermal system for the treatment of chemotherapy-induced nausea and vomiting.

PubMed

Howell, Julian; Smeets, Jean; Drenth, Henk-Jan; Gill, David

2009-12-01

To determine the pharmacokinetic (PK) profile of granisetron transdermal formulation and examine its possible relationship with age, gender, and renal function. This article describes a Phase I PK study and a post hoc pooled population PK analysis. The Phase I study was a randomized, cross-over study that assessed PK parameters of three granisetron patch sizes and oral granisetron. The pooled population PK analysis included data from three trials in healthy subjects (n = 48) and from Phase II and III studies in patients with cancer (n = 793). The population PK model was used to investigate granisetron exposure and its possible relationship with age, gender, and renal function. Following oral dosing, plasma granisetron concentration was quantifiable at 1 h, and maximal mean concentration (4.7 ng/mL) was reached 2 h after administration. With transdermal application, maximal concentration was reached 48 h post-application; t(1/2) was 36 h. With oral dosing, overall exposure after 5 days was 306 ng/mL.h, and C(avg) 2.6 ng/mL. This corresponded to an AUC(0-infinity) for the 52 cm(2) patch of 420 ng/mL.h and C(avg) 2.2 ng/mL over 6 days. Clearance was not affected by age, gender, weight, or renal function. The 52 cm( 2) granisetron patch achieves a similar exposure to that of a 2 mg oral dose and provides continuous delivery of granisetron over 6 days. The patch may have utility in treating chemotherapy-induced nausea and vomiting where prolonged drug delivery is advantageous. No dose adjustments would be needed based on age or renal function.

Methylphenidate Transdermal System: A Multisite, Open-Label Study of Dermal Reactions in Pediatric Patients Diagnosed With ADHD

PubMed Central

Squires, Liza; Li, Yunfeng; Civil, Richard; Paller, Amy S.

2010-01-01

Objective: To characterize dermal reactions and examine methylphenidate (MPH) sensitization in subjects receiving methylphenidate transdermal system (MTS). Method: This multicenter, open-label, dose-optimization study utilized MTS doses of 10, 15, 20, and 30 mg in children aged 6 to 12 years, inclusive (N = 305), with a DSM-IV-TR primary diagnosis of attention-deficit/hyperactivity disorder. The study was conducted between January 8, 2007, and August 23, 2007. Subjects wore MTS on their hips for 9 hours per day, alternating sides daily for a total of 7 weeks. Assessments included the Experience of Discomfort scale, Transdermal System Adherence scale, and Dermal Response Scale (DRS; 0 = no irritation, 7 = strong reaction). On-study reevaluations were conducted to characterize DRS scores ≥ 4. Epicutaneous allergy patch testing was conducted for DRS scores ≥ 6, persistent DRS scores ≥ 4, DRS score increase following an assessment of ≥ 4, or DRS scores of 4 or 5 following elective discontinuation. Results: Approximately half of subjects experienced definite erythema at the patch site that generally dissipated within 24 hours. Four subjects experienced a DRS score of 4 (1%): erythema in 1 subject resolved on study treatment, 2 cases resolved poststudy and subjects tolerated oral MPH, and 1 subject discontinued treatment. The latter subject was referred for patch testing and was diagnosed with allergic contact sensitization to MPH. Conclusions: Few severe dermal effects were seen with MTS treatment. Dermal reactions were characterized as contact dermatitis and dissipated rapidly. On patch testing, 1 subject (0.3%) manifested sensitization to MPH. Trial Registration: clinicaltrials.gov Identifier: NCT00434213 PMID:21494336

Clonidine Transdermal Patch

MedlinePlus

... agonist hypotensive agents. It works by decreasing your heart rate and relaxing the blood vessels so that blood ... doctor may ask you to check your pulse (heart rate) daily and will tell you how rapid it ...

Pharmacokinetic overview of ethinyl estradiol dose and bioavailability using two transdermal contraceptive systems and a standard combined oral contraceptive

PubMed Central

Hofmann, Birte; Reinecke, Isabel; Schuett, Barbara; Merz, Martin; Zurth, Christian

2014-01-01

Objective: To determine the relative bioavailability of ethinyl estradiol (EE) and gestodene (GSD) after application of a novel transdermal contraceptive patch vs. a standard combined oral contraceptive (COC) pill (study 1), and to evaluate the pharmacokinetics (PK) of EE after application of the EE/GSD patch compared with an EE/norelgestromin (NGMN) patch (study 2). Materials: Participants were healthy, non-obese women aged 18 – 45 years (study 1) or 18 – 35 years (study 2). Compositions of study treatments were as follows: 0.55 mg EE/2.1 mg GSD (EE/GSD patch); 0.02 mg EE/0.075 mg GSD (standard COC); 0.6 mg EE/6 mg NGMN (EE/NGMN patch). Methods: In study 1, which consisted of 3 treatment periods (each followed by 7 patch- or pill-free days), treatments were administered in one of two randomized orders: either P–M–E (EE/GSD patch (P) every 7 days for 28 days → COC (M) once-daily for 21 days → two 7-day patch-wearing periods followed by one 10-day patch-wearing phase (E)), or the same treatments administered in sequence M–P–E. For study 2, participants received either the EE/GSD patch or EE/NGMN patch for seven treatment cycles (one patch per week for 3 weeks followed by a 7-day patch-free interval). Results: In study 1, average daily exposure to EE was similar for treatments P and M; the mean daily area under the concentration-time curve (AUC) ratio of treatment P vs. treatment M for EE was 1.06 (90% confidence interval (CI): 0.964 – 1.16), indicating average daily delivery similar to oral administration of 0.019 – 0.023 mg EE. For unbound GSD, average daily exposure was lower for treatment P vs. treatment M. The mean AUC ratio of treatment P vs. treatment M for unbound GSD was 0.820 (90% CI: 0.760 – 0.885), indicating average daily delivery from the patch of 0.057 – 0.066 mg GSD. Prolonged patch wearing did not result in a distinct decline in GSD and EE serum concentrations. In study 2, AUC at steady state (AUC0–168,ss), average steady-state serum concentration, and maximum steady-state serum concentration for EE was 2.0 – 2.7-fold higher for the EE/NGMN patch vs. the EE/GSD patch. The EE/GSD patch was well tolerated in both studies. Conclusions: Based on the 90% CI of the AUC ratio of oral treatment vs. patch application for unbound GSD and EE, the daily doses of GSD and EE released from the EE/GSD patch over the 7-day application period provided the same systemic exposure as those recorded after daily oral administration of a COC containing 0.02 mg EE and 0.06 mg GSD. The EE/GSD patch showed reduced EE exposure compared with the EE/NGMN patch. Together with its good tolerability, these properties support the EE/GSD patch as an effective and well-tolerated alternative to available transdermal and oral contraceptives. PMID:25295716

The androgen-deficient aging male: current treatment options.

PubMed

Tenover, J Lisa

2003-01-01

All delivery forms of testosterone should be equally efficacious in treating the androgen-deficient aging male if adequate serum testosterone levels are obtained. The testosterone preparations available in North America include the oral undecanoate, injectable testosterone esters, the scrotal patch, the nonscrotal transdermal patch, and the transdermal gels. Selection of a specific testosterone preparation for replacement therapy depends on many factors, including the magnitude and pattern of serum testosterone levels produced, side effects of the particular formulation, reversibility if an adverse event should occur, convenience of use, cosmetic issues related to the preparation, and cost. In addition, potential adverse effects of testosterone therapy applicable to all forms of testosterone delivery, such as fluid retention, gynecomastia, polycythemia, worsening of sleep apnea, change in cardiovascular-disease risk, or alterations in prostate health, need to be considered both prior to therapy and during treatment monitoring.

Rotigotine is a potent agonist at dopamine D1 receptors as well as at dopamine D2 and D3 receptors.

PubMed

Wood, Martyn; Dubois, Vanessa; Scheller, Dieter; Gillard, Michel

2015-02-01

Rotigotine acts as a dopamine receptor agonist with high affinity for the dopamine D2, D3, D4 and D5 receptors but with a low affinity for the dopamine D1 receptor. We have investigated this further in radioligand binding and functional studies and compared the profile of rotigotine with that of other drugs used in the treatment of Parkinson's disease (PD). The binding of rotigotine to human dopamine D1, D2, D3, D4 and D5 receptors was determined in radioligand binding studies using [(3)H]rotigotine and compared with that of standard antagonist radioligands. Functional interactions of rotigotine with human dopamine receptors was also determined. [(3)H]rotigotine can be used as an agonist radioligand to label all dopamine receptor subtypes and this can be important to derive agonist affinity estimates. Rotigotine maintains this high affinity in functional studies at all dopamine receptors especially D1, D2 and D3 receptors and, to a lesser extent, D4 and D5 receptors. Rotigotine, like apomorphine but unlike ropinirole and pramipexole, was a potent agonist at all dopamine receptors. Rotigotine is a high-potency agonist at human dopamine D1, D2 and D3 receptors with a lower potency at D4 and D5 receptors. These studies differentiate rotigotine from conventional dopamine D2 agonists, used in the treatment of PD, such as ropinirole and pramipexole which lack activity at the D1 and D5 receptors, but resembles that of apomorphine which has greater efficacy in PD than other dopamine agonists but has suboptimal pharmacokinetic properties. © 2014 The British Pharmacological Society.

Rotigotine is a potent agonist at dopamine D1 receptors as well as at dopamine D2 and D3 receptors

PubMed Central

Wood, Martyn; Dubois, Vanessa; Scheller, Dieter; Gillard, Michel

2015-01-01

Background and Purpose Rotigotine acts as a dopamine receptor agonist with high affinity for the dopamine D2, D3, D4 and D5 receptors but with a low affinity for the dopamine D1 receptor. We have investigated this further in radioligand binding and functional studies and compared the profile of rotigotine with that of other drugs used in the treatment of Parkinson's disease (PD). Experimental Approach The binding of rotigotine to human dopamine D1, D2, D3, D4 and D5 receptors was determined in radioligand binding studies using [3H]rotigotine and compared with that of standard antagonist radioligands. Functional interactions of rotigotine with human dopamine receptors was also determined. Key Results [3H]rotigotine can be used as an agonist radioligand to label all dopamine receptor subtypes and this can be important to derive agonist affinity estimates. Rotigotine maintains this high affinity in functional studies at all dopamine receptors especially D1, D2 and D3 receptors and, to a lesser extent, D4 and D5 receptors. Rotigotine, like apomorphine but unlike ropinirole and pramipexole, was a potent agonist at all dopamine receptors. Conclusions and Implications Rotigotine is a high-potency agonist at human dopamine D1, D2 and D3 receptors with a lower potency at D4 and D5 receptors. These studies differentiate rotigotine from conventional dopamine D2 agonists, used in the treatment of PD, such as ropinirole and pramipexole which lack activity at the D1 and D5 receptors, but resembles that of apomorphine which has greater efficacy in PD than other dopamine agonists but has suboptimal pharmacokinetic properties. PMID:25339241

Pharmacokinetics of a Transdermal Fentanyl Solution in Suffolk Sheep (Ovis aries)

PubMed Central

Jen, Kimberly Y; Dyson, Melissa C; Lester, Patrick A; Nemzek, Jean A

2017-01-01

Sheep used as surgical models require appropriate pain management, and the commonly used transdermal fentanyl patches require a long predosing period to achieve adequate plasma concentrations. The aim of this study was to assess the pharmacokinetic parameters of an FDA-approved transdermal fentanyl solution (TFS) that has yet to be tested in sheep. In this study, we compared TFS at 2.7 mg/kg (n = 2), 1.7 mg/kg (n = 3), and 0.5 mg/kg (n = 3) with the control fentanyl patch at 2 µg/kg/h (n = 1); both products were applied topically to the intrascapular region. Plasma concentrations showed significant interanimal variability. Severe adverse effects occurred at both 2.7 and 1.7 mg/kg TFS and mild to moderate adverse effects were noted at 0.5 mg/kg. At all 3 doses, TFS had greater maximal concentration, clearance rate, and volume of distribution; shorter time to maximal concentration; and similar half-lives to those of the patch. In addition, we validated the use of a commercial human fentanyl ELISA kit, which positively correlated with the liquid chromatography–mass spectroscopy data, but absolute values did not match. Overall, at all 3 dosages tested (0.5, 1.7, and 2.7 mg/kg), TFS delivered fentanyl plasma concentrations that exceeded the minimal effective concentration; however, adverse effects were noted at all 3 dosages. Caution and further study are required before the use of TFS in sheep can be recommended fully. PMID:28903827

In vivo dopamine agonist properties of rotigotine: Role of D1 and D2 receptors.

PubMed

Fenu, Sandro; Espa, Elena; Pisanu, Augusta; Di Chiara, Gaetano

2016-10-05

Rotigotine acts in vitro as a full agonist of dopamine D1 receptors at concentrations almost superimposable to those at which it acts on D2 receptors. However in vivo evidence of the differences between the agonist activity of rotigotine at D1 receptors from that on the D2 receptors has not been provided yet. In order to test the ability of rotigotine to stimulate dopamine D1 and D2 receptors in vivo, we studied the effect of SCH39166 and eticlopride, selective dopamine D1 and D2/D3 receptor antagonists respectively, on rotigotine-induced contralateral turning behavior in 6-hydroxydopamine lesioned rats. Furthermore, the expression of the immediate-early gene c-fos in the caudate-putamen, was evaluated. As a comparison, we tested the D2/D3 agonist pramipexole. In primed rats, rotigotine (0.035, 0.1 and 0.35mg/kg) induced dose-dependent contralateral turning. Turning induced by 0.1mg/kg of rotigotine was reduced by pretreatment with the D1 antagonist SCH39166 and the D2 antagonist eticlopride. In drug-naive rats, rotigotine was less effective in eliciting turning but SCH39166 still reduced turning induced by rotigotine (0.35mg/kg). Pramipexole induced contralateral turning only in primed rats. SCH39166 potentiated and eticlopride abolished pramipexole-induced turning. Rotigotine induced Fos expression in the caudate-putamen and SCH39166 completely blocked it. Pramipexole failed to induce Fos. These results indicate that rotigotine acts in vivo as an agonist of D1 and D2 receptors while pramipexole is devoid of D1 activity in vivo. Given their differing DA receptor profiles, rotigotine and pramipexole might differ in their spectrum of application to the therapy of Parkinson's disease. Copyright © 2016 Elsevier B.V. All rights reserved.

A comparison of bleeding patterns and cycle control using two transdermal contraceptive systems: a multicenter, open-label, randomized study.

PubMed

Gruber, D; Skřivánek, A; Serrani, M; Lanius, V; Merz, M

2015-02-01

To investigate the bleeding pattern and cycle control parameters of a contraceptive patch containing 0.55 mg ethinyl estradiol (EE) and 2.1 mg gestodene (GSD) compared with a patch containing 0.6 mg EE and 6 mg norelgestromin (NGMN). In this phase III, open-label, randomized, parallel-group trial, healthy women aged 18-35 years (smokers aged 18-30 years) received either the EE/GSD patch (n=200) or the EE/NGMN patch (n=198). Treatment consisted of one patch per week for 3 weeks followed by a 7-day, patch-free interval for seven cycles. Bleeding control was assessed in two 90-day reference periods. In reference period 1, mean number of bleeding/spotting days was comparable across treatment groups (p>0.05). However, in reference period 2, there were fewer bleeding/spotting days in the EE/GSD patch group (15.7 versus 18.4; p<0.0001). Mean number of bleeding/spotting episodes was comparable across groups for both reference periods, but bleeding/spotting episodes were shorter for the EE/GSD patch than the EE/NGMN patch during reference period 1 (5.13 days versus 5.53 days, respectively; p<0.05) and reference period 2 (5.07 versus 5.66; p=0.0001). Both treatment groups showed a similar frequency of withdrawal bleeding episodes; however, across all seven cycles, the length of these episodes was consistently shorter with the EE/GSD patch (p<0.01). There were no notable treatment differences in intracyclic bleeding. Bleeding pattern and cycle control achieved with the EE/GSD patch was similar to that of the EE/NGMN patch. The paper presents data on the bleeding pattern and cycle control parameters of an investigational transdermal contraceptive patch containing EE and GSD compared with an approved contraceptive patch containing EE and NGMN. This descriptive study found that bleeding patterns associated with the EE/GSD patch were similar to those of an EE/NGMN patch providing higher EE exposure. Copyright © 2015 Elsevier Inc. All rights reserved.

Ethosomes as delivery system for transdermal administration of vinpocetine.

PubMed

Mao, Yan-Ting; Hua, Hai-Ying; Zhang, Xiang-Guo; Zhu, Dong-Xue; Li, Feng; Gui, Zhen-Hua; Zhao, Yong-Xing

2013-05-01

The purpose of the present study was to develop a novel transdermal vinpocetine patch containing a stable formulation and with good entrapment efficiency, and percutaneous absorption which via ethosome. Ethosome was found to be a more efficient delivery carrier with high encapsulation capacities (79.5% +/- 1.8%) and nanometric size (180.7 +/- 1.5 nm). In vitro percutaneous permeation experiments demonstrated that the permeation of vinpocetine through abdominal skin of Sprague Dawley was significantly increased when ethosome was used. The vinpocetine transdermal fluxes from ethosome gel (3.56 +/- 0.13 microg/cm2/h) were 6.72 and 3.10 times higher than that of vinpocetine gel solution and vinpocetine aueous solution, respectively. Furthermore, the AUC(0 --> infinity), and eliminiation half-life by the transdermal administration were significantly higher than those by the intragastric administration (P < 0.01). The study demonstrated that ethosome is a promising vesicular carrier for enhancing percutaneous absorption of vinpocetine.

Electron beam processed transdermal delivery system for administration of an anti-anginal agent

NASA Astrophysics Data System (ADS)

Kotiyan, P. N.; Vavia, P. R.; Bharadwaj, Y. K.; Sabarwal, S.; Majali, A. B.

2002-12-01

Electron beam irradiation was used to synthesize a matrix type transdermal system of isosorbide dinitrate, an effective anti-anginal agent. The drug was dissolved in two monomeric systems, 2-ethylhexyl acrylate (EHA) and 2-ethylhexyl acrylate : methyl methacrylate (9 : 1). The solutions were then directly irradiated on a backing membrane (Scotchpak ®1006) at different doses to get transdermal patches. The developed systems were evaluated for residual monomer content, equilibrium weight swelling ratio, weight uniformity, thickness uniformity, drug content, peel strength, in vitro release and skin permeation kinetics. They possessed excellent tack and adhesive properties. In the case of isosorbide dinitrate-EHA systems, an increase in the peel strength values with respect to the skin was observed with increasing radiation doses. The systems exhibited promising skin permeation kinetics favorable for transdermal drug delivery. The radiation stability of the drug in the pure solid state form was also assessed.

Nanoparticle-Enabled Transdermal Drug Delivery Systems for Enhanced Dose Control and Tissue Targeting.

PubMed

Palmer, Brian C; DeLouise, Lisa A

2016-12-15

Transdermal drug delivery systems have been around for decades, and current technologies (e.g., patches, ointments, and creams) enhance the skin permeation of low molecular weight, lipophilic drugs that are efficacious at low doses. The objective of current transdermal drug delivery research is to discover ways to enhance skin penetration of larger, hydrophilic drugs and macromolecules for disease treatment and vaccination. Nanocarriers made of lipids, metals, or polymers have been successfully used to increase penetration of drugs or vaccines, control drug release, and target drugs to specific areas of skin in vivo. While more research is needed to identify the safety of nanocarriers, this technology has the potential to expand the use of transdermal routes of administration to a wide array of therapeutics. Here, we review the current state of nanoparticle skin delivery systems with special emphasis on targeting skin diseases.

Nanoparticle enabled transdermal drug delivery systems for enhanced dose control and tissue targeting

PubMed Central

Palmer, Brian C.; DeLouise, Lisa A.

2017-01-01

Transdermal drug delivery systems have been around for decades, and current technologies (e.g. patches, ointments, and creams) enhance the skin permeation of low molecular weight, lipophilic drugs that are efficacious at low doses. The objective of current transdermal drug delivery research is to discover ways to enhance skin penetration of larger, hydrophilic drugs and macromolecules for disease treatment and vaccination. Nanocarriers made of lipids, metals, or polymers have been successfully used to increase penetration of drugs or vaccines, control drug release, and target drugs to specific areas of skin in vivo. While more research is needed to identify the safety of nanocarriers, this technology has the potential to expand the use of transdermal routes of administration to a wide array of therapeutics. Here, we review the current state of nanoparticle skin delivery systems with special emphasis on targeting skin diseases. PMID:27983701

Transdermal Delivery of Drugs with Microneedles—Potential and Challenges

PubMed Central

Ita, Kevin

2015-01-01

Transdermal drug delivery offers a number of advantages including improved patient compliance, sustained release, avoidance of gastric irritation, as well as elimination of pre-systemic first-pass effect. However, only few medications can be delivered through the transdermal route in therapeutic amounts. Microneedles can be used to enhance transdermal drug delivery. In this review, different types of microneedles are described and their methods of fabrication highlighted. Microneedles can be fabricated in different forms: hollow, solid, and dissolving. There are also hydrogel-forming microneedles. A special attention is paid to hydrogel-forming microneedles. These are innovative microneedles which do not contain drugs but imbibe interstitial fluid to form continuous conduits between dermal microcirculation and an attached patch-type reservoir. Several microneedles approved by regulatory authorities for clinical use are also examined. The last part of this review discusses concerns and challenges regarding microneedle use. PMID:26131647

Safety and efficacy of transdermal buprenorphine versus oral tramadol for the treatment of post-operative pain following surgery for fracture neck of femur: A prospective, randomised clinical study.

PubMed

Desai, Sameer N; Badiger, Santhoshi V; Tokur, Shreesha B; Naik, Prashanth A

2017-03-01

Transdermal buprenorphine, which is used in chronic pain management, has rarely been studied for use in acute pain management. The aim of this study was to compare the safety and efficacy of transdermal buprenorphine patch to oral tramadol for post-operative analgesia, following proximal femur surgeries. Fifty adult patients undergoing surgery for hip fracture under spinal anaesthesia were included in this study. One group (Group TDB) received transdermal buprenorphine 10 mcg/h patch applied a day before the surgery and other group received oral tramadol 50 mg three times a day for analgesia (Group OT). They were allowed to take diclofenac and paracetamol tablets for rescue analgesia. Pain scores at rest, on movement, rescue analgesic requirement and side effects were compared between the groups over 7 days. Chi-square and independent sample t -test were used for categorical and continuous variables, respectively. Resting pain scores and pain on movement were significantly lower in TDB Group on all 7 days starting from 24 h post-operatively. Rescue analgesic requirement was significantly lower in TDB Group compared to OT Group. All the patients needed rescue analgesic in OT Group whereas 68% of the patients needed the same in TDB Group. Incidence of vomiting was less and satisfaction scores were much higher in TDB Group as compared to OT Group (79% vs. 66%, P < 0.001). Transdermal buprenorphine can be safely used for post-operative analgesia and is more efficacious in reducing post-operative pain after 24 hours, with fewer side effects when compared to oral tramadol.

Interpretation of urine drug testing results in patients using transdermal buprenorphine preparations for the treatment of chronic noncancer pain.

PubMed

Markman, John D; Barbosa, William A; Gewandter, Jennifer S; Frazer, Maria; Rast, Shirley; Dugan, Michelle; Nandigam, Kiran; Villareal, Armando; Kwong, Tai C

2015-06-01

To determine whether the prevailing liquid chromatography and tandem mass spectroscopy assay (LC-MS/MS) assay designed to monitor buprenorphine compliance of the sublingual formulation used in the substance abuse treatment setting can be extrapolated to the transdermal formulation used in the chronic pain treatment setting, which is 1000-fold less concentrated. Retrospective chart review. Self-reported compliant patients using the transdermal or sublingual formulations of buprenorhphine. Transdermal patch application was also visually confirmed during clinic visits. Urine drug test results from a LC-MS/MS were compared between samples from transdermal and sublingual patients. While all sublingual patients tested positive for at least one metabolite of buprenorphine, only 69% of the transdermal patients did so. In addition, the most abundant metabolite in the transdermal patients was buprenorphine-glucuronide, as compared with norbuprenorphine-glucuronide in sublingual patients. These data suggest that currently available urine drug tests for buprenorphine, including the more expensive LC-MS/MS based assays, may not be sufficiently sensitive to detect the metabolites from transdermal buprenorphine patients. This study highlights the need to evaluate the value and sensitivity of urine drug tests given the wide range of buprenorphine dosing in clinical practice. These results underscore the need for additional cost benefit analyses comparing different confirmatory drug testing techniques including many commercially available drug testing options. © 2014 Wiley Periodicals, Inc. Wiley Periodicals, Inc.

Recent Advances in Skin Penetration Enhancers for Transdermal Gene and Drug Delivery.

PubMed

Amjadi, Morteza; Mostaghaci, Babak; Sitti, Metin

2017-01-01

There is a growing interest in transdermal delivery systems because of their noninvasive, targeted, and on-demand delivery of gene and drugs. However, efficient penetration of therapeutic compounds into the skin is still challenging largely due to the impermeability of the outermost layer of the skin, known as stratum corneum. Recently, there have been major research activities to enhance the skin penetration depth of pharmacological agents. This article reviews recent advances in the development of various strategies for skin penetration enhancement. We show that approaches such as ultrasound waves, laser, and microneedle patches have successfully been employed to physically disrupt the stratum corneum structure for enhanced transdermal delivery. Rather than physical approaches, several non-physical route have also been utilized for efficient transdermal delivery across the skin barrier. Finally, we discuss some clinical applications of transdermal delivery systems for gene and drug delivery. This paper shows that transdermal delivery devices can potentially function for diverse healthcare and medical applications while further investigations are still necessary for more efficient skin penetration of gene and drugs. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Intranasal delivery of rotigotine to the brain with lactoferrin-modified PEG-PLGA nanoparticles for Parkinson's disease treatment.

PubMed

Bi, Chenchen; Wang, Aiping; Chu, Yongchao; Liu, Sha; Mu, Hongjie; Liu, Wanhui; Wu, Zimei; Sun, Kaoxiang; Li, Youxin

Sustainable and safe delivery of brain-targeted drugs is highly important for successful therapy in Parkinson's disease (PD). This study was designed to formulate biodegradable poly(ethylene glycol)-poly(lactic-co-glycolic acid) (PEG-PLGA) nanoparticles (NPs), which were surface-modified with lactoferrin (Lf), for efficient intranasal delivery of rotigotine to the brain for the treatment of PD. Rotigotine NPs were prepared by nanoprecipitation, and the effect of various independent process variables on the resulting properties of NPs was investigated by a Box-Behnken experimental design. The physicochemical and pharmaceutical properties of the NPs and Lf-NPs were characterized, and the release kinetics suggested that both NPs and Lf-NPs provided continuous, slow release of rotigotine for 48 h. Neither rotigotine NPs nor Lf-NPs reduced the viability of 16HBE and SH-SY5Y cells; in contrast, free rotigotine was cytotoxic. Qualitative and quantitative cellular uptake studies demonstrated that accumulation of Lf-NPs was greater than that of NPs in 16HBE and SH-SY5Y cells. Following intranasal administration, brain delivery of rotigotine was much more effective with Lf-NPs than with NPs. The brain distribution of rotigotine was heterogeneous, with a higher concentration in the striatum, the primary region affected in PD. This strongly suggested that Lf-NPs enable the targeted delivery of rotigotine for the treatment of PD. Taken together, these results demonstrated that Lf-NPs have potential as a carrier for nose-to-brain delivery of rotigotine for the treatment of PD.

Intranasal delivery of rotigotine to the brain with lactoferrin-modified PEG-PLGA nanoparticles for Parkinson’s disease treatment

PubMed Central

Bi, Chenchen; Wang, Aiping; Chu, Yongchao; Liu, Sha; Mu, Hongjie; Liu, Wanhui; Wu, Zimei; Sun, Kaoxiang; Li, Youxin

2016-01-01

Sustainable and safe delivery of brain-targeted drugs is highly important for successful therapy in Parkinson’s disease (PD). This study was designed to formulate biodegradable poly(ethylene glycol)–poly(lactic-co-glycolic acid) (PEG-PLGA) nanoparticles (NPs), which were surface-modified with lactoferrin (Lf), for efficient intranasal delivery of rotigotine to the brain for the treatment of PD. Rotigotine NPs were prepared by nanoprecipitation, and the effect of various independent process variables on the resulting properties of NPs was investigated by a Box–Behnken experimental design. The physicochemical and pharmaceutical properties of the NPs and Lf-NPs were characterized, and the release kinetics suggested that both NPs and Lf-NPs provided continuous, slow release of rotigotine for 48 h. Neither rotigotine NPs nor Lf-NPs reduced the viability of 16HBE and SH-SY5Y cells; in contrast, free rotigotine was cytotoxic. Qualitative and quantitative cellular uptake studies demonstrated that accumulation of Lf-NPs was greater than that of NPs in 16HBE and SH-SY5Y cells. Following intranasal administration, brain delivery of rotigotine was much more effective with Lf-NPs than with NPs. The brain distribution of rotigotine was heterogeneous, with a higher concentration in the striatum, the primary region affected in PD. This strongly suggested that Lf-NPs enable the targeted delivery of rotigotine for the treatment of PD. Taken together, these results demonstrated that Lf-NPs have potential as a carrier for nose-to-brain delivery of rotigotine for the treatment of PD. PMID:27994458

The Fentanyl Patch Boil-Up - A Novel Method of Opioid Abuse.

PubMed

Schauer, Cameron K M W; Shand, James A D; Reynolds, Thomas M

2015-11-01

Fentanyl is a potent opioid analgesic used in the treatment of pain. Transdermal fentanyl patches are now widely utilized as an acceptable and efficacious method of medication delivery. Unfortunately, the potential for their abuse is well recognized. Previous case reports have documented deaths after intravenous (IV) misuse of fentanyl which had been extracted from Duragesic (liquid reservoir type) patches. We present a case of IV fentanyl abuse after the extraction from a Mylan (matrix type) patch. This method of abuse has not previously been described in the literature. © 2015 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Dysphagia Causes Symptom Fluctuations after Oral L-DOPA Treatment in a Patient with Parkinson Disease.

PubMed

Sato, Hiromasa; Yamamoto, Toshiyuki; Sato, Masako; Furusawa, Yoshihiko; Murata, Miho

2018-01-01

The causes of "delayed-on" and "no-on" phenomena in Parkinson disease (PD) are thought to have some impact on the progress of L-DOPA from the time of ingestion until it reaches the brain and is converted to dopamine. Dysphagia can cause fluctuating symptom expression in L-DOPA therapy for PD. A 69-year-old man with PD presented with "delayed-on" and "no-on" phenomena. The patient developed a gait disorder at age 60 years, and he began coughing on his food during breakfast at age 64 years. Even though he was independent in daily life, he could not eat because of dysphagia in an "off" state. Videofluoroscopic examination of swallowing in an "off" state revealed bradykinesia of the tongue and the retention of tablets in the epiglottic vallecula. We trained him to keep his tongue in strong contact with the upper incisors before swallowing. After rehabilitation of dysphagia, the frequency of "delayed-on" and "no-on" phenomena decreased, and his peak L-DOPA plasma concentration was elevated. Additionally, transdermal rotigotine (RTG) was initiated at a maintenance dose of 9.0 mg. The patient reported improvement in swallowing, and the frequency of "no-on" phenomena decreased. In PD patients, the "no-on" phenomenon can be caused by posterior contractile dysfunction of the tongue, and it can be improved with training of the tongue and transdermal RTG administration.

Case report of severe bradycardia due to transdermal fentanyl.

PubMed

Hawley, Pippa

2013-09-01

This case report describes a patient who developed severe bradycardia due to transdermal fentanyl. There have been no prior case reports of this occurring in palliative care, but the frequency of association of fentanyl with bradycardia in the anesthesia setting suggests it may be more common than realized. Palliative care settings often have a policy of not routinely checking vital signs, and symptoms of bradycardia could be misinterpreted as the dying process. A patient with recurrent ovarian cancer was admitted with nausea and abdominal pain due to bowel obstruction and fever from a urinary tract infection. A switch from injectable hydromorphone to transdermal fentanyl resulted in symptomatic severe bradycardia within 36 h, without any other signs of opioid toxicity and with good analgesic effect. The fentanyl patch was removed. Atropine was not required. The patient made an uneventful recovery. Transdermal buprenorphine was subsequently used satisfactorily for long-term background pain control, with additional hydromorphone when needed. The delayed absorption of fentanyl via the transdermal route makes early identification of fentanyl-induced bradycardia key to prompt reversal. Patients with resting or relative bradycardia may be at higher than average risk.

Navigating sticky areas in transdermal product development.

PubMed

Strasinger, Caroline; Raney, Sam G; Tran, Doanh C; Ghosh, Priyanka; Newman, Bryan; Bashaw, Edward D; Ghosh, Tapash; Shukla, Chinmay G

2016-07-10

The benefits of transdermal delivery over the oral route to combat such issues of low bioavailability and limited controlled release opportunities are well known and have been previously discussed by many in the field (Prausnitz et al. (2004) [1]; Hadgraft and Lane (2006) [2]). However, significant challenges faced by developers as a product moves from the purely theoretical to commercial production have hampered full capitalization of the dosage forms vast benefits. While different technical aspects of transdermal system development have been discussed at various industry meetings and scientific workshops, uncertainties have persisted regarding the pharmaceutical industry's conventionally accepted approach for the development and manufacturing of transdermal systems. This review provides an overview of the challenges frequently faced and the industry's best practices for assuring the quality and performance of transdermal delivery systems and topical patches (collectively, TDS). The topics discussed are broadly divided into the evaluation of product quality and the evaluation of product performance; with the overall goal of the discussion to improve, advance and accelerate commercial development in the area of this complex controlled release dosage form. Published by Elsevier B.V.

Membranous Dysmenorrhea: A Case Series

PubMed Central

Omar, Hatim A.; Smith, Shawn J.

2007-01-01

The purpose was to illustrate the variability of hormonal contraception of patients that presented with membranous dysmenorrheal. A case analysis chart review was completed on six patients referred to a Pediatric Gynecologist in an academic setting. In each case the patient underwent a thorough pelvic and bimanual exam. Following the initial presentation, each patient continued to be followed on a regular visits. Cases: Two were using the transdermal contraceptive patch and oral contraceptive, but following the expulsion of decidual cast, they were both placed on depot medroxyprogesterone acetate (DMPA) without further complications. Three of the six cases were on DMPA prior to the similar occurrence of membranous dysmenorrheal and following this incident, continued on DMPA without further problems. The final case was on the transdermal patch prior to decidual cast expulsion and remained on this form of hormonal contraception without further complications. These cases indicate that membranous dysmenorrheal is not limited to the use of DMPA. PMID:18060329

Evaluations of dielectric property and drug release profile of 5-FU patches based on plasma charged electrets

NASA Astrophysics Data System (ADS)

Wang, YUAN; Hejuan, LIANG; Ping, HUANG; Xiaoqiang, AN; Jian, JIANG; Lili, CUI

2018-05-01

In the present study, the electret 5-fluorouracil patch was developed, the effective surface potential, piezoelectric coefficient d 33, open-circuit thermally stimulated discharge (TSD) current spectra and shear adhesion of the patch were measured. The drug release profile of the patch was determined by using high performance liquid chromatography method. A stable potential difference which was positively dependent on the surface potential of the electret was generated on two sides of the patch. The measurements of d 33 coefficient, TSD current spectra and adhesion performance showed that the electrostatic field of the electret could cause polarization and cohesive strength decreasing of the matrix molecules, change the distribution and interaction of the drug molecules in patch, therefore to increase the release of drug from the transdermal patch.

Effects of a transdermal lidocaine patch on indicators of postoperative pain in dogs undergoing midline ovariohysterectomy.

PubMed

Merema, Danielle K; Schoenrock, Emily K; Le Boedec, Kevin; McMichael, Maureen A

2017-05-15

OBJECTIVE To determine the effects of a transdermal lidocaine patch (TLP) on indicators of postoperative pain in healthy dogs following ovariohysterectomy. DESIGN Randomized, blinded controlled trial. ANIMALS 40 healthy shelter-owned female dogs admitted to a student surgery program for ovariohysterectomy. PROCEDURES Dogs were randomly assigned to receive after ovariohysterectomy a 5-cm-wide strip of TLP applied topically on both sides of the incision, for the full length of the incision and a wound dressing (n = 19) or a placebo patch (nonmedicated wound dressing; 21). All dogs underwent midline ovariohysterectomy. Immediately afterward, dogs received 2 IM morphine injections, carprofen (SC, q 12 h for 2 days), and the assigned patch (left in place for 18 hours). Postoperative comfort was evaluated by use of the short form of the Glasgow Composite Measures Pain Scale and serum cortisol concentrations measured prior to premedication and 1, 2, 4, 6, 8, 10, and 18 hours after surgery. RESULTS No significant difference in pain scores or serum cortisol concentrations was identified between dogs that received the TLP and dogs that received a placebo patch after ovariohysterectomy. CONCLUSIONS AND CLINICAL RELEVANCE The TLP provided no additional analgesic benefit to dogs treated concurrently with recommended doses of morphine and carprofen following ovariohysterectomy. Additional studies are needed to investigate whether similar results might be achieved in dogs treated concurrently with other analgesics. (J Am Vet Med Assoc 2017;250:1140-1147).

Transdermal absorption of memantin--effect of chemical enhancers, iontophoresis, and role of enhancer lipophilicity.

PubMed

del Rio-Sancho, S; Serna-Jiménez, C E; Calatayud-Pascual, M A; Balaguer-Fernández, C; Femenía-Font, A; Merino, V; López-Castellano, A

2012-09-01

The transdermal administration of memantine may have advantages with respect to oral therapy when treating advanced stages of Alzheimer's disease. With the ultimate objective of administrating memantine through a transdermal patch, the absorption of the drug across skin was evaluated by means of in vitro permeation studies. The effect of several chemical enhancers was studied in order to enhance percutaneous absorption of the memantine. The iontophoretic transdermal transport of memantine hydrochloride using a current density of 0.5 mA/cm(2) was also investigated. Results demonstrated that pre-treatment of the skin with R-(+)-limonene, laurocapram, decenoic acid, or oleic acid produced a statistically significant increment in the transdermal flux of memantine hydrochloride with respect to the control. Iontophoresis exhibited the greatest ability to enhance the flux of drug with respect to the control; nevertheless, the results obtained with R-(+)-limonene indicate that this compound could be of great use as a percutaneous enhancer in a memantine transdermal delivery system. In this study, the relationship between enhancement activity and lipophilicity was also studied. Satisfactory correlations have been obtained between the optimum lipophilicity of the enhancer and n-octanol/water partition coefficients of drugs. This relationship is a very useful tool that could allow to reduce time and to optimize the selection of appropriate enhancers for transdermal formulations. Copyright © 2012 Elsevier B.V. All rights reserved.

The efficacy and tolerability of rotigotine on patients with periodic limb movement in sleep: A systematic review and meta-analysis.

PubMed

Wu, Meng-Ni; Tseng, Ping-Tao; Chen, Tien-Yu; Chen, Yen-Wen; Liou, Li-Min; Lin, Pao-Yen; Hsu, Chung-Yao

2018-01-01

There is still no consensus on the treatment for periodic limb movement in sleep (PLMS). This study aimed to determine the efficacy and tolerability of rotigotine in patients suffering from PLMS. Publications listed in PubMed, ScienceDirect, The Cochrane Library, and ClinicalTrials.gov were reviewed to assess the efficacy of rotigotine on PLMS. Analyses of PLMS frequency before and after rotigotine treatments (pre- and post-intervention studies) and PLMS frequency between placebo and rotigotine treatments (placebo-controlled trial studies) were included in our study. A systematic review and meta-analysis was conducted. Five publications involving 197 participants were included in this study. Among these articles, pre- and post-intervention data involving 55 participants were available from three articles, while placebo-controlled trial data from 107 participants receiving rotigotine and 70 participants receiving a placebo were available from an additional three articles. In the pre- and post-intervention studies, the periodic limb movement index was significantly decreased after therapy with rotigotine with a difference in means of -5.866/h (95% CI, -10.570 to -1.162, p = 0.015). In comparison with the placebo, the use of rotigotine significantly lowered the periodic limb movement index, with a difference in means of -32.105/h (95% CI, -42.539 to -21.671, p < 0.001), reduced the PLMS with arousal index, with a difference in means of -7.160/h (95% CI, -9.310 to -5.010, p < 0.001), and increased the withdrawal rate, with an odds ratio of 3.421 (95% CI, 1.230 to 9.512, p = 0.018). This meta-analysis revealed the considerable efficacy of rotigotine in alleviating the frequency of PLMS. However, the high withdrawal rate should be taken into account.

Safety and Efficacy of Rotigotine for Treating Parkinson's Disease: A Meta-Analysis of Randomised Controlled Trials.

PubMed

Chen, Fei; Jin, Lingjing; Nie, Zhiyu

2017-01-01

We aimed to comprehensively analyse the safety and efficiency of rotigotine for treating Parkinson's disease (PD). We conducted systematic literature searches of Cochrane library, PubMed and Embase databases up to April 2016, with 'Rotigotine', 'Parkinson Disease ' and 'Parkinson's disease' as key searching terms. Outcomes, including Unified Parkinson's Disease Rating Scale (UPDRS) Part III and Part II scores, 'off' time, adverse events (AEs), serious AEs and discontinuation because of AEs, were compared between rotigotine and placebo groups under a fixed or random effect model. For dichotomous and continuous data, risk ratio (RR) and weighted mean difference with their corresponding 95% confidence intervals (95% CIs) were taken as the effect sizes to calculate merged results. Twelve eligible studies were included. For patients with early or advanced PD, rotigotine could significantly improve UPDRS Part III and Part II scores (p < 0.001) and it had significantly higher incidence of AEs than the placebo (p < 0.001). Regarding discontinuation because of AEs, rotigotine showed a significant advantage over placebo in patients with early PD, whereas the overall result demonstrated no statistically significant difference between the groups. Rotigotine can improve daily living and motor ability of patients with PD, although it has higher incidence of AEs. Rotigotine might be more appropriate for patients with advanced PD than for those with early PD. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Rotigotine, a dopamine receptor agonist, increased BDNF protein levels in the rat cortex and hippocampus.

PubMed

Adachi, Naoki; Yoshimura, Aya; Chiba, Shuichi; Ogawa, Shintaro; Kunugi, Hiroshi

2018-01-01

Brain-derived neurotrophic factor (BDNF) critically controls the fate and function of the neuronal network and has received much attention as a target of many brain diseases. Dopaminergic system dysfunction has also been implicated in a variety of neuropsychiatric diseases. Rotigotine, a non-ergot dopamine receptor agonist, is used in the treatment of Parkinson's disease and restless legs syndrome. To investigate the effects of rotigotine on neuronal functions both in vivo and in vitro, rats and primary cortical neurons were administered rotigotine, and the mRNA and protein expression levels of BDNF, its receptor TrkB and downstream signaling molecules, and synaptic proteins were determined. We found that BDNF protein was increased in the cortex and hippocampus of rats after 7days of rotigotine treatment. In contrast, BDNF mRNAs were reduced 6h after rotigotine treatment in cultured neurons presumably through the transient suppression of neuronal activity. We identified differential expression of D1, D2, and D3 receptors in the rat brain and cultured neurons. The observed increase in the expression of BDNF protein in the cortex and hippocampus after subchronic administration of rotigotine suggests that it may exert its medical effect in part through improving BDNF function in the brain. In addition, our results highlight the complex relationships between rotigotine and BDNF expression, which depend on the brain region, time course, and dose of the drug. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Conductive polymer nanotube patch for fast and controlled in vivo transdermal drug delivery

NASA Astrophysics Data System (ADS)

Nguyen, Thao M.

Transdermal drug delivery has created new applications for existing therapies and offered an alternative to the traditional oral route where drugs can prematurely metabolize in the liver causing adverse side effects. Opening the transdermal delivery route to large hydrophilic drugs is one of the greatest challenges due to the hydrophobicity of the skin. However, the ability to deliver hydrophilic drugs using a transdermal patch would provide a solution to problems of other delivery methods for hydrophilic drugs. The switching of conductive polymers (CP) between redox states cause simultaneous changes in the polymer charge, conductivity, and volume—properties that can all be exploited in the biomedical field of controlled drug delivery. Using the template synthesis method, poly(3,4-ethylenedioxythiophene (PEDOT) nanotubes were synthesized electrochemically and a transdermal drug delivery patch was successfully designed and developed. In vitro and in vivo uptake and release of hydrophilic drugs were investigated. The relationship between the strength of the applied potential and rate of drug release were also investigated. Results revealed that the strength of the applied potential is proportional to the rate of drug release; therefore one can control the rate of drug release by controlling the applied potential. The in vitro studies focused on the kinetics of the drug delivery system. It was determined that the drug released mainly followed zero-order kinetics. In addition, it was determined that applying a releasing potential to the transdermal drug delivery system lead to a higher release rate constant (up to 7 times greater) over an extended period of time (˜24h). In addition, over 24 hours, an average of 80% more model drug molecules were released with an applied potential than without. The in vivo study showed that the drug delivery system was capable of delivering model hydrophilic drugs molecules through the dermis layer of the skin within 30 minutes, while the control showed no visible drugs at the same depth. Most importantly, it was determined that the delivery of drugs into the blood stream was stable within 20 minutes. The functionalization of CP was also studied in order to enhance the properties and drug loading capabilities of the polymers. The co-polymerization of poly(3,4-(2-methylene)propylenedioxythiophene) (PMProDot) with polystyrene (PS) and polyvinylcarbazole (PVK) through the highly reactive methylene group was achieved. The modified PMProDot nanotubes demonstrated response times that were two times faster than without modification. The modification of PEDOT nanotubes with polydopamine, a biocompatible polymer, was also investigated and achieved. In depth characterization of functionalized CP demonstrate the ability to fine tune the properties of the polymer in order to achieve the required therapeutic drug release profile.

A statistical experimental design approach to evaluate the influence of various penetration enhancers on transdermal drug delivery of buprenorphine.

PubMed

Taghizadeh, S Mojtaba; Moghimi-Ardakani, Ali; Mohamadnia, Fatemeh

2015-03-01

A series of drug-in-adhesive transdermal drug delivery systems (patch) with different chemical penetration enhancers were designed to deliver drug through the skin as a site of application. The objective of our effort was to study the influence of various chemical penetration enhancers on skin permeation rate and adhesion properties of a transdermal drug delivery system using Box-Behnken experimental design. The response surface methodology based on a three-level, three-variable Box-Behnken design was used to evaluate the interactive effects on dependent variables including, the rate of skin permeation and adhesion properties, namely peel strength and tack value. Levulinic acid, lauryl alcohol, and Tween 80 were used as penetration enhancers (patch formulations, containing 0-8% of each chemical penetration enhancer). Buprenorphine was used as a model penetrant drug. The results showed that incorporation of 20% chemical penetration enhancer into the mixture led to maximum skin permeation flux of buprenorphine from abdominal rat skin while the adhesion properties decreased. Also that skin flux in presence of levulinic acid (1.594 μg/cm(2) h) was higher than Tween 80 (1.473 μg/cm(2) h) and lauryl alcohol (0.843 μg/cm(2) h), and in mixing these enhancers together, an additional effect was observed. Moreover, it was found that each enhancer increased the tack value, while levulinic acid and lauryl alcohol improved the peel strength but Tween 80 reduced it. These findings indicated that the best chemical skin penetration enhancer for buprenorphine patch was levulinic acid. Among the designed formulations, the one which contained 12% (wt/wt) enhancers exhibited the highest efficiency.

Programmable carbon nanotube membrane-based transdermal nicotine delivery with microdialysis validation assay.

PubMed

Gulati, Gaurav Kumar; Chen, Tao; Hinds, Bruce Jackson

2017-01-01

To evaluate the performance of switchable carbon nanotubes (CNT) membrane devices for transdermal nicotine delivery, we have developed an in-vitro microdialysis method that allow us to detect variable transdermal fluxes of nicotine through CNT devices and can be applied directly to in-vivo studies. Microdialysis membranes were placed beneath the porcine skin and its nicotine levels increased 6-8 times when the CNT membrane on skin was turned from OFF to ON state by application of bias. Fluxes in the ON state were approximately 3 times that of commercial nicotine patches and switching times were less than two hours, thus suggesting the improved therapeutic potential of our device. Blue tooth enabled CNT devices that can be programmed by smartphone and coupled with remote counseling application for enhanced smoking cessation treatments. Copyright © 2016. Published by Elsevier Inc.

Transdermal fentanyl: pharmacology and toxicology.

PubMed

Nelson, Lewis; Schwaner, Robert

2009-12-01

To evaluate the underlying pharmacology, safety, and misuse/abuse of transdermal fentanyl, one of the cornerstone pharmacotherapies for patients with chronic pain. Literature was identified through searches of Medline (PubMed) and several textbooks in the areas of pharmacology, toxicology, and pain management. A bibliographical review of articles identified by these searches was also performed. Search terms included combinations of the following: fentanyl, transdermal, patch, pharmacology, kinetics, toxicity, and poisoning. All pertinent clinical trials, retrospective studies, and case reports relevant to fentanyl pharmacology and transdermal fentanyl administered by any route and published in English were identified. Each was reviewed for data regarding the clinical pharmacology, abuse, misuse, and safety of transdermal fentanyl. Data from these studies and information from review articles and pharmaceutical prescribing information were included in this review. Fentanyl is a high-potency opioid that has many uses in the treatment of both acute and chronic pain. Intentional or unintentional misuse, as well as abuse, may lead to significant clinical consequences, including death. Both the US Food and Drug Administration (FDA) and Health Canada have warned of potential pitfalls associated with transdermal fentanyl, although these have not been completely effective in preventing life-threatening adverse events and fatalities related to its inappropriate use. Clinically consequential adverse effects may occur unexpectedly with normal use of transdermal fentanyl, or if misused or abused. Misuse and therapeutic error may be largely preventable through better education at all levels for both the prescriber and patient. The prevention of intentional misuse or abuse may require regulatory intervention.

An observational clinical and video-polysomnographic study of the effects of rotigotine in sleep disorder in Parkinson's disease.

PubMed

Wang, Yan; Yang, Yue-Chang; Lan, Dan-Mei; Wu, Hui -Juan; Zhao, Zhong-Xin

2017-05-01

Sleep disturbance is common in Parkinson's disease (PD) and negatively impacts quality of life. There is little data on how dopamine agonists influence nocturnal sleep in PD, particularly in sleep laboratory data to measure sleep parameters and their changes objectively. The goal of this open-label study was to objectively evaluate the effect of rotigotine on sleep in PD patients by video-polysomnographic methods. A total of 25 PD patients with complaints of nocturnal sleep impairment were enrolled. The sleep quality before and after stable rotigotine therapy was evaluated subjectively through questionnaire assessments and objectively measured by video-polysomnographic methods. The Parkinsonism, depression, anxiety, and quality of life of PD patients were also evaluated through questionnaire assessments. At the end of rotigotine treatment, the PD daytime functioning, motor performance, depression, subjective quality of sleep, and the quality of life improved. Video-polysomnographic analysis showed that the sleep efficiency and stage N1% were increased, while the sleep latency, wake after sleep onset, and the periodic leg movements in sleep index were decreased after rotigotine treatment. Video-polysomnographic analysis confirmed the subjective improvement of sleep after rotigotine treatment. This observation suggests that in PD rotigotine is a treatment option for patients complaining from sleep disturbances.

Fatal fentanyl patch misuse in a hospitalized patient with a postmortem increase in fentanyl blood concentration.

PubMed

Moore, Philip W; Palmer, Robert B; Donovan, Joseph Ward

2015-01-01

Opioid-related mortality happens, even in healthcare settings. We describe serial postmortem fentanyl blood concentrations in a hospital inpatient who fatally abused transdermal fentanyl. This is a single-patient case report. A 42-year-old man with lymphoma was started on transdermal fentanyl therapy while hospitalized for chronic abdominal pain. The patient was last seen awake 1.3 h prior to being found apneic and cyanotic. During the resuscitation attempt, a small square-shaped film was removed from the patient's oropharynx. Femoral blood was collected 0.5 and 2 h postmortem, and the measured fentanyl concentration increased from 1.6 to 14 ng/mL. Study limitations include potential laboratory or collection errors and missing data. (i) Providers must be vigilant for signs of fentanyl patch abuse. (ii) Postmortem blood concentrations are not static postmortem, likely secondary to decreasing pH, increased aqueous solubility, and tissue redistribution, and are therefore unlikely to accurately represent antemortem blood concentrations. © 2014 American Academy of Forensic Sciences.

Post Hoc Analysis of Data from Two Clinical Trials Evaluating the Minimal Clinically Important Change in International Restless Legs Syndrome Sum Score in Patients with Restless Legs Syndrome (Willis-Ekbom Disease)

PubMed Central

Ondo, William G.; Grieger, Frank; Moran, Kimberly; Kohnen, Ralf; Roth, Thomas

2016-01-01

Study Objectives: Determine the minimal clinically important change (MCIC), a measure determining the minimum change in scale score perceived as clinically beneficial, for the international restless legs syndrome (IRLS) and restless legs syndrome 6-item questionnaire (RLS-6) in patients with moderate to severe restless legs syndrome (RLS/Willis-Ekbom disease) treated with the rotigotine transdermal system. Methods: This post hoc analysis analyzed data from two 6-mo randomized, double-blind, placebo-controlled studies (SP790 [NCT00136045]; SP792 [NCT00135993]) individually and as a pooled analysis in rotigotine-treated patients, with baseline and end of maintenance IRLS and Clinical Global Impressions of change (CGI Item 2) scores available for analysis. An anchor-based approach and receiver operating characteristic (ROC) curves were used to determine the MCIC for the IRLS and RLS-6. We specifically compared “much improved vs minimally improved,” “much improved/very much improved vs minimally improved or worse,” and “minimally improved or better vs no change or worse” on the CGI-2 using the full analysis set (data as observed). Results: The MCIC IRLS cut-off scores for SP790 and SP792 were similar. Using the pooled SP790+SP792 analysis, the MCIC total IRLS cut-off score (sensitivity, specificity) for “much improved vs minimally improved” was −9 (0.69, 0.66), for “much improved/very much improved vs minimally improved or worse” was −11 (0.81, 0.84), and for “minimally improved or better vs no change or worse” was −9 (0.79, 0.88). MCIC ROC cut-offs were also calculated for each RLS-6 item. Conclusions: In patients with RLS, the MCIC values derived in the current analysis provide a basis for defining meaningful clinical improvement based on changes in the IRLS and RLS-6 following treatment with rotigotine. Citation: Ondo WG, Grieger F, Moran K, Kohnen R, Roth T. Post hoc analysis of data from two clinical trials evaluating the minimal clinically important change in international restless legs syndrome sum score in patients with restless legs syndrome (Willis-Ekbom Disease). J Clin Sleep Med 2016;12(1):63–70. PMID:26446245

Caregiver Preference and Treatment Compliance in Patients with Mild-to-Moderate Alzheimer's Disease in South Korea: RECAP Study Results.

PubMed

Lee, Kang Joon; Cho, Seong-Jin; Kim, Byeong Chae; Park, Minseok; Lee, Jae-Hong

2017-02-01

The aim of this study was to assess caregiver preference and treatment compliance with oral and transdermal medications in a "real-world" setting in patients with mild-to-moderate Alzheimer's disease (AD) in South Korea. Real-world evaluation of compliance and preference in Alzheimer's disease treatment (RECAP) was a 24-week, multicenter, prospective, non-interventional study in patients with AD treated with oral or transdermal therapy. Here, we report data from patients living in South Korea. Eligible patients were grouped into one of two treatment cohorts: oral (donepezil, galantamine, rivastigmine, or memantine) or transdermal (rivastigmine patch). Caregiver preference, patient compliance, and physician preference were assessed at week 24 (end of the study). Safety was assessed by reported adverse events (AEs). A total of 398 patients were enrolled (oral 51.8%; transdermal 48.2%) and 79.4% completed the study. Caregivers of patients that were exposed to either the oral or transdermal monotherapy showed a preference for the treatment to which the patients were exposed (both p < 0.0001). However, caregivers of patients that were exposed to both forms of treatments reported a higher preference for transdermal monotherapy (65.9%; p < 0.0041). Patients in both treatment cohorts showed good compliance, with an overall mean (SD) score of 8.84 (1.514) (a median of 9). Of the 15 participating physicians, eight indicated their preference for transdermal therapy and seven preferred oral therapy at week 24. A total of 133 (33.4%) patients reported at least one AE during the study period (oral: 60 patients; transdermal: 73 patients). The study showed higher caregiver preference for transdermal monotherapy over oral monotherapy when patients with AD were exposed to both forms of treatment and good patient compliance for both oral and transdermal treatments.

The efficacy and tolerability of rotigotine on patients with periodic limb movement in sleep: A systematic review and meta-analysis

PubMed Central

Chen, Tien-Yu; Chen, Yen-Wen; Liou, Li-Min; Lin, Pao-Yen

2018-01-01

Objective There is still no consensus on the treatment for periodic limb movement in sleep (PLMS). This study aimed to determine the efficacy and tolerability of rotigotine in patients suffering from PLMS. Methods Publications listed in PubMed, ScienceDirect, The Cochrane Library, and ClinicalTrials.gov were reviewed to assess the efficacy of rotigotine on PLMS. Analyses of PLMS frequency before and after rotigotine treatments (pre- and post-intervention studies) and PLMS frequency between placebo and rotigotine treatments (placebo-controlled trial studies) were included in our study. A systematic review and meta-analysis was conducted. Results Five publications involving 197 participants were included in this study. Among these articles, pre- and post-intervention data involving 55 participants were available from three articles, while placebo-controlled trial data from 107 participants receiving rotigotine and 70 participants receiving a placebo were available from an additional three articles. In the pre- and post-intervention studies, the periodic limb movement index was significantly decreased after therapy with rotigotine with a difference in means of −5.866/h (95% CI, −10.570 to −1.162, p = 0.015). In comparison with the placebo, the use of rotigotine significantly lowered the periodic limb movement index, with a difference in means of −32.105/h (95% CI, −42.539 to −21.671, p < 0.001), reduced the PLMS with arousal index, with a difference in means of −7.160/h (95% CI, −9.310 to −5.010, p < 0.001), and increased the withdrawal rate, with an odds ratio of 3.421 (95% CI, 1.230 to 9.512, p = 0.018). Conclusions This meta-analysis revealed the considerable efficacy of rotigotine in alleviating the frequency of PLMS. However, the high withdrawal rate should be taken into account. PMID:29668694

Rotigotine Objectively Improves Sleep in Parkinson's Disease: An Open-Label Pilot Study with Actigraphic Recording.

PubMed

Calandra-Buonaura, Giovanna; Guaraldi, Pietro; Doria, Andrea; Zanigni, Stefano; Nassetti, Stefania; Favoni, Valentina; Cevoli, Sabina; Provini, Federica; Cortelli, Pietro

2016-01-01

Sleep disturbances represent important predictors of poor quality of life (QoL) in Parkinson's disease (PD). This open-label pilot study aimed to objectively assess, by means of actigraphic recording, effect of rotigotine on sleep in PD patients with self-reported sleep complaints. 15 PD patients underwent one-week actigraphic recording before (T0) and during (T1) rotigotine treatment, which was titrated to the dose subjectively improving motor symptoms (4-8 mg/24 h). Sleep disturbances, daytime sleepiness, cognitive performance, QoL, and depression were also evaluated with questionnaires. Actigraphic recordings showed a significant reduction in nocturnal motor activity and mean duration of wake episodes after sleep onset during rotigotine treatment compared to baseline. In 10 patients presenting objective evidence of poor sleep quality at T0 (sleep efficiency ≤ 85%), rotigotine also significantly improved other sleep parameters and further reduced nocturnal motor activity and mean duration of wake episodes. A significant decrease in number and duration of daytime sleep episodes was also observed at T1. Finally we confirmed that rotigotine significantly improves perceived sleep quality and QoL. Our study showed for the first time that rotigotine is associated with an objective improvement of nocturnal and diurnal sleep disturbances in PD patients with self-reported sleep complaints. This study is registered with AIFA-observational study registry number 12021.

Rotigotine in the treatment of primary restless legs syndrome: A meta-analysis of randomized placebo-controlled trials.

PubMed

Ding, Jun; Fan, Wei; Chen, Hong-hui; Yan, Peng; Sun, Sheng-gang; Zheng, Jin

2015-04-01

The aim of this study was to summarize the efficacy and tolerability of rotigotine in the treatment of primary restless legs syndrome (RLS). PubMed, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) were searched for English-language randomized controlled trials (RCTs) that assessed the effectiveness of rotigotine for RLS. The pooled mean change from baseline in International RLS (IRLS) Study Group Rating Scalescore and relative risk (RR) of response based on the Clinical Global Impression-Improvement (CGI-I) scale score were applied to evaluate the outcomes. The pooled proportions of adverse events (AEs) were also estimated. Six RCTs were included. The meta-analysis showed a favorable effectiveness of rotigotine versus placebo on RLS [mean change on IRLS score: mean difference (MD)=-4.80; 95% confidence interval (CI): -5.90 to -3.70; P<0.00001 and RR of response on CGI-I was 2.19; 95% CI: 1.86 to 2.58, P<0.00001]. The most common AEs were application site reactions, nausea, headache and fatigue. In general, rotigotine was well-tolerated in patients with primary RLS. Based on the findings from the meta-analysis, rotigotine was more significantly efficacious in the treatment of RLS than placebo. Nevertheless, long-term studies and more evidence of comparisons of rotigotine with other dopamine agonists are needed.

Application of methyl methacrylate copolymers to the development of transdermal or loco-regional drug delivery systems.

PubMed

Cilurzo, Francesco; Selmin, Francesca; Gennari, Chiara G M; Montanari, Luisa; Minghetti, Paola

2014-07-01

Methyl methacrylate copolymers (Eudragit®) have been exploited to develop transdermal patches, medicated plasters (hereinafter patches) and, more recently, film-forming sprays, microsponges and nanoparticles intended to be applied on the skin. The article reviews the information regarding the application of Eudragits in the design and development of these dosage forms focusing on the impact of formulative variables on the skin drug penetration and the patch adhesive properties. Eudragits combined with a large amount of plasticizers are used to design the pressure-sensitive adhesives, specialized materials used in the patch development. They have to assure the drug skin penetration and the contact with the skin. Most of the studies mainly deal with the former aspect. The authors used a Eudragit type opportunely plasticized to merely investigate the in vitro or in vivo skin permeability of a loaded drug. However, the summa of these data evidenced that a strict connection between the matrix hydrophilicity and drug penetration probably exists. The criticisms of adhesion are addressed in a limited number of papers reporting data on technological properties, namely tack, shear adhesion and peel adhesion, while the structural data of the Eudragit adhesives, rheology and surface free energy are not described, excepting the case of Eudragit E. Among other applications, micro- and nanosystems exploiting the ionizable nature of some Eudragits can offer novel opportunities to develop pH-sensitive drug delivery systems suitable for triggering its release onto the skin.

Pharmacokinetics and pharmacodynamics of glycyrrhetinic acid with Paeoniflorin after transdermal administration in dysmenorrhea model mice.

PubMed

Ding, Xue; Sun, Yuming; Wang, Qing; Pu, Tingting; Li, Xiaohui; Pan, Yaqing; Yang, Yang

2016-07-15

Glycyrrhetinic acid (GA) and paeoniflorin (PF) are the main active ingredients in Chinese peony- Liquorice Decoction, a widely used Traditional Chinese Medicine. The aim of this work was to investigate the combinatory analgesic effect of GA and PF after percutaneous administration and to define their pharmacokinetic/pharmacodynamic (PK/PD) characteristics. GA and PF were produced to transdermal patches based on previous research, and the permeation parameters of GA and PF in the patches were investigated with in vitro experiments. Dysmenorrhea model mice were then produced to compare the analgesic effects of the patches with different proportions of GA-PF. In the in vivo assessment, the number of writhes exhibited by the dysmenorrhea mice was recorded at designated time points, and skin, muscle under skin and plasma samples were collected, for assessments of drug distribution, pharmacokinetics parameters and PK/PD characteristics. In dysmenorrhea mice, GA-PF and meloxicam (the positive control drug) could relieve pain to equal degrees. Specifically, a single dose of the optimized patches (10%GA-10%PF, wt) exerted a steady analgesic effect for 48h in dysmenorrhea mice, but this effect lagged behind the changes in the plasma concentration. Evaluation with the Bliss Independence criterion revealed that the two ingredients displayed a synergistic effect. Then the PK/PD relationship of GA in this compound preparation was defined with this synergistic effect. The preparation might be suitable for topical spasmolysis and anti-inflammatory therapy. Copyright © 2016 Elsevier GmbH. All rights reserved.

Rivastigmine transdermal patch and physical exercises for Alzheimer's disease: a randomized clinical trial.

PubMed

Aguiar, Paula; Monteiro, Larissa; Feres, Ana; Gomes, Irênio; Melo, Ailton

2014-01-01

To determine the effects of rivastigmine patch associated with physical exercise versus rivastigmine patch alone in quality of life (QOL), cognition, activities of daily living (ADL) and functional mobility in Alzheimer's disease (AD)subjects. A randomized, controlled, single-blinded trial was conducted in 40 patients with mild to moderate stages of AD. All patients were daily treated with rivastigmine transdermal patch at a stable dose of 4.6 mg and randomized into two groups: physical exercises or control. The exercise program consisted of aerobic, flexibility, strength and balance movements, twice a week for 6 months. Main outcomes were Quality of Life in Alzheimer's disease scale (QOL), Activities of Daily Living Questionnaire (ADL), Mini-Mental State Examination (MMSE) and "Time Up and Go Test". Thirty-four patients completed the study. After 6 months, there was a significant improvement in QOL of patients randomized to physical exercise group (P< 0.05). In both groups, there was an improvement on caregivers QOL (P>0.05). When considering cognitive functions, there was no difference between groups. The ability to perform ADL worsened in the group enrolled to RTP alone. There was an improvement in functional mobility in the group treated with RTP. Our results suggest that the association between physical exercises and RTP improves QOL in patients with AD. Cognition remained unchanged in both groups. Regarding the effect of physical exercises in ADL, further trials are necessary to confirm these results.

Rheology-A pre-formulation tool for evaluating mechanical and thermal properties of transdermal formulations

NASA Astrophysics Data System (ADS)

Modi, Nisarg

Rheological characterization of pharmaceutical gel is of importance as it provides fundamental information required for the assessment of some of the final properties of a product such as viscosity, elasticity, quality and physical storage stability. The effect of formulation and process variables on product characteristics such as consistency, drug release, and physical stability can also be attained. Moreover, some of the transdermal patch problems such as leaking from reservoir patch or cold flow in matrix patch can also be estimated using rheological characterization. During this research, various tests were employed to characterize the mechanical properties of gel such as oscillation test (Frequency and Amplitude Sweep), flow and viscosity curves and yield point measurements, as well as temperature sweep and temperature ramp test. The present studies evaluate rheological properties of hydroxypropyl cellulose (Klucel HF) gels prepared containing fatty acids with different carbon chain length at different homogenization speed. A controlled stress rheometer was used to study the effect of different number of carbon chain fatty acids, homogenization speed and storage period on the rheological properties and microstructure of transdermal gels. The studies demonstrated that as the carbon chain length increased (C10-C 18) the thixotropic area decreased, which suggested that the stability of gel structure was increased with increase in carbon chain of fatty acids. Cohesive Energy was affected by the homogenization speed and carbon chain of fatty acids. There was decreased in cohesive energy as increase in carbon chain of fatty acids. Temperature sweep data revealed that gels prepared with oleic acid (C18) at 25000 RPM gave the best thermal stability after the longest storage period (60-Days) compare to the capric(C10) acid and Lauirc (C12) acid. There was only 31% decreased in temperature loop area for oleic (C18) acid as compare to 54% and 86% for capric (C10) acid and lauric acid (C12) respectively. During different mixing speeds at initial time period (t=0), oleic acid showed lowest temperature loop area, which was not affected by storage period. Furthermore, by applying power law model to frequency sweep data, mechanical propereties of transdermal gels were evaluated. Transdermal gels are "physical gels" in nature which showed both frequency dependency and also had a cross-over point. Moreover, the value of n is less than 1. Time Temperature superposition principle can apply to the rheological data of Transdermal gels to obtain the thermal properties of formulations. Thermal properties of transdermal gels are very difficult to measure using traditional DSC equipment. By applying TTS principle, frequency sweep data were obtained between 5-50 °C and extrapolated to achieve the glass transition temperature, free volume and thermal expansion co-efficient of the formulations. Last but not least, In-vitro studies using human cadaver skin showed that Capric acid is the best permeability enhancing agent for escitalopram oxalate in current formulations. Furthermore, increase in carbon chain length of fatty acids decreased the permeability enhancing effect of Escitalopram Oxalate through human cadaver skin during In-vitro diffusion studies.

Comparison of abuse, suspected suicidal intent, and fatalities related to the 7-day buprenorphine transdermal patch versus other opioid analgesics in the National Poison Data System.

PubMed

Coplan, Paul M; Sessler, Nelson E; Harikrishnan, Venkatesh; Singh, Richa; Perkel, Charles

2017-01-01

Prescription opioid related abuse, suicide and death are significant public health problems. This study compares rates of poison center calls categorized as intentional abuse, suspected suicidal intent or fatality for the 7-day buprenorphine transdermal system/patch (BTDS) with other extended-release and long-acting (ER/LA) opioids indicated for chronic pain. Retrospective 24-month cohort study using National Poison Data System data from July 2012 through June 2014. BTDS was introduced in the United States in January 2011. Numbers and rates of calls of intentional abuse, suspected suicidal intent and fatalities were evaluated for BTDS, ER morphine, ER oxycodone, fentanyl patch, ER oxymorphone and methadone tablets/capsules, using prescription adjustment to account for community availability. Rate ratios (RR) and 95% confidence intervals (CI) were calculated. Absolute numbers and prescription-adjusted rates of intentional abuse and suspected suicidal intent with BTDS were significantly lower (p < .0001) than for all other ER/LA opioid analgesics examined. No fatalities associated with BTDS exposure were reported. This post-marketing evaluation of BTDS indicates infrequent poison center calls for intentional abuse and suspected suicidal intent events, suggesting lower rates of these risks with BTDS compared to other ER/LA opioids.

Effects of smoking and body mass index on the exposure of fentanyl in patients with cancer.

PubMed

Kuip, Evelien J M; Oldenmenger, Wendy H; Thijs-Visser, Martine F; de Bruijn, Peter; Oosten, Astrid W; Oomen-de Hoop, Esther; Koolen, Stijn L W; Van der Rijt, Carin C D; Mathijssen, Ron H J

2018-01-01

The transdermal fentanyl patch is widely used to treat cancer-related pain despite its wide inter- and intrapatient variability in pharmacokinetics. The aim of this study was to investigate whether smoking and body size (i.e. body mass index) influence fentanyl exposure in patients with cancer. These are factors that typically change during treatment and disease trajectories. We performed an explorative cohort study in patients with cancer using transdermal fentanyl patches (Durogesic®), by taking a blood sample for pharmacokinetic analysis one day after applying a patch in patients with a stable fentanyl dose. A total of 88 patients were evaluable. Although no statistically significant difference was found, the plasma concentrations of non-smokers was 28% (95% CI [-14%; +89-%]) higher than those of smokers normalizing for a dose of 25μg/min. Patients with a low BMI (< 20 kg/m2) had almost similar (10% (95% CI [-39%; +97%]) higher) plasma concentrations compared to patients with a high BMI (> 25 kg/m2). A wider variation in fentanyl plasma concentrations was found in this study than anticipated. Due to this variation, studies in larger patient cohorts are needed to further investigate the effect of smoking on plasma concentration of fentanyl and thereby clarify the clinical significance of our findings.

Rotigotine protects against glutamate toxicity in primary dopaminergic cell culture.

PubMed

Oster, Sandra; Radad, Khaled; Scheller, Dieter; Hesse, Marlen; Balanzew, Wladimir; Reichmann, Heinz; Gille, Gabriele

2014-02-05

In Parkinson disease the degeneration of dopaminergic neurones is believed to lead to a disinhibition of the subthalamic nucleus thus increasing the firing rate of the glutamatergic excitatory projections to the substantia nigra. In consequence, excessive glutamatergic activity will cause excitotoxicity and oxidative stress. In the present study we investigated mechanisms of glutamate toxicity and the neuroprotective potential of the dopamine agonist rotigotine towards dopaminergic neurones in mouse mesencephalic primary culture. Glutamate toxicity was mediated by the N-methyl-d-aspartic acid (NMDA) receptor and accompanied by a strong calcium influx into dopaminergic neurones for which the L-type voltage-sensitive calcium channels play an important role. The rate of superoxide production in the culture was highly increased. Deleterious nitric oxide production did not participate in glutamate-mediated excitotoxicity. Pretreatment of cultures with rotigotine significantly increased the survival of dopaminergic neurones exposed to glutamate. Rotigotine exerted its protective effects via dopamine receptor stimulation (presumably via dopamine D3 receptor) and decreased significantly the production of superoxide radicals. When cultures were preincubated with Phosphoinositol 3-Kinase (PI3K) inhibitors the protective effect of rotigotine was abolished suggesting a decisive role of the PI3K/Akt pathway in rotigotine-mediated neuroprotection. Consistently, exposure to rotigotine induced the activation of Akt by phosphorylation followed by phosphorylation, and thus inactivation, of the pro-apoptotic factor glycogen synthase kinase-3-beta (GSK-3-β). Taken together, our work contributed to elucidating the mechanisms of glutamate toxicity in mesencephalic culture and unravelled the signalling pathways associated with rotigotine-induced neuroprotection against glutamate toxicity in primary dopaminergic cultures. Copyright © 2013 Elsevier B.V. All rights reserved.

Transdermal Scopolamine Withdrawal Syndrome Case Report in the Pediatric Cerebral Palsy Population.

PubMed

Chowdhury, Nasim A; Sewatsky, Mary Laura; Kim, Heakyung

2017-08-01

Sialorrhea in children with cerebral palsy (CP) results in aspiration, decreased social integration, and poor quality of life. Management options include transdermal anticholinergics such as the scopolamine patch. A controlled clinical trial has proven botulinum toxin (BTX) injections into the salivary glands are an effective alternative to transdermal anticholinergics with a safer side effect profile. Multiple studies of the injections in diverse populations demonstrate reduction in saliva production with improvement in quality of life and decrease in hospitalization-associated costs. The authors describe a 15-year-old boy with spastic quadriplegic CP who developed emesis, nausea, and lethargy 1 day after the first injection of botulinum toxin A (BTX-A) to his salivary glands for sialorrhea management. The authors ascribed his symptoms to scopolamine withdrawal. Given the lack of exposure in the medical literature, there is minimal awareness of the withdrawal syndrome from transdermal scopolamine in children with or without CP, resulting in delayed diagnosis and potential complications. Treatment of the withdrawal syndrome has been successful with meclizine though safety and efficacy has not been established in children younger than 12 despite frequent clinical and over-the-counter use. Prompt diagnosis of the transdermal scopolamine withdrawal syndrome can result in quicker treatment and a shorter hospital stay.

Effectiveness of Rotigotine plus intensive and goal-based rehabilitation versus Rotigotine alone in "de-novo" Parkinsonian subjects: a randomized controlled trial with 18-month follow-up.

PubMed

Ferrazzoli, D; Ortelli, P; Riboldazzi, G; Maestri, R; Frazzitta, G

2018-04-01

Dopamine Replacement Therapy (DRT) represents the most effective treatment for Parkinson's disease (PD). Nevertheless, several symptoms are unresponsive to treatment and its long-term use leads to serious side effects. To optimize the pharmacological management of PD, dopamine-agonists are often prescribed to "de-novo" patients. Moreover, several studies have shown the effectiveness and the synergic effect of rehabilitation in treating PD. To evaluate the synergism between DRT and rehabilitation in treating PD, by investigating the short and the long-term effectiveness of a multidisciplinary, intensive and goal-based rehabilitation treatment (MIRT) in a group of patients treated with Rotigotine. In this multicenter, single blinded, parallel-group, 1:1 allocation ratio, randomized, non-inferiority trial, 36 "de-novo" PD patients were evaluated along 18 months: 17 were treated with Rotigotine plus MIRT; 19 were treated with Rotigotine alone (R). The primary outcome measure was the total score of Unified Parkinson's Disease Rating Scale (UPDRS). The secondary outcomes included the UPDRS sub-sections II and III (UPDRS II-III), the 6-Minute Walk Test (6MWT), the Timed Up and Go Test (TUG) and the amount of Rotigotine. Patients were evaluated at baseline (T0), 6 months (T1), 1 year (T2), and at 18 months (T3). No differences in UPDRS scores in the two groups (total score, III part and II part, p = 0.48, p = 0.90 and p = 0.40, respectively) were found in the time course. Conversely, a greater improvement in Rotigotine + MIRT group was observed for 6MWT (p < 0.0001) and TUG (p = 0.03). Along time, the dosage of Rotigotine was higher in patients who did not undergo MIRT, at all observation times following T0. Over the course of 18 months, the effectiveness of the combined treatment (Rotigotine + MIRT) on the patients' global clinical status, evaluated with total UPDRS, was not inferior to that of the pharmacological treatment with Rotigotine alone. Importantly, rehabilitation allowed patients to gain better motor performances with lower DRT dosage.

Rotigotine in Hemodialysis-Associated Restless Legs Syndrome: A Randomized Controlled Trial.

PubMed

Dauvilliers, Yves; Benes, Heike; Partinen, Markku; Rauta, Virpi; Rifkin, Daniel; Dohin, Elisabeth; Goldammer, Nadine; Schollmayer, Erwin; Schröder, Hanna; Winkelman, John W

2016-09-01

Restless legs syndrome (RLS) has been associated with insomnia, decreased quality of life, and increased morbidity and mortality in end-stage renal disease. This randomized controlled trial investigated effects of rotigotine in patients with RLS and end-stage renal disease. Double-blind placebo-controlled study. Adults with moderate to severe RLS (International RLS Study Group Rating Scale [IRLS] ≥ 15) and Periodic Limb Movement Index (PLMI) ≥ 15 who were receiving thrice-weekly hemodialysis enrolled from sites in the United States and Europe. Following randomization and titration (≤21 + 3 days) to optimal-dose rotigotine (1-3mg/24 h) or placebo, patients entered a 2-week maintenance period. Polysomnography was performed at baseline and the end of maintenance. Primary efficacy outcome: reduction in PLMI, assessed by ratio of PLMI at end of maintenance to baseline. Secondary/other outcomes (P values exploratory) included mean changes from baseline in PLMI, IRLS, and Clinical Global Impression item 1 (CGI-1 [severity of illness]) score. 30 patients were randomly assigned (rotigotine, 20; placebo, 10); 25 (15; 10) completed the study with evaluable data. Mean (SD) PLMI ratio (end of maintenance to baseline) was 0.7±0.4 for rotigotine and 1.3±0.7 for placebo (analysis of covariance treatment ratio, 0.44; 95% CI, 0.22 to 0.88; P=0.02). Numerical improvements were observed with rotigotine versus placebo in IRLS and CGI-1 (least squares mean treatment differences of -6.08 [95% CI, -12.18 to 0.02; P=0.05] and -0.81 [95% CI, -1.94 to 0.33; P=0.2]). 10 of 15 rotigotine and 2 of 10 placebo patients were CGI-1 responders (≥50% improvement). Hemodialysis did not affect unconjugated rotigotine concentrations. The most common adverse events (≥2 patients) were nausea (rotigotine, 4 [20%]; placebo, 0); vomiting (3 [15%]; 0); diarrhea (1 [5%]; 2 [20%]); headache (2 [10%]; 0); dyspnea (2 [10%]; 0); and hypertension (2 [10%]; 0). Small sample size and short duration. Rotigotine improved periodic limb movements and RLS symptoms in the short term among ESRD patients requiring hemodialysis in a small-scale study. No dose adjustments are necessary for hemodialysis patients. Copyright © 2016 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

An update on the safety of current therapies for Alzheimer's disease: focus on rivastigmine.

PubMed

Khoury, Rita; Rajamanickam, Jayashree; Grossberg, George T

2018-03-01

Alzheimer's disease (AD) is the most common cause of major neurocognitive disorders worldwide. Despite all research efforts, therapeutic options for AD are still limited to two drug classes: cholinesterase inhibitors (ChEIs) and the NMDA-receptor antagonist memantine. Donepezil, rivastigmine and galantamine are the three ChEIs FDA-approved as first-line treatment for AD. Although they share the same mode of action, they differ in terms of their pharmacologic characteristics and route of administration, which can impact their safety and tolerability profile. Rivastigmine, available in both oral and transdermal patch formulations, is a slowly reversible dual inhibitor of acetyl and butyryl cholinesterase, selective for the G1 isoform of acetylcholinesterase, without hepatic metabolism by the CYP-450 system. Despite its unique features, it has been associated with a higher incidence of adverse events in comparison to other ChEIs. The oral form, approved for the treatment of mild to moderate AD, is associated with a higher incidence of gastrointestinal side effects. The transdermal patch formulation approved for use across all stages of AD has been shown to have a better tolerability profile in comparison to both the oral form and even other ChEIs. One important tolerability concern is adverse dermatologic reactions, which are mostly benign, and can be either preventable or manageable. One important safety concern is the risk of treatment overdose by administering multiple patches at the same time, potentially leading to fatal outcomes. This can be prevented by educating patients and caregivers about the proper use of the patch. The goal for the future would be to optimize the patch formulation to increase both efficacy and safety.

Lactoferrin-modified rotigotine nanoparticles for enhanced nose-to-brain delivery: LESA-MS/MS-based drug biodistribution, pharmacodynamics, and neuroprotective effects

PubMed Central

Bi, Chenchen; Duan, Dongyu; Chu, Liuxiang; Yu, Xin; Wu, Zimei; Wang, Aiping; Sun, Kaoxiang

2018-01-01

Introduction Efficient delivery of rotigotine into the brain is crucial for obtaining maximum therapeutic efficacy for Parkinson’s disease (PD). Therefore, in the present study, we prepared lactoferrin-modified rotigotine nanoparticles (Lf-R-NPs) and studied their biodistribution, pharmacodynamics, and neuroprotective effects following nose-to-brain delivery in the rat 6-hydroxydopamine model of PD. Materials and methods The biodistribution of rotigotine nanoparticles (R-NPs) and Lf-R-NPs after intranasal administration was assessed by liquid extraction surface analysis coupled with tandem mass spectrometry. Contralateral rotations were quantified to evaluate pharmacodynamics. Tyrosine hydroxylase and dopamine transporter immunohistochemistry were performed to compare the neuroprotective effects of levodopa, R-NPs, and Lf-R-NPs. Results Liquid extraction surface analysis coupled with tandem mass spectrometry analysis, used to examine rotigotine biodistribution, showed that Lf-R-NPs more efficiently supplied rotigotine to the brain (with a greater sustained amount of the drug delivered to this organ, and with more effective targeting to the striatum) than R-NPs. The pharmacodynamic study revealed a significant difference (P<0.05) in contralateral rotations between rats treated with Lf-R-NPs and those treated with R-NPs. Furthermore, Lf-R-NPs significantly alleviated nigrostriatal dopaminergic neurodegeneration in the rat model of 6-hydroxydopamine-induced PD. Conclusion Our findings show that Lf-R-NPs deliver rotigotine more efficiently to the brain, thereby enhancing efficacy. Therefore, Lf-R-NPs might have therapeutic potential for the treatment of PD. PMID:29391788

Lactoferrin-modified rotigotine nanoparticles for enhanced nose-to-brain delivery: LESA-MS/MS-based drug biodistribution, pharmacodynamics, and neuroprotective effects.

PubMed

Yan, Xiuju; Xu, Lixiao; Bi, Chenchen; Duan, Dongyu; Chu, Liuxiang; Yu, Xin; Wu, Zimei; Wang, Aiping; Sun, Kaoxiang

2018-01-01

Efficient delivery of rotigotine into the brain is crucial for obtaining maximum therapeutic efficacy for Parkinson's disease (PD). Therefore, in the present study, we prepared lactoferrin-modified rotigotine nanoparticles (Lf-R-NPs) and studied their biodistribution, pharmacodynamics, and neuroprotective effects following nose-to-brain delivery in the rat 6-hydroxydopamine model of PD. The biodistribution of rotigotine nanoparticles (R-NPs) and Lf-R-NPs after intranasal administration was assessed by liquid extraction surface analysis coupled with tandem mass spectrometry. Contralateral rotations were quantified to evaluate pharmacodynamics. Tyrosine hydroxylase and dopamine transporter immunohistochemistry were performed to compare the neuroprotective effects of levodopa, R-NPs, and Lf-R-NPs. Liquid extraction surface analysis coupled with tandem mass spectrometry analysis, used to examine rotigotine biodistribution, showed that Lf-R-NPs more efficiently supplied rotigotine to the brain (with a greater sustained amount of the drug delivered to this organ, and with more effective targeting to the striatum) than R-NPs. The pharmacodynamic study revealed a significant difference ( P <0.05) in contralateral rotations between rats treated with Lf-R-NPs and those treated with R-NPs. Furthermore, Lf-R-NPs significantly alleviated nigrostriatal dopaminergic neurodegeneration in the rat model of 6-hydroxydopamine-induced PD. Our findings show that Lf-R-NPs deliver rotigotine more efficiently to the brain, thereby enhancing efficacy. Therefore, Lf-R-NPs might have therapeutic potential for the treatment of PD.

Fentanyl patches: preventable overdose.

PubMed

2010-02-01

Fentanyl is a potent opioid analgesic marketed for the treatment of stable intense chronic pain, particularly in the form of a transdermal patch. These delivery devices carry the same risk of adverse effects and drug interactions as conventional formulations of opioids. The patches carry an added risk of fentanyl overdose because they contain very high doses, both before and after use. High-risk situations for overdose were identified by examining the results of pharmacovigilance studies and medication error prevention programmes, as well as an observational study, case reports, and a French legal action. The main situations exposing patients to a risk of overdose are: confusion between two dose strengths, forgetting to remove the patch; accidental transfer of the patch to another person, application of more than one patch, cutting the patches, self-medication, and ingestion. Increased skin temperature facilitates fentanyl absorption and thus increases the risk of overdose; high-risk situations include fever, electric blankets, and intense physical exercise. In practice, the precautions for treatment and patch disposal must be followed exactly if this delivery system is to serve as a valid alternative to morphine for selected patients with stable intense chronic pain.

75 FR 49992 - Peter W.S. Grigg, M.D.; Revocation of Registration

Federal Register 2010, 2011, 2012, 2013, 2014

2010-08-16

... denial of any pending application to renew or modify the registration on the ground that his ``continued... also unlawfully distributed four fentanyl 400 mg. tablets and one fentanyl transdermal patch 12 mcg./hr... legitimate medical purposes.'' Id. Respondent also admitted that on this date, he distributed to the officer...

Effects of cabergoline and rotigotine on tacrine-induced tremulous jaw movements in rats.

PubMed

Koganemaru, Go; Abe, Hiroshi; Kuramashi, Aki; Ebihara, Kosuke; Matsuo, Hisae; Funahashi, Hideki; Yasuda, Kazuya; Ikeda, Tetsuya; Nishimori, Toshikazu; Ishida, Yasushi

2014-11-01

We examined the effects of two dopamine agonists, cabergoline and rotigotine, on tacrine-induced tremor and c-Fos expression in rats. Rats received intraperitoneal injection of cabergoline (0.5, 1.0, or 5.0mg/kg), rotigotine (1.0, 2.5, or 10.0mg/kg), or vehicle 30min before intraperitoneal injection of tacrine (5.0mg/kg). The number of tremulous jaw movements (TJMs) after tacrine administration was counted for 5min. Animals were sacrificed 2h later under deep anesthesia, and the brain sections were immunostained in order to evaluate the c-Fos expression. Induction of TJMs by tacrine was dose-dependently reduced by pretreatment with cabergoline and rotigotine. The number of c-Fos-positive cells was significantly enhanced in the medial striatum, nucleus accumbens core, and nucleus accumbens shell after tacrine administration, and the enhanced expression of c-Fos in these three regions was significantly attenuated by cabergoline, while rotigotine suppressed c-Fos expression in two regions except the nucleus accumbens core. These results suggest that tacrine-induced TJMs would be relieved by either cabergoline or rotigotine and that anticholinesterase-induced TJMs and the ameliorating effects of dopamine agonists would relate to neuronal activation in the striatum and nucleus accumbens. Copyright © 2014 Elsevier Inc. All rights reserved.

Spatially controlled coating of continuous liquid Interface production microneedles for transdermal protein delivery.

PubMed

Caudill, Cassie L; Perry, Jillian L; Tian, Shaomin; Luft, J Christopher; DeSimone, Joseph M

2018-06-09

Microneedle patches, arrays of micron-scale projections that penetrate skin in a minimally invasive manner, are a promising tool for transdermally delivering therapeutic proteins. However, current microneedle fabrication techniques are limited in their ability to fabricate microneedles rapidly and with a high degree of control over microneedle design parameters. We have previously demonstrated the ability to fabricate microneedle patches with a range of compositions and geometries using the novel additive manufacturing technique Continuous Liquid Interface Production (CLIP). Here, we establish a method for dip coating CLIP microneedles with protein cargo in a spatially controlled manner. Microneedle coating mask devices were fabricated with CLIP and utilized to coat polyethylene glycol-based CLIP microneedles with model proteins bovine serum albumin, ovalbumin, and lysozyme. The design of the coating mask device was used to control spatial deposition and loading of coated protein cargo on the microneedles. CLIP microneedles rapidly released coated protein cargo both in solution and upon insertion into porcine skin. The model enzyme lysozyme was shown to retain its activity throughout the CLIP microneedle coating process, and permeation of bovine serum albumin across full thickness porcine skin was observed after application with coated CLIP microneedles. Protein-coated CLIP microneedles were applied to live mice and showed sustained retention of protein cargo in the skin over 72 h. These results demonstrate the utility of a versatile coating platform for preparation of precisely coated microneedles for transdermal therapeutic delivery. Copyright © 2018. Published by Elsevier B.V.

Topical Non-Iontophoretic Application of Acetylcholine and Nitroglycerin via a Translucent Patch: A New Means for Assessing Microvascular Reactivity

PubMed Central

Schonberger, Robert B.; Worden, William S.; Shahmohammadi, Kaveh; Menn, Kirsten; Silverman, Tyler J.; Stout, Robert G.; Shelley, Kirk H.; Silverman, David G.

2007-01-01

Objective: Assessments of endothelial cell function with acetylcholine have typically used systemic, regional intra-arterial, or iontophoretic delivery of drug. Each of these techniques induces systemic and/or local changes that compromise their safety or effectiveness. Using translucent drug preparations applied under laser Doppler flowmetry (LDF) probes, we tested whether local vasodilation can be induced with non-iontophoretic transdermal delivery of acetylcholine and how such dilation would compare to the dilation achieved with topical nitroglycerin in healthy volunteers. Methods: Ten subjects without known vascular disease were recruited for LDF monitoring at sites of drug application for this preliminary investigation. Topical acetylcholine chloride, nitroglycerin, and placebo were applied via translucent patches to the forehead directly below LDF probes. Results: LDF readings increased by 406 percent (245 percent to 566 percent) and 36 percent (26 percent to 46 percent), respectively, at the acetylcholine and placebo sites (p = .005 by Wilcoxon Signed Rank Test (WSRT) for acetylcholine vs. placebo); and they increased by 365 percent (179 percent to 550 percent) at the nitroglycerin site (p = .005 by WSRT for nitroglycerin vs. placebo; p = .6 vs. acetylcholine). Conclusion: Transdermal delivery of acetylcholine can induce significant local vasodilatory responses comparable to those achieved with nitroglycerin without requiring iontophoresis. The means of transdermal delivery and monitoring described herein may constitute a new minimally invasive way to interrogate the microvasculature and thereby assess the microcirculatory changes induced by various disorders and therapeutic interventions. PMID:17876370

Enhanced Transdermal Delivery by Combined Application of Dissolving Microneedle Patch on Serum-Treated Skin.

PubMed

Kim, Suyong; Dangol, Manita; Kang, Geonwoo; Lahiji, Shayan F; Yang, Huisuk; Jang, Mingyu; Ma, Yonghao; Li, Chengguo; Lee, Sang Gon; Kim, Chang Hyun; Choi, Young Wook; Kim, So Jeong; Ryu, Ja Hyun; Baek, Ji Hwoon; Koh, Jaesuk; Jung, Hyungil

2017-06-05

Dissolving microneedle (DMN), a transdermal drug delivery system in which drugs are encapsulated in a biodegradable polymeric microstructure, is designed to dissolve after skin penetration and release the encapsulated drugs into the body. However, because of limited loading capacity of drugs within microsized structures, only a small dosage can be delivered, which is often insufficient for patients. We propose a novel DMN application that combines topical and DMN application simultaneously to improve skin permeation efficiency. Drugs in pretreated topical formulation and encapsulated drugs in DMN patch are delivered into the skin through microchannels created by DMN application, thus greatly increasing the delivered dose. We used 4-n-butylresorcinol to treat human hyperpigmentation and found that sequential application of serum formulation and DMNs was successful. In skin distribution experiments using Alexa Fluor 488 and 568 dyes as model drugs, we confirmed that the pretreated serum formulation was delivered into the skin through microchannels created by the DMNs. In vitro skin permeation and retention experiments confirmed that this novel combined application delivered more 4-n-butylresorcinol into the skin than traditional DMN-only and serum-only applications. Moreover, this combined application showed a higher efficacy in reducing patients' melanin index and hyperpigmented regions compared with the serum-only application. As combined application of DMNs on serum-treated skin can overcome both dose limitations and safety concerns, this novel approach can advance developments in transdermal drug delivery.

[Efficacy of Transdermal Patch of Bisoprolol for Paroxysmal Atrial Fibrillation after Open Heart Surgery].

PubMed

Yamamoto, Kenji; Yamada, Tomoyuki; Hamuro, Mamoru; Kawatou, Masahide; Enomoto, Sakae

2017-11-01

2014 American Association for Thoracic Surgery (AATS) guidelines recommend beta blocker for prevention and management of perioperative atrial fibrillation and flutter for thoracic surgical procedures. In recent years, transdermal patch of bisoprolol (TDPB) has become available in Japan. We examined the efficacy of TDPB for paroxysmal atrial fibrillation (PAF) after open heart surgery. Among 289 patients who had undergone open heart surgery in our hospital from December 2013 to April 2016, 48(16.6%)patients, for whom TDPB was used for PAF, were analyzed retrospectively. The summary of our PAF protocol:HR >80;a sheet of TDPB (4 mg) is pasted, HR≤60;TDPB is removed, HR >140 persisted;another sheet of TDPB is added. Eighteen of the 48 (37.5%) patients recovered sinus rhythm within 24 hours. Six patients( 12.5%), because of persistent tachycardia, shifted to continuous infusion of landiolol. Ten underwent electrical defibrillation during hospitalization. In 3 patients, TDPB was removed due to advanced bradycardia. TDPB could be used safely and feasibly for PAF after open heart surgery.

Selection and use of crystallization inhibitors for matrix-type transdermal drug-delivery systems containing sex steroids.

PubMed

Lipp, R

1998-12-01

The purpose of this study was to stabilize transdermal drug-delivery systems (TDDS) highly loaded with sex steroids against recrystallization of drugs during storage. To facilitate the selection of potential crystallization inhibitors a drug-excipient interaction test was also established. Analysis of the thermal behaviour of 1:1 steroid-excipient mixtures by differential scanning calorimetry (DSC) revealed that oestradiol and gestodene interact strongly with silicone dioxide and povidones, e.g. povidone K12. The addition of povidone K12 to polyacrylate-based matrix TDDS containing either 3% oestradiol or 2% gestodene resulted in stable systems which did not recrystallize during storage at 25 degrees C for more than 5 years. Significant recrystallization was, on the other hand, observed in non-stabilized reference patches even after 1 to 2 months storage. The DSC screening model proved very effective for selection of inhibitors of the crystallization of sex steroids in matrix TDDS. The crystallization inhibitor approach is a highly versatile stabilization tool for matrix patches containing high concentrations of sex steroids.

A noninterventional study evaluating the effectiveness of rotigotine and levodopa combination therapy in younger versus older patients with Parkinson's disease.

PubMed

Woitalla, Dirk; Dunac, Antoine; Safavi, Ali; Ceravolo, Maria-Gabriella; Gomez Esteban, Juan Carlos; Pavese, Nicola; Asgharnejad, Mahnaz; Joeres, Lars; Schuller, Jan-Christof; Chaudhuri, K Ray

2018-06-19

PD0013 was a 6-month noninterventional study in clinical practice comparing effectiveness/tolerability of rotigotine+levodopa in younger (<70 years) vs. older (≥70 years) Parkinson's disease (PD) patients. Patients previously received levodopa for ≥6 months as monotherapy/in combination with another dopamine-agonist (DA). Primary variable: Unified PD Rating Scale (UPDRS) Part-II change from baseline to end-of-observation-period (EOP). 91 younger/99 older patients started rotigotine; 68 younger/62 older patients completed the study. Most switched from levodopa+another DA. Addition of rotigotine as first DA was more common in older patients (20.2% vs.15.4%). Mean ± SD rotigotine-exposure: 6.1 ± 3.4 mg/24h younger vs. 4.9 ± 2.4 mg/24h older. Eleven patients changed levodopa dose. At EOP, improvement in mean UPDRS-II was greater in younger patients (p = 0.0289). UPDRS-II responder-rate (≥20% decrease in UPDRS-II score) was higher in younger patients (42.3% vs. 25.9%). Improvement across age groups was similar on PD Sleep Scale-2 and Clinical Global Impressions-Improvement Scale. Adverse drug reactions (ADRs), and discontinuations because of ADRs, were more common among older patients. There were no new safety signals. Despite low rotigotine doses, when added to levodopa/switched from levodopa+another DA, rotigotine led to greater improvement in UPDRS-II in younger patients (<70 years). Individual patient data revealed clinically meaningful improvements in UPDRS-II in both groups.

Design and characterization of diclofenac diethylamine transdermal patch using silicone and acrylic adhesives combination.

PubMed

Panchaxari, Dandigi M; Pampana, Sowjanya; Pal, Tapas; Devabhaktuni, Bhavana; Aravapalli, Anil Kumar

2013-01-07

The objective of the study was to develop and characterize Diclofenac Diethylamine (DDEA) transdermal patch using Silicone and acrylic adhesives combination. Modified solvent evaporation method was employed for casting of film over Fluoropolymer coated polyester release liner. Initial studies included solubilization of drug in the polymers using solubilizers. The formulations with combination of adhesives were attempted to combine the desirable features of both the adhesives. The effect of the permeation enhancers on the drug permeation were studied using pig ear skin. All the optimized patches were subjected to adhesion, dissolution and stability studies. A 7-day skin irritancy test on albino rabbits and an in vivo anti-inflammatory study on wistar rats by carrageenan induced paw edema method were also performed. The results indicated the high percent drug permeation (% CDP-23.582) and low solubility nature (1%) of Silicone adhesive and high solubility (20%) and low% CDP (10.72%) of acrylic adhesive. The combination of adhesives showed desirable characteristics for DDEA permeation with adequate % CDP and sufficient solubility. Release profiles were found to be dependent on proportion of polymer and type of permeation enhancer. The anti-inflammatory study revealed the sustaining effect and high percentage inhibition of edema of C4/OLA (99.68%). The acute skin irritancy studies advocated the non-irritant nature of the adhesives used. It was concluded that an ideal of combination of adhesives would serve as the best choice, for fabrication of DDEA patches, for sustained effect of DDEA with better enhancement in permeation characteristics and robustness.

Design and characterization of diclofenac diethylamine transdermal patch using silicone and acrylic adhesives combination

PubMed Central

2013-01-01

Background and purpose of the study The objective of the study was to develop and characterize Diclofenac Diethylamine (DDEA) transdermal patch using Silicone and acrylic adhesives combination. Methods Modified solvent evaporation method was employed for casting of film over Fluoropolymer coated polyester release liner. Initial studies included solubilization of drug in the polymers using solubilizers. The formulations with combination of adhesives were attempted to combine the desirable features of both the adhesives. The effect of the permeation enhancers on the drug permeation were studied using pig ear skin. All the optimized patches were subjected to adhesion, dissolution and stability studies. A 7-day skin irritancy test on albino rabbits and an in vivo anti-inflammatory study on wistar rats by carrageenan induced paw edema method were also performed. Results The results indicated the high percent drug permeation (% CDP-23.582) and low solubility nature (1%) of Silicone adhesive and high solubility (20%) and low% CDP (10.72%) of acrylic adhesive. The combination of adhesives showed desirable characteristics for DDEA permeation with adequate % CDP and sufficient solubility. Release profiles were found to be dependent on proportion of polymer and type of permeation enhancer. The anti-inflammatory study revealed the sustaining effect and high percentage inhibition of edema of C4/OLA (99.68%). The acute skin irritancy studies advocated the non-irritant nature of the adhesives used. Conclusion It was concluded that an ideal of combination of adhesives would serve as the best choice, for fabrication of DDEA patches, for sustained effect of DDEA with better enhancement in permeation characteristics and robustness. PMID:23351568

Switching Therapy from Intravenous Landiolol to Transdermal Bisoprolol in a Patient with Thyroid Storm Complicated by Decompensated Heart Failure and Gastrointestinal Dysfunction.

PubMed

Godo, Shigeo; Kawazoe, Yu; Ozaki, Hiroshi; Fujita, Motoo; Kudo, Daisuke; Nomura, Ryosuke; Shimokawa, Hiroaki; Kushimoto, Shigeki

2017-10-01

Thyroid storm is a life-threatening disorder that remains a therapeutic challenge. Although β-blockers are the mainstay for treatment, their use can be challenging in cases complicated by rapid atrial fibrillation and decompensated heart failure. We present a case of thyroid storm-associated atrial fibrillation and decompensated heart failure complicated by gastrointestinal dysfunction secondary to diffuse peritonitis that was successfully managed by a switching therapy, in which the continuous intravenous administration of landiolol was changed to bisoprolol via transdermal patch, in the acute phase treatment. This switching therapy may offer a promising therapeutic option for this potentially lethal disorder.

Critical attributes of transdermal drug delivery system (TDDS)--a generic product development review.

PubMed

Ruby, P K; Pathak, Shriram M; Aggarwal, Deepika

2014-11-01

Bioequivalence testing of transdermal drug delivery systems (TDDS) has always been a subject of high concern for generic companies due to the formulation complexity and the fact that they are subtle to even minor manufacturing differences and hence should be clearly qualified in terms of quality, safety and efficacy. In recent times bioequivalence testing of transdermal patches has gained a global attention and many regulatory authorities worldwide have issued recommendations to set specific framework for demonstrating equivalence between two products. These current regulatory procedures demand a complete characterization of the generic formulation in terms of its physicochemical sameness, pharmacokinetics disposition, residual content and/or skin irritation/sensitization testing with respect to the reference formulation. This paper intends to highlight critical in vitro tests in assessing the therapeutic equivalence of products and also outlines their valuable applications in generic product success. Understanding these critical in vitro parameters can probably help to decode the complex bioequivalence outcomes, directing the generic companies to optimize the formulation design in reduced time intervals. It is difficult to summarize a common platform which covers all possible transdermal products; hence few case studies based on this approach has been presented in this review.

Effect of Asparagus racemosus extract on transdermal delivery of carvedilol: a mechanistic study.

PubMed

Sapra, Bharti; Jain, Subheet; Tiwary, Ashok K

2009-01-01

This study was designed for investigating the effect of Asparagus racemosus (AR) extract and chitosan (CTN) in facilitating the permeation of carvedilol (CDL) across rat epidermis. Transdermal flux of carvedilol through heat-separated rat epidermis was investigated in vitro using vertical Keshary-Chien diffusion cells. Biophysical and microscopic manifestations of epidermis treated with AR extract, CTN, and AR extract-CTN mixture were investigated by using differential scanning calorimetry, transepidermal water loss, scanning electron microscopy (SEM), and transmission electron microscopy (TEM). Biochemical estimations of cholesterol, sphingosine, and triglycerides were carried out for treated excised as well as viable rat epidermis. The antihypertensive activity of the patches in comparison with that of oral carvedilol was studied in deoxycorticosterone acetate-induced hypertensive rats. The permeation of carvedilol across excised rat epidermis was significantly higher (p < 0.05) when AR extract, CTN, or AR extract-CTN mixture was used as donor vehicle as compared to propylene glycol/ethanol (7:3) mixture. Epidermis obtained after 12 h treatment of viable rat skin with AR extract-CTN mixture showed significantly higher (p < 0.05) permeability to CDL as compared to that after treatment with AR extract or CTN alone. Further, the application of patches containing AR extract-CTN mixture resulted in sustained release of CDL which was able to control the hypertension in deoxycorticosterone acetate-induced hypertensive rats through 36 h. Estimation of micro constituents in rat epidermis revealed maximum extraction of cholesterol, sphingosine, and triglycerides after treatment with AR extract-CTN mixture. This was manifested in altered lipid and protein-specific thermotropic transitions. Further, increase in intercellular space, disordered lipid structure, and corneocyte detachment as observed in SEM and TEM suggested great potential of AR extract for use as percutaneous permeation enhancer. The developed transdermal patches of CDL containing AR extract-CTN mixture exhibited better performance as compared to oral administration in controlling hypertension in rats.

Oral and transdermal DL-methylphenidate-ethanol interactions in C57BL/6J mice: potentiation of locomotor activity with oral delivery.

PubMed

Bell, Guinevere H; Griffin, William C; Patrick, Kennerly S

2011-12-01

Many abusers of dl-methylphenidate co-abuse ethanol. The present animal study examined behavioral effects of oral or transdermal DL-methylphenidate in combination with a high, depressive dose of ethanol to model co-abuse. Locomotor activity of C57BL/6J mice was recorded for 3 h following dosing with either oral DL-methylphenidate (7.5 mg/kg) or transdermal DL-methylphenidate (Daytrana®;1/4 of a 12.5 cm(2) patch; mean dose 7.5 mg/kg), with or without oral ethanol (3 g/kg). Brains were enantiospecifically analyzed for the isomers of methylphenidate and the transesterification metabolite ethylphenidate. An otherwise depressive dose of ethanol significantly potentiated oral DL-methylphenidate induced increases in total distance traveled for the first 100 min (p<0.05). Transdermal DL-methylphenidate increased total distance traveled after a latency of 80 min, though this effect was not potentiated by concomitant ethanol. Mean 3 h brain D-methylphenidate concentrations were significantly elevated by ethanol in both the oral (65% increase) and transdermal (88% increase) groups. The corresponding L-ethylphenidate concentrations were 10 ng/g and 130 ng/g. Stimulant induced motor activity in rodents may correlate with abuse liability. Potentiation of DL-methylphenidate motor effects by concomitant ethanol carries implications regarding increased abuse potential of DL-methylphenidate when combined with ethanol. Copyright © 2011 Elsevier Inc. All rights reserved.

Effect of rivastigmine or memantine add-on therapy is affected by butyrylcholinesterase genotype in patients with probable Alzheimer's disease.

PubMed

Han, Hyun Jeong; Kwon, Jay C; Kim, Jung Eun; Kim, Shin Gyeom; Park, Jong-Moo; Park, Kyung Won; Park, Key Chung; Park, Kee Hyung; Moon, So Young; Seo, Sang Won; Choi, Seong Hye; Cho, Soo-Jin

2015-01-01

The K variant of butyrylcholinesterase (BCHE-K) exhibits a reduced acetylcholine-hydrolyzing capacity; so the clinical response to rivastigmine may differ in Alzheimer's disease (AD) patients with the BCHE-K gene. To investigate the clinical response to rivastigmine transdermal patch monotherapy or memantine plus rivastigmine transdermal patch therapy in AD patients based on the BCHE-K gene. A total of 146 probable AD patients consented to genetic testing for butyrylcholinesterase and underwent the final efficacy evaluations. Responders were defined as patients with an equal or better score on the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) at 16 weeks compared to their baseline score. BCHE-K carriers showed a lower responder rate on the ADAS-cog than non-carriers (38.2 vs. 61.7%, p = 0.02), and this trend was evident in AD patients with apolipoprotein E ε 4 (35 vs. 60.7%, p = 0.001). The presence of the BCHE-K allele predicted a worse response on the ADAS-cog (odds ratio 0.35, 95% confidence interval 0.14-0.87), after adjusting for demographic and baseline cognitive and functional variables. The BCHE-K genotype may be related to a poor cognitive response to rivastigmine patch or memantine add-on therapy, especially in the presence of apolipoprotein E ε 4.

[Pharmaceutical counseling of non-conventional dosage forms concerning the health-literacy and the patient adherence in public medication dispensing -Questionnaire surveys in Hungarian community pharmacies.

PubMed

Somogyi, O; Zelko, R

Although the non-conventional dosage forms (e.g. modified release per oral systems or transdermal patches) have more significant advantages than other conventional dosage forms, the pa- tients have to apply them correctly in their home medicine using to reach the effective and safe therapy. A guideline of relevant application instructions contribute to development of an effective pharmaceutical counseling in community pharmacies. The counseling and advices can improve the patients' knowledge concerning application rules of different new dosage forms (health- literacy) with patient adherence. Finally it will result more effective and safer therapies. The aim of our Hungarian questionnaire surveys was to explore the patients' drug application habits or application errors and improve special verbal counseling of mentioned non-conventional dosage forms in community pharmacies. Understandable patient information leaflets were developed about application rules and besides the levels of patients' reading comprehension was evaluated in case of the leaflet of medicinal patches. The results show that a properly developed text is useful for the majority of patients but they need the verbal explanation as well, moreover there is a demand for the verbal counseling in community pharmacies. The most common application errors were explored and the most effective instructions or application rules were collected for the pharmacists and patients concerning the modified release tablets or capsules and transdermal patches.

Skin patch and vaginal ring versus combined oral contraceptives for contraception.

PubMed

Lopez, Laureen M; Grimes, David A; Gallo, Maria F; Stockton, Laurie L; Schulz, Kenneth F

2013-04-30

The delivery of combination contraceptive steroids from a transdermal contraceptive patch or a contraceptive vaginal ring offers potential advantages over the traditional oral route. The transdermal patch and vaginal ring could require a lower dose due to increased bioavailability and improved user compliance. To compare the contraceptive effectiveness, cycle control, compliance (adherence), and safety of the contraceptive patch or the vaginal ring versus combination oral contraceptives (COCs). Through February 2013, we searched MEDLINE, POPLINE, CENTRAL, LILACS, ClinicalTrials.gov, and ICTRP for trials of the contraceptive patch or the vaginal ring. Earlier searches also included EMBASE. For the initial review, we contacted known researchers and manufacturers to identify other trials. We considered randomized controlled trials comparing a transdermal contraceptive patch or a contraceptive vaginal ring with a COC. Data were abstracted by two authors and entered into RevMan. For dichotomous variables, the Peto odds ratio (OR) with 95% confidence intervals (CI) was calculated. For continuous variables, the mean difference was computed. We also assessed the quality of evidence for this review. We found 18 trials that met our inclusion criteria. Of six patch studies, five examined the marketed patch containing norelgestromin plus ethinyl estradiol (EE); one studied a patch in development that contains levonorgestrel (LNG) plus EE. Of 12 vaginal ring trials, 11 examined the same marketing ring containing etonogestrel plus EE; one studied a ring being developed that contains nesterone plus EE.Contraceptive effectiveness was not significantly different for the patch or ring versus the comparison COC. Compliance data were limited. Patch users showed better compliance than COC users in three trials. For the norelgestromin plus EE patch, ORs were 2.05 (95% CI 1.83 to 2.29) and 2.76 (95% CI 2.35 to 3.24). In the levonorgestrel plus EE patch report, patch users were less likely to have missed days of therapy (OR 0.36; 95% CI 0.25 to 0.51). Of four vaginal ring trials, one found ring users had more noncompliance (OR 3.99; 95% CI 1.87 to 8.52), while another showed more compliance with the regimen (OR 1.67; 95% CI 1.04 to 2.68).More patch users discontinued early than COC users. ORs from two meta-analyses were 1.59 (95% CI 1.26 to 2.00) and 1.56 (95% CI 1.18 to 2.06) and another trial showed OR 2.57 (95% CI 0.99 to 6.64). Patch users also had more discontinuation due to adverse events than COC users. Users of the norelgestromin-containing patch reported more breast discomfort, dysmenorrhea, nausea, and vomiting. In the levonorgestrel-containing patch trial, patch users reported less vomiting, headaches, and fatigue.Of 11 ring trials with discontinuation data, two showed the ring group discontinued less than the COC group: OR 0.32 (95% CI 0.16 to 0.66) and OR 0.52 (95% CI 0.31 to 0.88). Ring users were less likely to discontinue due to adverse events in one study (OR 0.32; 95% CI 0.15 to 0.70). Compared to the COC users, ring users had more vaginitis and leukorrhea but less vaginal dryness. Ring users also reported less nausea, acne, irritability, depression, and emotional lability than COC users.For cycle control, only one trial study showed a significant difference. Women in the patch group were less likely to have breakthrough bleeding and spotting. Seven ring studies had bleeding data; four trials showed the ring group generally had better cycle control than the COC group. Effectiveness was not significantly different for the methods compared. Pregnancy data were available from half of the patch trials but two-thirds of ring trials. The patch could lead to more discontinuation than the COC. The patch group had better compliance than the COC group. Compliance data came from half of the patch studies and one-third of the ring trials. Patch users had more side effects than the COC group. Ring users generally had fewer adverse events than COC users but more vaginal irritation and discharge.The quality of the evidence for this review was considered low for the patch and moderate for the ring. The main reasons for downgrading were lack of information on the randomization sequence generation or allocation concealment, the outcome assessment methods, high losses to follow up, and exclusions after randomization.

Effects of Transdermal Testosterone on Natriuretic Peptide Levels in Women: A Randomized Placebo-Controlled Pilot Study

PubMed Central

Lin, Eleanor; McCabe, Elizabeth; Newton-Cheh, Christopher; Bloch, Kenneth; Buys, Emmanuel; Wang, Thomas; Miller, Karen K.

2011-01-01

Objective To investigate whether testosterone administration alters natriuretic peptide levels in women. Design Three-month, double-blind, randomized, placebo-controlled study. Setting Clinical research center. Patients 51 women with hypoandrogenemia due to hypopituitarism. Intervention Transdermal testosterone (300 mcg daily) or placebo patch. Main Outcome Measure N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels. Results NT-proBNP levels decreased in the transdermal testosterone group compared with placebo over three months (p = 0.009). The difference between groups remained significant after controlling for baseline age, systolic blood pressure, body mass index, and homeostasis model of assessment-insulin resistance (p = 0.008). Change in NT-proBNP over three months was inversely associated with change in free testosterone levels (ρ = −0.41, p = 0.01). Conclusions Testosterone administration to women results in decreased natriuretic peptide levels, suggesting that testosterone may be an inverse regulator of the natriuretic peptide system. Clinical Trials Registration Number NCT00027430 PMID:22137497

[Nitroglycerin patch for tocolysis--a prospective randomized comparison with fenoterol by infusion].

PubMed

Schleussner, E; Richter, S; Gross, W; Kähler, C; Möller, A; Möller, U; Seewald, H J

2001-01-01

To evaluate tocolytic efficacy of transdermal glyceryl trinitrate (GTN) in comparison to fenoterol per infusionem in a prospective randomized multicenter study. 50 pregnant women between 27 and 35 weeks of gestation with preterm labour were treated with either GTN patches (0.4-0.8 mg/h) or fenoterol per infusionem (60-120 micrograms/h) up to stop of contractions or 35 weeks in maximum. The primary outcomes were the prolongation of gestation by 48 h, 7 days or up to 37 weeks of gestation as well as the neonatal outcome. The progression of cervical ripening and maternal side effects during tocolysis were assessed as secondary outcome criteria. There was no difference in successful tocolysis for 48 h and 7 days in both groups, whereas significantly more women passed 37 weeks after GTN therapy. So mean duration of pregnancy, birth weight and height were greater, whereas transfer into neonatal care unit was significantly rare after GTN. There were no differences in neonatal outcome and progression of cervical ripening during tocolysis. Maternal side effects during GTN were fewer and weaker compared with fenoterol. Circa 70% of GTN treated women had a headache temporary, whereas more than 90% of the patients with fenoterol suffered from tachycardia and tremor. Tocolytic efficacy of transdermal GTN was at least equivalent to the established beta-mimetic therapy with fenoterol. Because of the lower preterm delivery rate transfer into neonatal care for control was significantly rarer after GTN with equally good neonatal outcome in both groups. Beside the headache transdermal GTN therapy had lower maternal side effects in comparison to fenoterol.

Perioperative analgesia with a buprenorphine transdermal patch for hallux valgus surgery: a prospective, randomized, controlled study

PubMed Central

Xu, Can; Li, Mingqing; Wang, Chenggong; Li, Hui; Liu, Hua

2018-01-01

Purpose Hallux valgus surgery often results in significant postoperative pain. Adequate control of pain is essential for patient satisfaction and improves the outcome of the procedure. This study aimed to investigate the perioperative analgesic effect of a buprenorphine transdermal patch in patients who underwent hallux valgus surgery. Patients and methods A total of 90 patients were randomly divided into the following three groups based on the perioperative analgesic method: flurbiprofen axetil intravenous injection (Group F), oral celecoxib (Group C), and buprenorphine transdermal delivery system (BTDS) (Group BTDS). The pain status, degree of satisfaction, adverse effects, and administration of tramadol hydrochloride for uncontrolled pain were recorded on the night before surgery, postoperative day 1, postoperative day 2, and postoperative day 3. Results The BTDS could effectively control perioperative pain for patients undergoing hallux valgus surgery. The analgesic effect of the BTDS was better than that of oral celecoxib. In addition, statistically significant differences were not observed in the visual analog scale (VAS) scores, adverse effects, and rescue analgesia between the patients who received the BTDS and the patients who received the flurbiprofen axetil intravenous injection. However, the degree of patient satisfaction of the BTDS group was significantly higher (P<0.05) than that of the other two groups. Conclusion The BTDS (a preemptive analgesia regimen) could exert an analgesic effect during the perioperative period for patients who had received hallux valgus surgery, and this effect is beneficial for sustaining postoperative physiological and psychological states and promoting functional rehabilitation. PMID:29731664

Combined hormonal contraceptive (CHC) use among obese women and contraceptive effectiveness: a systematic review.

PubMed

Dragoman, Monica V; Simmons, Katharine B; Paulen, Melissa E; Curtis, Kathryn M

2017-02-01

To evaluate from the literature whether combined hormonal contraception (CHC), including combined oral contraception pills (COCs), transdermal patch, vaginal ring or combined injectables, have different effectiveness or failure rates by body weight or body mass index (BMI). We searched PubMed and the Cochrane Library databases for all articles in all languages published between inception and February 2016, for evidence relevant to body weight or BMI, CHC use and contraceptive effectiveness. The quality of each individual study was assessed using the system for evaluating evidence developed by the United States Preventive Services Task Force. From 2874 articles, we identified 15 reports for inclusion, all of fair to poor quality. Fourteen studies measured the association of obesity status and contraceptive failure among COC users. Three fair quality and one poor quality study reported increased COC failure among a heterogeneous population of overweight and obese women compared with normal weight women, while eight fair quality and two poor quality studies did not find an association. Two fair quality studies reported on contraceptive transdermal patches. One pooled analysis described a higher proportion of pregnancies among women using the patch who weighed ≥90 kg; another secondary analysis suggested BMI>30 was associated with increased failure. No studies directly compared contraceptive effectiveness using the combined vaginal ring or combined injectable. Current available evidence addressing the risk of CHC failure in obese compared to normal weight women is limited to fair and poor quality studies. Studies of COCs show mixed results, though absolute differences in COC failure by body weight and BMI are small. Based on limited evidence, it appears that increasing body weight and BMI may contribute to decreasing contraceptive patch effectiveness. Copyright © 2017. Published by Elsevier Inc.

Effectiveness of switching to the rivastigmine transdermal patch from oral cholinesterase inhibitors: a naturalistic prospective study in Alzheimer's disease.

PubMed

Cagnin, Annachiara; Cester, Alberto; Costa, Bruno; Ermani, Mario; Gabelli, Carlo; Gambina, Giuseppe

2015-03-01

Oral donepezil and rivastigmine are two commonly used cholinesterase inhibitors (ChEIs) used in Alzheimer's disease (AD). The rivastigmine transdermal patch formulation has high tolerability profile, allowing patients to achieve optimal therapeutic doses and providing potential advantages over oral ChEIs. This is a 6-month, multicentre, observational efficacy and tolerability study of switching from oral ChEIs to rivastigmine patch in AD patients who failed to show benefit from previous treatment. The reasons of the switch were: (1) lack/loss of benefit from previous oral ChEI treatment; (2) tolerability problems. The primary outcome was cognitive changes measured with the mini-mental state examination (MMSE) test. Secondary outcomes were modifications of functional independence and behavioral disturbances and occurrence of adverse events (AEs) after switching. 174 patients, over 180 patients screened, entered the study (lack/loss of efficacy: 57 %, tolerability problems: 33 %, both reasons: 10 %). 6 months after switching 56 % of patients stabilized or increased the MMSE score respect to baseline. The only predictor of this outcome was the response at 3 months. In the group with lack/loss of response to oral ChEI, the decline of the MMSE score changed from -3.4 ± 2.5 points in the 6 months before switching to -0.5 ± 3.2 in the 6 months after the switch (p < 0.001). There were no significant changes in the IADL or NPI scores. Drug discontinuation rate was 20 %, due to AEs (18 %) and lack of compliance (2 %). Switching from an unsuccessful oral ChEI therapy to rivastigmine patch is effective and safe in more than half of the switched patients after a 6-month period.

Investigating the role of ion-pair strategy in regulating nicotine release from patch: Mechanistic insights based on intermolecular interaction and mobility of pressure sensitive adhesive.

PubMed

Li, Qiaoyun; Wan, Xiaocao; Liu, Chao; Fang, Liang

2018-07-01

The aim of this study was to prepare a drug-in-adhesive patch of nicotine (NIC) and use ion-pair strategy to regulate drug delivery rate. Moreover, the mechanism of how ion-pair strategy regulated drug release was elucidated at molecular level. Formulation factors including pressure sensitive adhesives (PSAs), drug loading and counter ions (C 4 , C 6 , C 8 , C 10 , and C 12 ) were screened. In vitro release experiment and in vitro transdermal experiment were conducted to determine the rate-limiting step in drug delivery process. FT-IR and molecular modeling were used to characterize the interaction between drug and PSA. Thermal analysis and rheology study were conducted to investigate the mobility variation of PSA. The optimized patch prepared with NIC-C 8 had the transdermal profile fairly close to that of the commercial product (p > 0.05). The release rate constants (k) of NIC, NIC-C 4 and NIC-C 10 were 21.1, 14.4 and 32.4, respectively. Different release rates of NIC ion-pair complexes were attributed to the dual effect of ion-pair strategy on drug release. On one hand, ion-pair strategy enhanced the interaction between drug and PSA, which inhibited drug release. On the other hand, using ion-pair strategy improved the mobility of PSA, which facilitated drug release. Drug release behavior was determined by combined effect of two aspects above. These conclusions provided a new idea for us to regulate drug release behavior from patch. Copyright © 2018 Elsevier B.V. All rights reserved.

Randomized comparative trial of nicotine polacrilex, a transdermal patch, nasal spray, and an inhaler.

PubMed

Hajek, P; West, R; Foulds, J; Nilsson, F; Burrows, S; Meadow, A

1999-09-27

There are several nicotine replacement products on the market, and physicians are likely to be asked with increasing frequency about which of these products their patients should use. To provide a basis for rational advice by comparing nicotine polacrilex (gum), a transdermal patch, nasal spray, and an inhaler. Randomized trial with assessments at the quit date and 1, 4, and 12 weeks later. Hospital smokers' clinic. Male and female community volunteers (N = 504) smoking 10 or more cigarettes per day and seeking help to stop smoking. Patients were given brief advice, and purchased their nicotine replacement treatment at approximately half the regular retail price. Nicotine replacement treatment use, ratings of withdrawal symptoms, ratings of product characteristics and helpfulness, and biochemically validated continuous lapse-free abstinence. The products did not differ in their effects on withdrawal discomfort, urges to smoke, or rates of abstinence. The continuous validated 12-week abstinence rates were 20%, 21%, 24%, and 24% in the gum, patch, spray, and inhaler groups, respectively. Compliance with recommended nicotine replacement treatment use was high for the patch, low for gum, and very low for the spray and the inhaler. The spray was underused because of adverse effects more often than the other products. In the subjects using the spray, the level of use among abstainers at week 1 predicted outcome at week 12. The inhaler was rated as more embarrassing to use than the other products, but provided at least as much nicotine as the gum. When asked about nicotine replacement treatment products available, physicians should note that, despite low compliance with the recommended dose of the spray and inhaler and differences in product ratings, overall, there are no notable differences between the products in their effects on withdrawal discomfort, perceived helpfulness, or general efficacy.

Comparison of Enhancement of Analgesic Effect of Intrathecal Neostigmine by Intrathecal Clonidine and Transdermal Nitroglycerin Patch on Bupivacaine Spinal Anesthesia.

PubMed

Mammen, Mathew V; Tripathi, Manoj; Chandola, Harish C; Tyagi, Amit; Bais, Prateek Singh; Sanjeev, Om Prakash

2017-01-01

Relief of pain is very important goal intraoperatively and postoperatively. Neostigmine has been used successfully intrathecally with other agents such as clonidine and opioids for pain relief. This study aims to compare and evaluate the efficacy and safety of combining intrathecal (IT) neostigmine with IT clonidine and transdermal nitroglycerin (tNTG) patch for the relief of pain in patients after surgery. This was a randomized, prospective, and comparative study. In this study, recruited patients were randomly allocated into three groups. Groups I, II, and III received intrathecally 25 μg of neostigmine + 15 mg hyperbaric 0.5% bupivacaine, 25 μg of neostigmine + 25 μg clonidine + 15 mg hyperbaric 0.5% bupivacaine, and 25 μg of neostigmine + tNTG patch (3 cm × 5 cm, 5 mg/24 h) +15 mg hyperbaric 0.5% bupivacaine, respectively. Heart rate, mean arterial pressure, analgesic properties, and complications were assessed and compared among groups. Mean and standard deviation were calculated. Test of analysis between two groups was done by t -test and among three groups by ANOVA, then P value was calculated. Duration of analgesia was significantly longer in Group III in comparison to Group II (7.142 ± 1.81 vs. 4.408 ± 0.813 h) and was significantly longer in Group II in comparison to Group I (4.408 ± 0.813 vs. 2.583 ± 0.493 h). Analgesic requirement was significantly less in Group III in comparison to Group II (1.9 ± 0.76 vs. 2.5 ± 0.51) and was significantly less in Group II in comparison to Group I (2.5 ± 0.51 vs. 3.1 ± 0.48). Sedation score was found significantly high in Group II than other groups. Both IT clonidine and tNTG patch with bupivacaine + neostigmine spinal anesthesia were found effective in pain control. Results were found better with tNTG patch.

Effect of palmitic acid on the characteristics and release profiles of rotigotine-loaded microspheres.

PubMed

Wang, Aiping; Liang, Rongcai; Liu, Wanhui; Sha, Chunjie; Li, Youxin; Sun, Kaoxiang

2016-01-01

The initial burst release is a major obstacle to the development of microsphere-formulated drug products. To investigate the influence of palmitic acid on the characteristics and release profiles of rotigotine-loaded poly(d,l-lactide-co-glycolide) microspheres. Rotigotine-loaded microspheres (RMS) were prepared using the oil-in-water emulsion solvent evaporation technique. The in vitro characteristics of the RMS were evaluated with scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and a particle size analyzer. The in vitro drug release and in vivo pharmacokinetics of the RMS were investigated. The SEM results showed that the addition of palmitic acid changed the surface morphology of the microspheres from smooth to dimpled and then to non-smooth as the palmitic acid content increased. DSC revealed the existence of molecularly dispersed forms of palmitic acid in the microspheres. The in vitro and in vivo release profiles indicated that the addition of 5% and 8% palmitic acid significantly decreased the burst release of rotigotine from the microspheres, and the late-stage release was delayed as the palmitic acid content increased across the investigated range (5-15%). The addition of palmitic acid to the microspheres significantly affects the release profile of rotigotine from RMS.

Population pharmacokinetics of transdermal fentanyl in patients with cancer-related pain.

PubMed

Kokubun, Hideya; Ebinuma, Keiichi; Matoba, Motohiro; Takayanagi, Risa; Yamada, Yasuhiko; Yago, Kazuo

2012-06-01

Determining the appropriate dose of transdermal fentanyl (TDF) for the alleviation of cancer pain requires determining the factors causing variations in serum fentanyl concentration after TDF treatment. The objective of this study was to identify these factors and incorporate them into a formula that can be used to predict serum fentanyl concentration after application of a TDF patch. Blood samples of cancer patients treated with a TDF patch for the alleviation of pain were collected at 24, 48, and 72 hours after application to evaluate population pharmacokinetics using the nonlinear mixed-effect model (NONMEM). Based upon this evaluation, Child-Pugh Score and use of a cytochrome P450 3A4 (CYP3A4) inducer were identified as the most significant factors in variations in serum fentanyl concentration and incorporated into the following Final Model formula: CL(fenta) (L/h) = 3.53 × (15 - Child-Pugh Score) × (1 + 1.38 × use or no use of CYP3A4 inducer). Bootstrap evaluation of the Final Model revealed a high convergence rate, suggesting that the model formula is a reliable and useful tool for determining TDF dose for the alleviation of cancer pain.

Genetic, pathological and physiological determinants of transdermal fentanyl pharmacokinetics in 620 cancer patients of the EPOS study.

PubMed

Barratt, Daniel T; Bandak, Benedikte; Klepstad, Pål; Dale, Ola; Kaasa, Stein; Christrup, Lona L; Tuke, Jonathan; Somogyi, Andrew A

2014-04-01

This study aimed to investigate whether CYP3A4/5 genetic variants, together with clinical and patient factors, influence serum fentanyl and norfentanyl concentrations and their ratio in cancer pain patients receiving transdermal fentanyl. CYP3A4*22 and CYP3A5*3 polymorphisms were analysed in 620 cancer pain patients receiving transdermal fentanyl (12.5-700 μg/h) from the European Pharmacogenetic Opioid Study. Using stepwise linear regression, CYP3A4/5 genetic variability was examined in combination with patient factors relating to organ drug elimination function and ABCB1 genetics for their association with serum fentanyl and norfentanyl concentrations and metabolic ratio (MR) (norfentanyl : fentanyl). Delivery rate-adjusted serum fentanyl concentrations (0.0012-1.1 nmol/l/μg.h) and MRs (0.08-499) varied widely. Only 43% of variability in serum fentanyl concentrations was accounted for by delivery rate and less than 50% by CYP3A4/5 genotypes and clinical variables (delivery rate, sex, comedications, kidney disease, BMI, serum albumin). CYP3A4*22 and CYP3A5*3 variants, CYP3A inhibitors and variables relating to liver and kidney function (serum albumin, glomerular filtration rate, kidney disease, BMI) were associated with MR, but accounted for only 14% of variability. Serum fentanyl concentrations and MR vary considerably between cancer pain patients on transdermal fentanyl patches. CYP3A4*22 and CYP3A5*3 genotypes, and multiple clinical factors, combine to influence transdermal fentanyl pharmacokinetics, but accounted for only a small proportion of variability in this study. Identification of the remaining factors determining serum fentanyl concentrations, and their relationship to efficacy and adverse effects may aid in improving the safety and effectiveness of transdermal fentanyl.

Pharmacokinetic Evaluation of Two Nicotine Patches in Smokers.

PubMed

Rasmussen, Scott; Horkan, Kathleen Halabuk; Kotler, Mitchell

2018-02-02

Smoking continues to be a major preventable cause of early mortality worldwide, and nicotine replacement therapy has been demonstrated to increase rates of abstinence among smokers attempting to quit. Nicotine transdermal systems (also known as nicotine patches) attach to the skin via an adhesive layer composed of a mixture of different-molecular-weight polyisobutylenes (PIBs) in a specific ratio. This randomized, single-dose, 2-treatment, crossover pharmacokinetic (PK) trial assessed the bioequivalence of nicotine patches including a replacement PIB adhesive (test) compared with the PIB adhesive historically used on marketed patches (reference). The test and reference patches were bioequivalent, as determined by the PK parameters of C max and AUC 0-t . In addition, the parameters T max and t 1/2 did not significantly differ between the 2 patches, supporting the bioequivalence finding from the primary analysis. The tolerability profiles of the patches containing the replacement and previously used PIB adhesives were similar; application-site adverse events did not significantly differ between test and reference patches. Overall, these data establish the bioequivalence of the nicotine patch with the replacement PIB adhesive formulation and the previously utilized PIB adhesive formulation. © 2018 The Authors. Clinical Pharmacology in Drug Development published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.

Pharmacokinetics of Memantine after a Single and Multiple Dose of Oral and Patch Administration in Rats.

PubMed

Lee, Soo-Han; Kim, Seung-Hyun; Noh, Yook-Hwan; Choi, Byung-Moon; Noh, Gyu-Jeong; Park, Woo-Dae; Kim, Eun-Jung; Cho, Ik-Hyun; Bae, Chun-Sik

2016-02-01

Memantine is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist used to treat Alzheimer's disease. We investigated memantine pharmacokinetics after oral, IV and patch administration in rats, and compared memantine pharmacokinetics after multiple- or single-dose oral and transdermal administration. Venous blood was collected at preset intervals in single- and multiple-dose studies. Non-compartmental pharmacokinetics was analysed for all formulations. The oral, IV and patch memantine doses were 10 mg/kg, 2 mg/kg and 8.21 ± 0.89 mg/kg, respectively. The maximum plasma concentration was lower and the half-life longer after patch administration than oral and IV administration. Memantine bioavailability was 41 and 63% for oral and patch administration, respectively. Steady state was achieved around 24 hr for oral and patch administration. The mean AUC increased after oral or patch administration from single to multiple dose. The memantine patch formulation displayed a longer duration of action and lower peak plasma concentration. However, drug exposure was similar to the oral formulation at each dose. Additionally, the memantine patch formulation displayed a smaller interindividual variability and lower accumulation than the oral formulation. © 2015 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Transdermal fentanyl in deliberate overdose in pediatrics.

PubMed

Lyttle, Mark D; Verma, Sapna; Isaac, Rhian

2012-05-01

The use of the fentanyl skin patch to provide pain relief in chronic pain conditions and oncology in adult practice has been common for several years, and an increase in use is now being seen in pediatric practice. Its use in drug misuse and suicide has also increased in recent years. We present the case of an adolescent who deliberately overdosed using fentanyl skin patches and describe the implications for management. This report serves to remind clinicians to consider this method of drug administration in children who display signs of opioid toxicity, where overdose may be subsequent to its use in therapy, recreation, or deliberate self-harm.

Sex hormone-binding globulin and antithrombin III activity in women with oral ultra-low-dose estradiol.

PubMed

Matsui, Sumika; Yasui, Toshiyuki; Kasai, Kana; Keyama, Kaoru; Yoshida, Kanako; Kato, Takeshi; Uemura, Hirokazu; Kuwahara, Akira; Matsuzaki, Toshiya; Irahara, Minoru

2017-07-01

Oral oestrogen increases the risk of venous thromboembolism (VTE) and increases production of sex hormone-binding globulin (SHBG) in a dose-dependent manner. SHBG has been suggested to be involved in venous thromboembolism. We examined the effects of oral ultra-low-dose oestradiol on circulating levels of SHBG and coagulation parameters, and we compared the effects to those of transdermal oestradiol. Twenty women received oral oestradiol (500 μg) every day (oral ultra-low-dose group) and 20 women received a transdermal patch (50 μg) as a transdermal group. In addition, the women received dydrogesterone continuously (5 mg) except for women who underwent hysterectomy. Circulating SHBG, antithrombin III (ATIII) activity, d-dimer, thrombin-antithrombin complex and plasmin-α2 plasmin inhibitor complex were measured before and 3 months after the start of treatment. SHBG was significantly increased at 3 months in the oral ultra-low-dose group, but not in the transdermal group. However, percent changes in SHBG were not significantly different between the two groups. In both groups, ATIII was significantly decreased at 3 months. In conclusion, even ultra-low-dose oestradiol orally increases circulating SHBG level. However, the magnitude of change in SHBG caused by oral ultra-low-dose oestradiol is small and is comparable to that caused by transdermal oestradiol. Impact statement Oral oestrogen replacement therapy increases production of SHBG which may be related to increase in VTE risk. However, the effect of oral ultra-low-dose oestradiol on SHBG has not been clarified. Even ultra-low-dose oestradiol orally increases circulating SHBG levels, but the magnitude of change in SHBG caused by oral ultra-low-dose oestradiol is small and is comparable to that caused by transdermal oestradiol. VTE risk in women receiving oral ultra-low-dose oestradiol may be comparable to that in women receiving transdermal oestradiol.

Finite element analysis of hollow out-of-plane HfO2 microneedles for transdermal drug delivery applications.

PubMed

Zhang, Yong-Hua; A Campbell, Stephen; Karthikeyan, Sreejith

2018-02-17

Transdermal drug delivery (TDD) based on microneedles is an excellent approach due to its advantages of both traditional transdermal patch and hypodermic syringes. In this paper, the fabrication method of hollow out-of-layer hafnium oxide (HfO 2 ) microneedles mainly based on deep reactive ion etching of silicon and atomic layer deposition of HfO 2  is described, and the finite element analysis of the microneedles based on ANSYS software is also presented. The fabrication process is simplified by using a single mask. The finite element analysis of a single microneedle shows that the flexibility of the microneedles can be easily adjusted for various applications. The finite element analysis of a 3 × 3 HfO 2 microneedle array applied on the skin well explains the "bed of nail" effect, i.e., the skin is not liable to be pierced when the density of microneedles in array increases. The presented research work here provides useful information for design optimization of HfO 2 microneedles used for TDD applications.

Novel UHPLC-MS/MS method for the determination of rotigotine in the plasma of patients with Parkinson's disease.

PubMed

Mohamed, Susan; Riva, Roberto; Contin, Manuela

2017-09-01

A novel ultra-high-pressure liquid chromatography-tandem mass spectrometry method was developed and validated for the determination of the dopamine receptor agonist rotigotine in human plasma. Following liquid-liquid extraction with tert-butyl methyl ether from 500 μL plasma, the chromatographic analysis was performed on a Gemini NX3 column using 5 mm pH 5.0 ammonium acetate-5 mm ammonium acetate in methanol as binary gradient mobile phase, at a flow rate of 0.3 mL/min. The MS/MS ion transitions were 316.00 → 147.00 for rotigotine and 256.10 → 211.00 for the internal standard (lamotrigine). The lower limit of quantitation was 50 pg/mL and the linearity was determined from 50 to 2500 pg/mL. The mean recovery was 96.9%. Both intra- and interassay imprecision and inaccuracy were ≤15% at all quality control concentrations. The method was successfully applied to measure morning trough plasma rotigotine concentrations in a series of patients with Parkinson's disease on chronic treatment. The present study describes the first fully validated method for rotigotine determination in human plasma. Copyright © 2017 John Wiley & Sons, Ltd.

Microprocessor in controlled transdermal drug delivery of anti-cancer drugs.

PubMed

Chandrashekar, N S; Shobha Rani, R H

2009-12-01

Microprocessor controlled transdermal delivery of anticancer drugs 5-Fluorouracil (5-FU) and 6-Mercaptopurine (6-MP) was developed and in vitro evaluation was done. Drugs were loaded based on the pharmacokinetics parameters. In vitro diffusion studies were carried at different current density (0.0, 0.1, 0.22, 0.50 mA/cm2). The patches were evaluated for the drug content, thickness, weight, folding endurance, flatness, thumb tack test and adhesive properties all were well with in the specification of transdermal patches with elegant and transparent in appearance. In vitro permeation studies through human cadaver skin showed, passive delivery (0.0 mA/cm2) of 6-MP was low. As the current density was progressively increased, the flux also increased. the flux also increased with 0.1 mA/cm2 for 15-20 min, but it was less than desired flux, 0.2 mA/cm2 for 30 min showed better flux than 0.1 mA/cm2 current, but lag time was more than 4 h, 0.5 mA/cm2 current for more than 1 h, flux was >159 microg/cm2 h which was desired flux for 6-MP. 5-FU flux reached the minimum effective concentration (MEC) of 54 microg/cm2 h with 0.5 mA/cm2 current for 30-45 min, drug concentration were within the therapeutic window in post-current phase. We concluded from Ohm's Law that as the resistance decreases, current increases. Skin resistance decrease with increase in time and current, increase in the drug permeation. Interestingly, for all investigated current densities, as soon as the current was switched off, 5-FU and 6-MP flux decreased fairly, but the controlled drug delivery can be achieved by switching the current for required period of time.

Influence of adsorbents in transdermal matrix patches on the release and the physical state of ethinyl estradiol and levonorgestrel.

PubMed

Schulz, Martin; Fussnegger, Bernhard; Bodmeier, Roland

2011-02-01

The drug release from medium molecular weight polyisobutene patches containing adsorbates (drug content: 0.2% ethinyl estradiol, 1.0% levonorgestrel; adsorbent content: 20%, w/w) increased in the order of no adsorbent

Ovarian activity in obese and nonobese women treated with three transdermal contraceptive patches delivering three different doses of ethinyl estradiol and levonorgestrel.

PubMed

Foegh, Marie; Archer, David F; Stanczyk, Frank Z; Rubin, Arkady; Mishell, Daniel R

2013-02-01

The effect of obesity on ovarian follicular suppression in women using low-estrogen dose contraceptive patches has not been determined. A Phase II, parallel-group, multicenter, three-cycle study evaluated three patches containing different ethinyl estradiol (EE) and levonorgestrel (LNG) doses. Serum levels of EE, LNG, sex hormone-binding globulin and progesterone were compared in 41 obese [body mass index (BMI) ≥30] and 75 nonobese (BMI <30) women. Suppression of ovulation during the luteal phase was dose dependent, with the highest dose (AG200-15) preventing progesterone increases in all women (cycles 2-3). In the follicular phase, the lowest-dose patch had the highest rate of increased progesterone in nonobese subjects. Progesterone levels ≥3.0 ng/mL in the follicular phase were more common in obese than nonobese women. AG200-15 suppresses ovulation in obese and nonobese women. All three patches found increased progesterone in the follicular phase, albeit more in obese versus nonobese women. Copyright © 2013 Elsevier Inc. All rights reserved.

Local transdermal therapy to the breast for breast cancer prevention and DCIS therapy: preclinical and clinical evaluation.

PubMed

Lee, Oukseub; Ivancic, David; Allu, Subhashini; Shidfar, Ali; Kenney, Kara; Helenowski, Irene; Sullivan, Megan E; Muzzio, Miguel; Scholtens, Denise; Chatterton, Robert T; Bethke, Kevin P; Hansen, Nora M; Khan, Seema A

2015-12-01

Women at high risk of breast cancer and those with carcinoma in situ need non-toxic, well-tolerated preventive interventions. One promising approach is drug delivery through the breast skin (local transdermal therapy, LTT). Our goal was to test novel drugs for LTT, to establish that LTT is applicable to non-steroidal drugs. Athymic nude rats were treated with oral tamoxifen, transdermal 4-hydroxytamoxifen (4-OHT) or endoxifen gel applied daily to the axillary mammary gland for 6 weeks (Study 1). Study 2 was identical to Study 1, testing transdermal telapristone acetate (telapristone) gel versus subcutaneous implant. At euthanasia, mammary glands and blood were collected. In Study 3, consenting women requiring mastectomy were randomized to diclofenac patch applied to the abdomen or the breast for 3 days preoperatively. At surgery, eight tissue samples per breast were collected from predetermined locations, along with venous blood. Drug concentrations were measured using liquid chromatography-tandem mass spectroscopy. Mammary tissue concentrations of 4-OHT, endoxifen, and telapristone were significantly higher in the axillary glands of the gel-treated animals, compared to inguinal glands or to systemically treated animals. Plasma concentrations were similar in gel and systemically treated animals. The clinical trial showed significantly higher mammary concentrations when diclofenac was applied to the breast skin versus the abdominal skin, but concentrations were variable. These results demonstrate that lipophilic drugs can be developed for LTT; although the nude rat is suitable for testing drug permeability, delivery is systemic. In human, however, transdermal application to the breast skin provides local delivery.

Adolescents' experiences using the contraceptive patch versus pills.

PubMed

Sucato, Gina S; Land, Stephanie R; Murray, Pamela J; Cecchini, Reena; Gold, Melanie A

2011-08-01

To compare use of the weekly transdermal contraceptive patch (patch) with daily combined hormonal contraceptive pills (pills) in adolescents. Prospective longitudinal study of adolescents' self-selected (non-randomized) use of the patch or pills. Urban, university hospital-affiliated, adolescent outpatient clinic. 13-22-year-old female adolescents seeking hormonal contraception, 40 who chose the patch and 40 who chose pills. Data were collected via self-report on paper questionnaires at three-cycle intervals for a total of up to nine cycles. Method continuation, perfect use, method satisfaction, quality of life, and side effects, including menstrual changes and perceived mood changes. After nine cycles, 38% of patch users and 60% of pill users were still using the method they had chosen at enrollment. There were no significant differences between the groups in self-reported perfect use. No differences were found in quality of life or side effects. Both patch and pill users noted menses became lighter and more predictable and reported decreased depression prior to their menses; only the pill group reported improvement in premenstrual anger. Method satisfaction was similar in both groups except patch users were more likely to report that their contraceptive method improved normal daily activities. Despite apparent advantages of the patch over the pill, adolescents using both methods continue to face challenges achieving perfect and sustained contraceptive use. 2011 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.

Microneedles for enhanced transdermal and intraocular drug delivery.

PubMed

Moffatt, Kurtis; Wang, Yujing; Raj Singh, Thakur Raghu; Donnelly, Ryan F

2017-10-01

Microneedle mediated delivery based research has garnered great interest in recent years. In the past, the initial focus was delivery of macromolecules of biological origin, however the field has now broadened its scope to include transdermal delivery of conventional low molecular weight drug molecules. Great success has been demonstrated utilising this approach, particularly in the field of vaccine delivery. Current technological advances have permitted an enhancement in design formulation, allowing delivery of therapeutic doses of small molecule drugs and biomolecules, aided by larger patch sizes and scalable manufacture. In addition, it has been recently shown that microneedles are beneficial in localisation of drug delivery systems within targeted ocular tissues. Microneedles have the capacity to modify the means in which therapeutics and formulations are delivered to the eye. However, further research is still required due to potential drawbacks and challenges. Indeed, no true microneedle-based transdermal or ocular drug delivery system has yet been marketed. Some concerns have been raised regarding regulatory issues and manufacturing processes of such systems, and those in the field are now actively working to address them. Microneedle-based transdermal and ocular drug delivery systems have the potential to greatly impact not only patient benefits, but also industry, and through diligence, innovation and collaboration, their true potential will begin to be realised within the next 3-5 years. Copyright © 2017 Elsevier Ltd. All rights reserved.

Efficacy and tolerability of transdermal granisetron for the control of chemotherapy-induced nausea and vomiting associated with moderately and highly emetogenic multi-day chemotherapy: a randomized, double-blind, phase III study.

PubMed

Boccia, Ralph V; Gordan, Lucio N; Clark, Gemma; Howell, Julian D; Grunberg, Steven M

2011-10-01

A novel transdermal formulation of granisetron (the granisetron transdermal delivery system (GTDS)) has been developed to deliver granisetron continuously over 7 days. This double-blind, phase III, non-inferiority study compared the efficacy and tolerability of the GTDS to daily oral granisetron for the control of chemotherapy-induced nausea and vomiting (CINV). Six hundred forty-one patients were randomized to oral (2 mg/day, 3-5 days) or transdermal granisetron (one GTDS patch, 7 days), before receiving multi-day chemotherapy. The primary endpoint was complete control of CINV (no vomiting/retching, no more than mild nausea, no rescue medication) from chemotherapy initiation until 24 h after final administration. The prespecified non-inferiority margin was 15%. Five hundred eighty-two patients were included in the per protocol analysis. The GTDS displayed non-inferiority to oral granisetron: complete control was achieved by 60% of patients in the GTDS group, and 65% in the oral granisetron group (treatment difference, -5%; 95% confidence interval, -13-3). Both treatments were well tolerated, the most common adverse event being constipation. The GTDS provides effective, well-tolerated control of CINV associated with moderately or highly emetogenic multi-day chemotherapy. It offers a convenient alternative route for delivering granisetron for up to 7 days that is as effective as oral granisetron.

A fatal outcome after unintentional overdosing of rivastigmine patches.

PubMed

Lövborg, Henrik; Jönsson, Anna K; Hägg, Staffan

2012-02-01

Rivastigmine is an acetylcholine esterase inhibitor used in the treatment of dementia. Patches with rivastigmine for transdermal delivery have been used to increase compliance and to reduce side effects. We describe an 87-year old male with dementia treated with multiple rivastigmine patches (Exelon 9,5 mg/24 h) who developed nausea, vomiting and renal failure with disturbed electrolytes resulting in death. The symptoms occurred after six rivastigmine patches had concomitantly been erroneously applied by health care personnel on two consecutive days. The terminal cause of death was considered to be uremia from an acute tubular necrosis that was assessed as a result of dehydration through vomiting. The rivastigmine intoxication was assessed as having caused or contributed to the dehydrated condition. The medication error occurred at least partly due to ambiguous labeling. The clinical signs were not initially recognized as adverse effects of rivastigmine. The presented case is a description of a rivastigmine overdose due to a medication error involving patches. This case indicates the importance of clear and unambiguous instructions to avoid administration errors with patches and to be vigilant to adverse drug reactions for early detection and correction of drug administration errors. In particular, instructions clearly indicating that only one patch should be applied at a time are important.

Pure akinesia: a kinematic analysis in a case responsive to rotigotine

PubMed Central

Di Fabio, Roberto; Serrao, Mariano; Pierelli, Francesco; Fragiotta, Gaia; Sandrini, Giorgio

2013-01-01

Summary A patient with pure akinesia is described. This rare gait disorder, poorly responsive to therapy, is characterized by gait impairment which may be associated with handwriting and speech difficulties, in the absence of further signs of extrapyramidal involvement. Here, we report the improvement in a patient suffering from pure akinesia after low doses of rotigotine, a non-ergolinic dopamine agonist, detailing the kinematic analysis before and after the treatment. After therapy, an improvement in all of the gait parameters, particularly gait speed, was observed with a trend toward normalization. Our case report suggests that rotigotine may be a therapeutic option in cases of pure akinesia. PMID:24125564

The impact of advertising on nicotine replacement therapy demand.

PubMed

Tauras, John A; Chaloupka, Frank J; Emery, Sherry

2005-05-01

While much is known about the economic determinants of tobacco use, very little is known about the economic determinants of nicotine replacement therapy (NRT) use. This paper is the first econometric study to examine the impact of advertising on NRT demand. Pooled cross-sectional time-series scanner-based data for 50 major metropolitan markets in the USA covering the period between the second quarter of 1996 and the second quarter of 2002 are used in the analysis. Fixed-effects modeling is employed to estimate the NRT demand equation. The estimates indicate that increased advertising of Nicoderm CQ transdermal patches and Nicotrol transdermal patches increases per-capita sales of established Nicoderm CQ and Nicotrol products, respectively. However, increased advertising of Nicorette polacrilex (gum) was found not to significantly increase sales of established Nicorette products. Moreover, decreases in the price of NRT and increases in the price of cigarettes were found to increase per-capita sales of NRT products. Given the documented efficacy of NRT, measures to increase peoples' awareness of NRT products through advertising, measures to decrease the price of NRT, and measures to increase the price of cigarettes would be effective means to increase the use of NRT, likely leading to decreased cigarette smoking and reductions in the future public health burden caused by tobacco use.

A practical guide to male hypogonadism in the primary care setting

PubMed Central

Dandona, P; Rosenberg, M T

2010-01-01

There is a high prevalence of hypogonadism in the older adult male population and the proportion of older men in the population is projected to rise in the future. As hypogonadism increases with age and is significantly associated with various comorbidities such as obesity, type 2 diabetes, hypertension, osteoporosis and metabolic syndrome, the physician is increasingly likely to have to treat hypogonadism in the clinic. The main symptoms of hypogonadism are reduced libido/erectile dysfunction, reduced muscle mass and strength, increased adiposity, osteoporosis/low bone mass, depressed mood and fatigue. Diagnosis of the condition requires the presence of low serum testosterone levels and the presence of hypogonadal symptoms. There are a number of formulations available for testosterone therapy including intramuscular injections, transdermal patches, transdermal gels, buccal patches and subcutaneous pellets. These are efficacious in establishing eugonadal testosterone levels in the blood and relieving symptoms. Restoration of testosterone levels to the normal range improves libido, sexual function, and mood; reduces fat body mass; increases lean body mass; and improves bone mineral density. Testosterone treatment is contraindicated in subjects with prostate cancer or benign prostate hyperplasia and risks of treatment are perceived to be high by many physicians. These risks, however, are often exaggerated and should not outweigh the benefits of testosterone treatment. PMID:20518947

Efficacy, safety and risk of augmentation of rotigotine for treating restless legs syndrome.

PubMed

Inoue, Yuichi; Hirata, Koichi; Hayashida, Kenichi; Hattori, Nobutaka; Tomida, Takayuki; Garcia-Borreguero, Diego

2013-01-10

The present study aimed to examine the long-term efficacy and safety of rotigotine treatment for restless legs syndrome (RLS), as well as the rate of clinically significant augmentation, in a 1-year open-label study of Japanese subjects. Japanese patients with RLS who had been treated with rotigotine or placebo in a double-blind trial were enrolled in a 1-year, open-label, uncontrolled extension study and treated with rotigotine at a dose of up to 3 mg/24 h after an 8-week titration phase. Outcomes included International Restless Legs Syndrome Study Group rating scale (IRLS scale), Pittsburgh Sleep Quality Index (PSQI), safety, and investigator-/expert panel-assessed augmentation (including Augmentation Severity Rating Scale). Overall, 185 patients entered the open-label study and 133 completed the study. IRLS and PSQI total scores improved throughout the 52-week treatment period (IRLS, from 23.2±5.1 to 7.8±7.6 and PSQI, from 8.0±3.1 to 5.0±2.9). Treatment-emergent adverse events were mild to moderate in severity, and included application site reactions (52.4%) and nausea (28.6%). Clinically significant augmentation occurred in five patients (2.7%). These results indicate a good long-term efficacy of rotigotine for treating RLS, with a relatively low risk of clinically significant augmentation. Copyright © 2012 Elsevier Inc. All rights reserved.

Identification and treatment of augmentation in patients with restless legs syndrome: practical recommendations.

PubMed

Geyer, James; Bogan, Richard

2017-09-01

Restless legs syndrome (RLS) is a chronic disorder causing clinically significant discomfort to approximately 3% of adults. Although RLS was first identified centuries ago, our understanding of this disorder, its causes, and its treatments is still evolving. In particular, our knowledge of the potential negative effects of RLS treatments, including dopaminergic augmentation, continues to expand. Augmentation, which refers to a paradoxical treatment-related increase in RLS symptoms, has been associated with all three dopamine agonists approved for the treatment of RLS - rotigotine, pramipexole, and ropinirole. This review presents key information on prevention and treatment of dopaminergic augmentation from the recently published consensus-based guidelines issued by the International RLS Study Group task force in conjunction with the European RLS Study Group and the RLS Foundation for first-line treatment of RLS/Willis-Ekbom disease. If dopamine agonists are used to treat RLS, it is recommended that the dosage should be kept as low as possible without exceeding the maximum dose recommended for RLS treatment. As the frequency of augmentation with the rotigotine patch may only be slightly lower than that associated with pramipexole or ropinirole, medications that are effective and have little risk of augmentation, such as alpha-2-delta ligands, may be considered for initial RLS treatment. In addition, we present our clinical experience with treating patients with dopaminergic augmentation by highlighting 2 case studies and practical considerations when treating different patient populations. Applying current RLS augmentation diagnosis and treatment guidelines, as well as collecting detailed histories of worsening RLS symptoms, is critical for patient safety and effective management of RLS augmentation.

Duragesic transdermal patch: postmortem tissue distribution of fentanyl in 25 cases.

PubMed

Anderson, D T; Muto, J J

2000-10-01

Fentanyl is a potent, short-acting narcotic analgesic widely used as a surgical anesthetic and for the control of pain when administered in the form of a transdermal patch. The success of the patch can be attributed to fentanyl's low molecular weight and its highly lipophilic nature, which enables it to be readily absorbed through the skin and subsequently distributed throughout the body. Over the past three years, the Los Angeles County Coroner's Toxicology Laboratory has encountered 25 cases involving Duragesic patches (fentanyl), and their postmortem tissue distributions are presented here. The analysis of fentanyl from postmortem specimens (3-mL or g sample size) consisted of an n-butyl chloride basic extraction followed by identification and quantitation on a gas chromatograph-mass spectrometer using the selected ion monitoring (SIM) mode. The fentanyl ions monitored were m/z 245, 146, and 189 and the internal standard, fentanyl-d5 ions, were m/z 250, 151, and 194 (quantitation ion underlined). The linear range of the assay was 1.67 microg/L to 500 microg/L with the limit of quantitation and detection of 1.67 microg/L. The postmortem tissue distribution ranges of fentanyl in the 25 fatalities were as follows: heart blood, 1.8-139 microg/L (23 cases); femoral blood, 3.1-43 microg/L (13 cases); vitreous, +<2.0-20 microg/L (4 cases); liver, 5.8-613 microg/kg (22 cases); bile, 3.5-262 microg/L (15 cases); urine, 2.9-895 microg/L (19 cases); gastric, 0-1200 microg total (17 cases); spleen, 7.8-79 microg/kg (3 cases); kidney, 11 microg/kg (1 case); and lung, 31 microg/kg (1 case). The age of the decedents in this study ranged from 19 to 84, with an average age of 46. The modes of death included 15 accidental, 5 natural, 3 suicidal, and 2 undetermined. The main objectives of this paper are to show the prevalence of fentanyl patches in our community and to aid the forensic toxicologist with the interpretation of postmortem fentanyl levels in casework.

Efficacy and safety of an over-the-counter transdermal nicotine patch as an aid for smoking cessation.

PubMed

Davidson, M; Epstein, M; Burt, R; Schaefer, C; Whitworth, G; McDonald, A

1998-01-01

To evaluate the efficacy and safety of a transdermal nicotine patch as an aid for smoking cessation in an over-the-counter setting. Multicenter, double-blind, randomized, placebo-controlled trial of 6-week duration with 18 weeks of follow-up. Four shopping mall precincts. The randomized sample consisted of 802 adults (mean age, 39 years) and was 89% white and 54% female. A smoking history of at least 20 cigarettes per day for 1 year and a score of 5 (on a 10-point scale) on a motivational assessment questionnaire were required for enrollment. Poststudy follow-up was limited to those who had quit smoking at the end of 6 weeks. Nicotine patches were provided at the shopping mall. Guidance consisted only of package instructions and a smoking cessation self-help booklet. Quit rates were defined as total abstinence from smoking for 4 consecutive weeks (treatment weeks 3-6), point prevalence smoking status at week 6, or nonsmoker at week 6 and week 24 (6-month postquit date). Smoking status was assessed by diaries, and verification for the first 2 quit rates was obtained by confirmation of carbon monoxide of 8 ppm or less in expired breath. Safety was evaluated by self-reported adverse events. Quit rate was 12% for the active treatment group and 5.5% for the placebo group, based on total abstinence for 4 consecutive weeks (P = .001) compared with quit rates of 19.5% and 7.5% for active treatment and placebo groups, respectively, based on point prevalence data at week 6. At 24 weeks, 8.2% of nonsmokers in the active treatment group and 4.0% in the placebo group remained nonsmokers. At least 1 adverse event was reported by 57% receiving the nicotine patch and 39% receiving placebo (P<.001). When the nicotine patch was used in an over-the-counter setting, quit rates were comparable to those reported for medical settings. A 2:1 quit rate advantage was achieved at week 6 and was maintained at 24 weeks.

Multiscale modeling of transdermal drug delivery

NASA Astrophysics Data System (ADS)

Rim, Jee Eun

2006-04-01

This study addresses the modeling of transdermal diffusion of drugs, to better understand the permeation of molecules through the skin, and especially the stratum corneum, which forms the main permeation barrier of the skin. In transdermal delivery of systemic drugs, the drugs diffuse from a patch placed on the skin through the epidermis to the underlying blood vessels. The epidermis is the outermost layer of the skin and can be further divided into the stratum corneum (SC) and the viable epidermis layers. The SC consists of keratinous cells (corneocytes) embedded in the lipid multi-bilayers of the intercellular space. It is widely accepted that the barrier properties of the skin mostly arises from the ordered structure of the lipid bilayers. The diffusion path, at least for lipophilic molecules, seems to be mainly through the lipid bilayers. Despite the advantages of transdermal drug delivery compared to other drug delivery routes such as oral dosing and injections, the low percutaneous permeability of most compounds is a major difficulty in the wide application of transdermal drug delivery. In fact, many transdermal drug formulations include one or more permeation enhancers that increase the permeation of the drug significantly. During the last two decades, many researchers have studied percutaneous absorption of drugs both experimentally and theoretically. However, many are based on pharmacokinetic compartmental models, in which steady or pseudo-steady state conditions are assumed, with constant diffusivity and partitioning for single component systems. This study presents a framework for studying the multi-component diffusion of drugs coupled with enhancers through the skin by considering the microstructure of the stratum corneum (SC). A multiscale framework of modeling the transdermal diffusion of molecules is presented, by first calculating the microscopic diffusion coefficient in the lipid bilayers of the SC using molecular dynamics (MD). Then a homogenization procedure is performed over a model unit cell of the heterogeneous SC, resulting in effective diffusion parameters. These effective parameters are the macroscopic diffusion coefficients for the homogeneous medium that is "equivalent" to the heterogeneous SC, and thus can be used in finite element simulations of the macroscopic diffusion process.

Transdermal delivery of AT1 receptor antagonists reduce blood pressure and reveals a vasodilatory effect in kidney blood vessels.

PubMed

Michalatou, Michaila; Androutsou, Maria Eleni; Antonopoulos, Markos; Vlahakos, Demetrios V; Agelis, George; Zulli, Anthony; Qaradakhi, Tawar; Mikkelsen, Kathleen; Apostolopoulos, Vasso; Matsoukas, John

2018-04-19

The Renin Angiotensin System (RAS) is pharmacologically targeted to reduce blood pressure, and patient compliance to oral medications is a clinical issue. The mechanisms of action of angiotensin receptor blockers (ARBs) in reducing blood pressure are not well understood, and is purported to be via a reduction of angiotensin II signaling. We aimed to develop a transdermal delivery method for ARBs (losartan potassium and valsartan) and to determine if ARBs reveal a vasodilatory effect of the novel RAS peptide, alamandine. In addition we determined the anti-hypertensive effects of the transdermal delivery patch. In vitro and in vivo experiments were performed to develop an appropriate therapeutic system, promising an alternative and more effective therapy in the treatment of hypertension. A variety of penetration enhancers were selected such as isopropyl myristate, propylene glycol, transcutol and dimenthyl sulfoxide to obtain a constant release of drugs through human skin. Small resistance vessels (kidney interlobar arteries) were mounted in organ baths and incubated with an ARB. Vasodilatory curves to alamandine were constructed Results: The in vivo studies demonstrates that systemic absorption of valsartan and losartan potassium using the appropriate formulations provides a steady state release and anti-hypertensive effect even after 24 hours of transdermal administration. No apparent skin irritations (erythema, edema) were observed with the tested formulations. We also show that blocking the AT1 receptor of rabbit interlobar arteries in vitro reveals a vasodilatory effect of alamandine. This study reveals potential mechanism of AT1 receptor blockade via alamandine, and is an important contribution in developing a favorable, convenient and painless antihypertensive therapy of prolonged duration through transdermal delivery of AT1 blockers. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

A randomized, 14-day, double-blind study evaluating conversion from hydrocodone/acetaminophen (Vicodin) to buprenorphine transdermal system 10 μg/h or 20 μg/h in patients with osteoarthritis pain.

PubMed

Ripa, Steven R; McCarberg, Bill H; Munera, Catherine; Wen, Warren; Landau, Craig J

2012-06-01

The objective of this study was to evaluate continued pain control and tolerability of converting patients from Vicodin (hydrocodone/acetaminophen; HCD/APAP) to the buprenorphine transdermal system (BTDS). Adult patients with pain from osteoarthritis receiving a stable dosage of HCD/APAP (i.e., 15 - 30 mg hydrocodone/day) were switched to an equivalent or near-equivalent dosage of open-label Vicodin for 7 days. Patients maintaining acceptable analgesia were stratified based on their Vicodin dosage and randomized to receive either titratable BTDS 10 μg/h or fixed-dose BTDS 20 μg/h. The primary efficacy variable was completion of the 14-day double-blind phase. Tolerability was assessed. A total of 84.3% of patients met the primary end point, completion of the 14-day double-blind phase (167/198 patients, 95% CI 79.3 - 89.4). Adverse events were consistent with those associated with the use of opioid analgesics and transdermal patches. There was a similar analgesic and tolerability profile when patients treated with Vicodin for osteoarthritis pain were switched to 7-day BTDS treatment.

In vivo real-time monitoring system of electroporation mediated control of transdermal and topical drug delivery.

PubMed

Blagus, Tanja; Markelc, Bostjan; Cemazar, Maja; Kosjek, Tina; Preat, Veronique; Miklavcic, Damijan; Sersa, Gregor

2013-12-28

Electroporation (EP) is a physical method for the delivery of molecules into cells and tissues, including the skin. In this study, in order to control the degree of transdermal and topical drug delivery, EP at different amplitudes of electric pulses was evaluated. A new in vivo real-time monitoring system based on fluorescently labeled molecules was developed, for the quantification of transdermal and topical drug delivery. EP of the mouse skin was performed with new non-invasive multi-array electrodes, delivering different amplitudes of electric pulses ranging from 70 to 570 V, between the electrode pin pairs. Patches, soaked with 4 kDa fluorescein-isothiocyanate labeled dextran (FD), doxorubicin (DOX) or fentanyl (FEN), were applied to the skin before and after EP. The new monitoring system was developed based on the delivery of FD to and through the skin. FD relative quantity was determined with fluorescence microscopy imaging, in the treated region of the skin for topical delivery and in a segment of the mouse tail for transdermal delivery. The application of electric pulses for FD delivery resulted in enhanced transdermal delivery. Depending on the amplitude of electric pulses, it increased up to the amplitude of 360 V, and decreased at higher amplitudes (460 and 570 V). Topical delivery steadily enhanced with increasing the amplitude of the delivered electric pulses, being even higher than after tape stripping used as a positive control. The non-invasive monitoring of the delivery of DOX, a fluorescent chemotherapeutic drug, qualitatively and quantitatively confirmed the effects of EP at 360 and 570 V pulse amplitudes on topical and transdermal drug delivery. Delivery of FEN at 360 and 570 V pulse amplitudes verified the observed effects as obtained with FD and DOX, by the measured physiological responses of the mice as well as FEN plasma concentration. This study demonstrates that with the newly developed non-invasive multi-array electrodes and with the varying electric pulse amplitude, the amount of topical and transdermal drug delivery to the skin can be controlled. Furthermore, the newly developed monitoring system provides a tool for rapid real-time determination of both, transdermal and topical delivery, when the delivered molecule is fluorescent. © 2013 Elsevier B.V. All rights reserved.

Trans-Dermal Fentanyl Patches are a Cost-Effective Method of Long-Term Analgesic Delivery Following Corneal Exposure to Sulfur Mustard Vapor

DTIC Science & Technology

2012-01-01

SM) exposure in rabbits involves delivery of the opioid receptor agonist buprenorphine using subcutaneously implanted osmotic pumps. The...significantly lower than the costs of purchasing and loading an osmotic pump with buprenorphine . Pump implantation took approximately 10 min per...general distress than did the buprenorphine cohort. The elevated behavioral changes exhibited by the rabbits with implanted pumps were likely a

Nitroglycerin patch for the treatment of chondrodermatitis nodularis helicis: a new therapeutic option.

PubMed

Garrido Colmenero, Cristina; Martínez García, Eliseo; Blasco Morente, Gonzalo; Tercedor Sánchez, Jesús

2014-01-01

Chondrodermatitis nodularis helicis (CNH) is an inflammatory process that affects the skin and cartilage of the ear. At present, there are many treatment options, although they are not always effective. Based on previous studies where nitroglycerin 2% gel was used, we propose the use of nitroglycerin patches. The purpose of this study was to evaluate the effectiveness of nitroglycerin patches in treating CNH. We performed a prospective study in 11 patients diagnosed with CNH treated with nitroglycerin patches 5 mg, 12 hours a day for 2 months. The therapeutic effectivity was determined by the improvement in the appearance and symptoms of the lesion. Seven of 11 patients (63.6%) had a complete response. One of 11 patients (9%) did not respond completely and surgical treatment was performed. Two of 11 patients (18.1%) stopped the treatment because of headache. One of 11 patients (9%) did not complete the treatment because the said patient forgot to apply the patch every night. Transdermal nitroglycerin has demonstrated efficacy in the treatment of the symptoms and lesional appearance of CNH noninvasive manner. The success rate is comparable with other published methods and the rate of adverse effects is acceptable. © 2014 Wiley Periodicals, Inc.

A mixed treatment comparison of gabapentin enacarbil, pramipexole, ropinirole and rotigotine in moderate-to-severe restless legs syndrome.

PubMed

Sun, Ying; van Valkenhoef, Gert; Morel, Thomas

2014-11-01

A mixed treatment comparison (MTC) was performed to investigate the relative efficacy and safety of licensed pharmaceuticals for moderate-to-severe restless legs syndrome (RLS). RLS trials published over the past 10 years were identified via systematic literature searches of MEDLINE, Embase, Cochrane CENTRAL, and manufacturers' websites. MTC was performed with WinBUGS software using a Bayesian approach. Identified primary outcomes: change in International RLS Study Group Rating Scale (IRLS) at week 12 and end of maintenance (EoM). IRLS and Clinical Global Impression - Improvement Scale (CGI-I) responders, RLS-6 items and adverse events (AEs). Twenty-eight clinical trials were identified. Fifteen were included in the primary analysis. Indirect comparisons were established among gabapentin enacarbil, pramipexole, ropinirole, rotigotine and placebo. Overall, the four active treatments showed similar efficacies as assessed by changes in IRLS scores, IRLS responders, CGI-I responders, and RLS-6 scores. The sole exception was change in IRLS at week 12, for which rotigotine was likely more efficacious than ropinirole (mean difference: -2.52 [95% CrI: -4.74, -0.40]). Indirect comparisons on safety endpoints indicated ropinirole was associated with a higher risk of nausea than the other agents, and was more likely to result in discontinuations due to lack of efficacy than pramipexole. Nausea was likely more frequent with pramipexole than gabapentin enacarbil, and rotigotine was more likely to result in discontinuation due to AEs than ropinirole and pramipexole. This MTC confirmed the superiority of gabapentin enacarbil, pramipexole, ropinirole, and rotigotine above placebo in alleviating RLS symptoms. Compared to ropinirole, rotigotine showed some additional benefit in terms of change in IRLS at Week 12. Choice of RLS drugs requires careful evaluation of effectiveness and safety profiles in clinical practice. Due to lack of head-to-head trials, inconsistency could not be assessed in our analysis. Head-to-head trials on a more homogeneous population are needed to validate the MTC results.

Striatal Dopamine Transporter Modulation After Rotigotine: Results From a Pilot Single-Photon Emission Computed Tomography Study in a Group of Early Stage Parkinson Disease Patients.

PubMed

Rossi, Carlo; Genovesi, Dario; Marzullo, Paolo; Giorgetti, Assuero; Filidei, Elena; Corsini, Giovanni Umberto; Bonuccelli, Ubaldo; Ceravolo, Roberto

Several in vitro data have reported negative interference by dopamine-agonists on the expression of dopamine transporter (DAT), whereas the majority of imaging studies have shown that neither L-dopa nor dopamine-agonists interfere with DAT availability. As yet, there are no in vivo studies on DAT expression after treatment with rotigotine. We evaluated presynaptic nigrostriatal function in 8 patients with de novo Parkinson disease (age, 59 ± 6.2 years; male/female sex, 5/3) using 123-I- N-ω-fluoropropyl-2-β-carbomethoxy-3-β-(4-iodophenyl)nortropane (FP-CIT) single-photon emission computed tomography before and after 3 months of treatment with rotigotine (mean dose, 7.75 ± 1.98 mg). For data analysis, specific (left and right caudate, left and right putamen) to nonspecific (occipital cortex) binding ratios, putamen-to-caudate ratios, and asymmetry indices were calculated. After rotigotine, motor symptoms improved in all patients (Unified Parkinson Disease Rating Scale III mean score, 11.88 ± 2.59 vs 7.63 ± 1.92 on therapy; P = 0.0022). Striatal FP-CIT levels showed a significant improvement in every patient at the follow-up scan. Comparisons between before and after treatment in the whole group revealed a significant improvement in FP-CIT uptake in both caudate and putamen (P < 0.001 in each nucleus). Putamen-to-caudate ratio and asymmetry indices did not show any significant difference before and after treatment. Although the study population was small, we found DAT overexpression after chronic treatment with rotigotine, presumably related to its pharmacological profile. The DAT upregulation by rotigotine in an opposite direction with respect to early Parkinson disease compensatory mechanisms might reduce the risk of dyskinesia, but it could imply less motor benefit because of less stimulation by the dopamine itself on dopaminergic receptors.

Skin Barrier Restoration and Moisturization Using Horse Oil-Loaded Dissolving Microneedle Patches.

PubMed

Lee, Chisong; Eom, Younghyon Andrew; Yang, Huisuk; Jang, Mingyu; Jung, Sang Uk; Park, Ye Oak; Lee, Si Eun; Jung, Hyungil

2018-01-01

Horse oil (HO) has skin barrier restoration and skin-moisturizing effects. Although cream formulations have been used widely and safely, their limited penetration through the stratum corneum is a major obstacle to maximizing the cosmetic efficacy of HO. Therefore, we aimed to encapsulate HO in a cosmetic dissolving microneedle (DMN) for efficient transdermal delivery. To overcome these limitations of skin permeation, HO-loaded DMN (HO-DMN) patches were developed and evaluated for their efficacy and safety using in vitro and clinical studies. Despite the lipophilic nature of HO, the HO-DMN patches had a sharp shape and uniform array, with an average length and tip diameter of 388.36 ± 16.73 and 38.54 ± 5.29 µm, respectively. The mechanical strength of the HO-DMN patches was sufficient (fracture force of 0.29 ± 0.01 N), and they could successfully penetrate pig skin. During the 4-week clinical evaluation, HO-DMN patches caused significant improvements in skin and dermal density, skin elasticity, and moisturization. Additionally, a brief safety assessment showed that the HO-DMN patches induced negligible adverse events. The HO-DMNs are efficient, safe, and convenient for wide use in cosmetic applications for skin barrier restoration and moisturization. © 2018 S. Karger AG, Basel.

Pharmacokinetic Modeling to Simulate the Concentration-Time Profiles After Dermal Application of Rivastigmine Patch.

PubMed

Nozaki, Sachiko; Yamaguchi, Masayuki; Lefèvre, Gilbert

2016-07-01

Rivastigmine is an inhibitor of acetylcholinesterases and butyrylcholinesterases for symptomatic treatment of Alzheimer disease and is available as oral and transdermal patch formulations. A dermal absorption pharmacokinetic (PK) model was developed to simulate the plasma concentration-time profile of rivastigmine to answer questions relative to the efficacy and safety risks after misuse of the patch (e.g., longer application than 24 h, multiple patches applied at the same time, and so forth). The model comprised 2 compartments which was a combination of mechanistic dermal absorption model and a basic 1-compartment model. The initial values for the model were determined based on the physicochemical characteristics of rivastigmine and PK parameters after intravenous administration. The model was fitted to the clinical PK profiles after single application of rivastigmine patch to obtain model parameters. The final model was validated by confirming that the simulated concentration-time curves and PK parameters (Cmax and area under the drug plasma concentration-time curve) conformed to the observed values and then was used to simulate the PK profiles of rivastigmine. This work demonstrated that the mechanistic dermal PK model fitted the clinical data well and was able to simulate the PK profile after patch misuse. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Effects of rotigotine on clinical symptoms, quality of life and sleep hygiene adequacy in haemodialysis-associated restless legs syndrome.

PubMed

Esteve, Vicent; Carneiro, Jose; Salazar, Gabriel; Pou, Mónica; Tapia, Irati; Fulquet, Miquel; Duarte, Verónica; Saurina, Anna; Moreno, Fátima; Ramírez de Arellano, Manel

Restless legs syndrome (RLS) is a neurological disorder characterised by bothersome symptoms associated with impaired quality of life and sleep hygiene. Rotigotine is a novel therapeutic alternative, although few studies have been published in patients on haemodialysis (HD) with RLS treated with rotigotine. 1.- To establish the prevalence of RLS in our HD unit. 2.- To evaluate the efficacy and safety profile of rotigotine and its effect on symptoms, quality of life and sleep hygiene in our HD population with RLS. A single-centre, 12-week prospective study. Two stages (6 weeks): stage 1 (no treatment) and stage 2 (rotigotine). We analysed: 1.- Demographic data, biochemistry data, HD suitability parameters and RLS medical treatment data. 2.- Lower extremity symptoms questionnaire (QS). 3.- RLS severity symptoms scale (SRLSS). 4.- RLS Quality of life: John Hopkins RLS-QoL (JH-QoL). 5.- Sleep hygiene: SCOPA Scale. We included 66 HD patients, 14 with RLS; 44.4% male, 70.2±9.9 years and 111.1±160.8 months on HD. And 22.9% RLS. Exclusively in stage 2, a significant improvement for QS (10±2.4 vs. 5.7±1.0), SRLSS (21±4 vs. 5.7±4.6), JH-QoL (22.1±4.4 vs. 4.3±4.0) and SCOPA (16±5.3 vs. 6.7±1.9) were observed. A 77.7 and 11.1%, showed partial (> 20%) and complete (> 80%) remission, respectively, while 55.5% achieved «zero» symptoms. Only one patient had gastrointestinal intolerance and none experienced augmentation effect. No changes in biochemical data, suitability for dialysis or medical treatment were found. The inter-group analysis showed a significant improvement in relation to QS, SRLSS, JH-QoL and SCOPA in stage 2. RLS showed a considerable prevalence in our HD unit. Rotigotine improved clinical symptoms, quality of life and sleep hygiene in RLS patients on HD and was found to be a safe drug with minimal side effects and total therapeutic compliance. Nevertheless, future studies should be performed to confirm the benefits of rotigotine in RLS patients on haemodialysis. Copyright © 2017 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.

Safety and efficacy of skin patches containing loxoprofen sodium in diabetic patients with overt nephropathy.

PubMed

Araki, Hisazumi; Kuwagata, Shogo; Soumura, Mariko; Yamahara, Kosuke; Morita, Yoshikata; Kume, Shinji; Isshiki, Keiji; Araki, Shin-ichi; Kashiwagi, Atsunori; Maegawa, Hiroshi; Uzu, Takashi

2014-06-01

Because oral nonsteroidal anti-inflammatory drugs (NSAIDs) have adverse effects on kidney function, patients with kidney diseases are administered these drugs as transdermal patches. Little is known about the effects of NSAID patches on renal function. We therefore assessed the effects of topical loxoprofen sodium on kidney function in type 2 diabetic patients with overt nephropathy. Twenty patients with type 2 diabetes and overt proteinuria and with knee and/or low back pain were treated with skin patches containing 100 mg loxoprofen on the knee or back for 24 h per day for 5 consecutive days. The degree of pain was assessed using a visual analogue scale (VAS). Blood and 24-h urine samples were obtained at baseline and at the end of the study. Glomerular filtration rate (GFR) was estimated from serum creatinine and cystatin C concentrations. The 20 patients consisted of 11 males and 9 females, of mean age 61.6 ± 13.9 years. Loxoprofen-containing patches significantly reduced VAS pain without affecting blood pressure, GFR or urinary prostaglandin E2 concentration. Serum concentrations of loxoprofen and its active trans-OH metabolite did not correlate with GFR. Loxoprofen-containing patches do not affect renal function in type 2 diabetic patients with overt nephropathy over a short-term period. Long-term studies are needed to clarify the safety of loxoprofen-containing patches in patients with chronic kidney diseases.

Solid‐in‐oil nanodispersions for transdermal drug delivery systems

PubMed Central

Kitaoka, Momoko; Wakabayashi, Rie; Kamiya, Noriho

2016-01-01

Abstract Transdermal administration of drugs has advantages over conventional oral administration or administration using injection equipment. The route of administration reduces the opportunity for drug evacuation before systemic circulation, and enables long‐lasting drug administration at a modest body concentration. In addition, the skin is an attractive route for vaccination, because there are many immune cells in the skin. Recently, solid‐in‐oil nanodisperison (S/O) technique has demonstrated to deliver cosmetic and pharmaceutical bioactives efficiently through the skin. S/O nanodispersions are nanosized drug carriers designed to overcome the skin barrier. This review discusses the rationale for preparation of efficient and stable S/O nanodispersions, as well as application examples in cosmetic and pharmaceutical materials including vaccines. Drug administration using a patch is user‐friendly, and may improve patient compliance. The technique is a potent transcutaneous immunization method without needles. PMID:27529824

Solid-in-oil nanodispersions for transdermal drug delivery systems.

PubMed

Kitaoka, Momoko; Wakabayashi, Rie; Kamiya, Noriho; Goto, Masahiro

2016-11-01

Transdermal administration of drugs has advantages over conventional oral administration or administration using injection equipment. The route of administration reduces the opportunity for drug evacuation before systemic circulation, and enables long-lasting drug administration at a modest body concentration. In addition, the skin is an attractive route for vaccination, because there are many immune cells in the skin. Recently, solid-in-oil nanodisperison (S/O) technique has demonstrated to deliver cosmetic and pharmaceutical bioactives efficiently through the skin. S/O nanodispersions are nanosized drug carriers designed to overcome the skin barrier. This review discusses the rationale for preparation of efficient and stable S/O nanodispersions, as well as application examples in cosmetic and pharmaceutical materials including vaccines. Drug administration using a patch is user-friendly, and may improve patient compliance. The technique is a potent transcutaneous immunization method without needles. © 2016 The Authors. Biotechnology Journal published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Formulations of Amlodipine: A Review

PubMed Central

Ahsan, Syed Furqan; Khan, Marium Fatima

2016-01-01

Amlodipine (AD) is a calcium channel blocker that is mainly used in the treatment of hypertension and angina. However, latest findings have revealed that its efficacy is not only limited to the treatment of cardiovascular diseases as it has shown to possess antioxidant activity and plays an important role in apoptosis. Therefore, it is also employed in the treatment of cerebrovascular stroke, neurodegenerative diseases, leukemia, breast cancer, and so forth either alone or in combination with other drugs. AD is a photosensitive drug and requires protection from light. A number of workers have tried to formulate various conventional and nonconventional dosage forms of AD. This review highlights all the formulations that have been developed to achieve maximum stability with the desired therapeutic action for the delivery of AD such as fast dissolving tablets, floating tablets, layered tablets, single-pill combinations, capsules, oral and transdermal films, suspensions, emulsions, mucoadhesive microspheres, gels, transdermal patches, and liposomal formulations. PMID:27822402

Smoking cessation during alcohol treatment: a randomized trial of combination nicotine patch plus nicotine gum.

PubMed

Cooney, Ned L; Cooney, Judith L; Perry, Bridget L; Carbone, Michael; Cohen, Emily H; Steinberg, Howard R; Pilkey, David T; Sevarino, Kevin; Oncken, Cheryl A; Litt, Mark D

2009-09-01

The primary aim was to compare the efficacy of smoking cessation treatment using a combination of active nicotine patch plus active nicotine gum versus therapy consisting of active nicotine patch plus placebo gum in a sample of alcohol-dependent tobacco smokers in an early phase of out-patient alcohol treatment. A secondary aim was to determine whether or not there were any carry-over effects of combination nicotine replacement on drinking outcomes. Small-scale randomized double-blind placebo-controlled clinical trial with 1-year smoking and drinking outcome assessment. Two out-patient substance abuse clinics provided a treatment platform of behavioral alcohol and smoking treatment delivered in 3 months of weekly sessions followed by three monthly booster sessions. Participants were 96 men and women with a diagnosis of alcohol abuse or dependence and smoking 15 or more cigarettes per day. All participants received open-label transdermal nicotine patches and were randomized to receive either 2 mg nicotine gum or placebo gum under double-blind conditions. Analysis of 1-year follow-up data revealed that patients receiving nicotine patch plus active gum had better smoking outcomes than those receiving patch plus placebo gum on measures of time to smoking relapse and prolonged abstinence at 12 months. Alcohol outcomes were not significantly different across medication conditions. Results of this study were consistent with results of larger trials of smokers without alcohol problems, showing that combination therapy (nicotine patch plus gum) is more effective than monotherapy (nicotine patch) for smoking cessation.

Rapid Intradermal Delivery of Liquid Formulations Using a Hollow Microstructured Array

PubMed Central

Burton, Scott A.; Ng, Chin-Yee; Simmers, Ryan; Moeckly, Craig; Brandwein, David; Gilbert, Tom; Johnson, Nathan; Brown, Ken; Alston, Tesha; Prochnow, Gayatri; Siebenaler, Kris

2010-01-01

ABSTRACT Purpose The purpose of this work is to demonstrate rapid intradermal delivery of up to 1.5 mL of formulation using a hollow microneedle delivery device designed for self-application. Methods 3M’s hollow Microstructured Transdermal System (hMTS) was applied to domestic swine to demonstrate delivery of a variety of formulations including small molecule salts and proteins. Blood samples were collected after delivery and analyzed via HPLC or ELISA to provide a PK profile for the delivered drug. Site evaluations were conducted post delivery to determine skin tolerability. Results Up to 1.5 mL of formulation was infused into swine at a max rate of approximately 0.25 mL/min. A red blotch, the size of the hMTS array, was observed immediately after patch removal, but had faded so as to be almost indistinguishable 10 min post-patch removal. One-mL deliveries of commercial formulations of naloxone hydrochloride and human growth hormone and a formulation of equine anti-tetanus toxin were completed in swine. With few notable differences, the resulting PK profiles were similar to those achieved following subcutaneous injection of these formulations. Conclusions 3M’s hMTS can provide rapid, intradermal delivery of 300–1,500 µL of liquid formulations of small molecules salts and proteins, compounds not typically compatible with passive transdermal delivery. PMID:20582455

Observational Case Series Evaluation of the Granisetron Transdermal Patch System (Sancuso) for the Management of Nausea/Vomiting of Pregnancy.

PubMed

Le, Tran N; Adler, Michael T; Ouillette, Holly; Berens, Pamela; Smith, Judith A

2017-07-01

Objective  The objective of this study was to observe the efficacy of antiemetic therapy (no emesis/retching episodes and no rescue medication use) when granisetron is administered via a transdermal patch system (TDS) in women who are 6 to 14 weeks pregnant when compared with oral ondansetron by evaluating the frequency of the use of rescue medications for control of nausea/vomiting of pregnancy (NVP). Methods  This was an observational case series study to observe the potential benefits of granisetron TDS compared with oral ondansetron for management of NVP in pregnant patients during the first trimester. Dates of data collection were September 1, 2014, through December 31, 2015. There was no direct contact with patient. The oral ondansetron and granisetron TDS patients were matched by age, 4:1. The proportion of patients who received rescue antiemetics was calculated from those patients who continued to experience NVP. Risk factors for NVP were identified and compared between groups. Descriptive statistics were used to describe study results. Results  Patients were prescribed rescue antiemetics in 0/3 patients in the granisetron TDS group compared with 2/12 patients in the oral ondansetron group. Conclusion  Prospective efficacy studies on the use of granisetron TDS for management of NVP are needed to confirm this clinical observation. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Recommendations for the Treatment of Patients With Parkinson Disease During Ramadan.

PubMed

Damier, Philippe; Al-Hashel, Jasem

2017-02-01

Every year, Ramadan fasting is practiced by many Muslim individuals. In cases of chronic disease, religious texts allow fasting to be broken. However, many believers still want to fast even at the risk of damaging their health. To our knowledge, there are no published recommendations on the medical management of Parkinson disease (PD) during Ramadan. Effective treatments exist in PD and usually require several daily drug intakes. Apart from worsening symptoms, interrupting PD treatment might lead to a severe withdrawal syndrome. Although no specific studies on this topic have led to formal recommendations, we suggest some options for adapting the treatment for patients who fast during Ramadan. The general principle is based on switching the patient's treatment to an equivalent dosage of a dopamine agonist that can be administered once daily or by transdermal patch. However, such an option is only feasible for patients who require a moderate amount of PD treatment and can tolerate dopamine agonist therapy. Because many patients with PD require regular multiple daily administration of dopamine-replacement medication, the management of Ramadan fasting is not easy. Switching the patient's treatment to an equivalent dosage of a dopamine agonist that can be administered once daily or by transdermal patch seems to be a reasonable option to consider for patients treated with a low-to-moderate amount of PD medication.

Gabapentin enacarbil, pregabalin and rotigotine are equally effective in restless legs syndrome: a comparative meta-analysis.

PubMed

Iftikhar, I H; Alghothani, L; Trotti, L M

2017-12-01

To synthesize evidence from available randomized controlled trials (RCT) to compare the efficacies of dopaminergic drugs (pramipexole, ropinirole and rotigotine) and α-2-δ ligands (gabapentin enacarbil and pregabalin) for the treatment of restless legs syndrome (RLS). We searched PubMed for all eligible RCTs. Network meta-analysis using frequentist methodology with random effect models was performed for mean changes in scores on the International RLS Study Group Rating Scale (IRLS) and for responder rates on Clinical Global Impressions-Improvement (CGI-I); analyzed as odds ratio (OR). Network meta-analysis of mean changes in IRLS data from 35 studies with 7333 participants showed that all treatments, in specific gabapentin enacarbil, followed by pregabalin and rotigotine were superior to placebo [mean reduction in IRLS scores: -5.31 (-6.74 to -3.87), -5.20 (-6.91 to -3.49), 5.17 (3.73-6.61), respectively] but there were no significant differences between active treatments. Network meta-analysis of 5137 participants from 24 studies showed that gabapentin enacarbil and rotigotine were associated with the highest CGI-I response rates [ORs: 5.68; (95% CI, 4.14-7.21); and 4.68 (2.87-6.49), compared to placebo, respectively]. No significant inter-treatment differences exist, except for that between gabapentin enacarbil and ropinirole. Based on IRLS scores and CGI-I response rates, while gabapentin enacarbil, pregabalin and rotigotine stand out as the most efficacious of all examined drugs, it is noteworthy that no significant inter-treatment differences exist, except for that between gabapentin enacarbil and ropiniriole (for CGI-I response rates). © 2017 EAN.

Transdermal iontophoresis of ranitidine: an opportunity in paediatric drug therapy.

PubMed

Djabri, Asma; Guy, Richard H; Delgado-Charro, M Begoña

2012-10-01

The objective of this study was to examine the use of transdermal iontophoresis for the delivery of ranitidine hydrochloride in children. Constant, direct current, anodal iontophoresis of ranitidine was performed in vitro across dermatomed pig skin. The effect of donor vehicle, current intensity, and drug concentration were first examined using aqueous solutions. It was found that drug delivery was higher at pH 7 (donor: 5mM Tris) than pH 5.6 (donor: water). In the presence of low levels of competing background electrolyte, ranitidine delivery increased linearly with applied current but was independent of the donor drug concentration. The second part of the study evaluated two Pluronic(®) F-127 gels as potential vehicles for ranitidine delivery. The formulations were characterised in terms of apparent viscosity, conductivity and passive permeation measurements. Iontophoretic delivery of ranitidine was only slightly affected when delivered from the gels relative to aqueous solutions. Overall the results demonstrated that therapeutic paediatric doses of ranitidine (neonates: 0.09-0.17 μmol/kg h; 1 month to 12 years: 0.36-0.71 μmol/kg h) could be easily achieved by transdermal iontophoresis with simple gel patches of practical surface area (0.2-1.5 cm(2)/kg). Copyright © 2012 Elsevier B.V. All rights reserved.

Safety of fentanyl initiation according to past opioid exposure among patients newly prescribed fentanyl patches

PubMed Central

Friesen, Kevin J.; Woelk, Cornelius; Bugden, Shawn

2016-01-01

Background: Although a convenient opioid delivery system, transdermal fentanyl patches have caused several deaths and resulted in safety warnings reminding prescribers that fentanyl patches should be prescribed only for patients who have adequate prior exposure to opioids. We conducted a longitudinal analysis of the safety of fentanyl initiation by examining past opioid exposure among patients newly prescribed fentanyl patches. Methods: We identified all patients in the province of Manitoba who were newly prescribed fentanyl patches between Apr. 1, 2001, and Mar. 31, 2013. We converted all prior opioid use to oral morphine equivalents and determined the average daily dose in the 7–30 days before initial fentanyl patch use. Fentanyl initiation was considered unsafe if the patient’s pre-fentanyl opioid exposure was below the recommended level. Results: We identified 11 063 patients who began using fentanyl patches during the study period. Overall, fentanyl initiation was deemed unsafe in 74.1% of cases because the patient’s prior opioid exposure was inadequate. Women and patients 65 years of age and older were more likely than men and younger patients, respectively, to have inadequate prior opioid exposure (p < 0.001 for each comparison). The proportion of patients who had unsafe prescriptions for fentanyl patches decreased significantly over the study period, from 87.0% in 2001 to 50.0% in 2012 (p < 0.001). Interpretation: The safety of fentanyl initiation improved over the study period, but still half of fentanyl patch prescriptions were written for patients with inadequate prior opioid exposure. Review of prior opioid exposure may be a simple but important way to improve the safe use of fentanyl patches. PMID:27044480

Structure-activity relationship of chemical penetration enhancers in transdermal drug delivery.

PubMed

Kanikkannan, N; Kandimalla, K; Lamba, S S; Singh, M

2000-06-01

Transdermal drug delivery (TDD) is the administration of therapeutic agents through intact skin for systemic effect. TDD offers several advantages over the conventional dosage forms such as tablets, capsules and injections. Currently there are about eight drugs marketed as transdermal patches. Examples of such products include nitroglycerin (angina pectoris), clonidine (hypertension), scopolamine (motion sickness), nicotine (smoking cessation), fentanil (pain) and estradiol (estrogen deficiency). Since skin is an excellent barrier for drug transport, only potent drugs with appropriate physicochemical properties (low molecular weight, adequate solubility in aqueous and non-aqueous solvents, etc) are suitable candidates for transdermal delivery. Penetration enhancement technology is a challenging development that would increase significantly the number of drugs available for transdermal administration. The permeation of drugs through skin can be enhanced by physical methods such as iontophoresis (application of low level electric current) and phonophoresis (use of ultra sound energy) and by chemical penetration enhancers (CPE). In this review, we have discussed about the CPE which have been investigated for TDD. CPE are compounds that enhance the permeation of drugs across the skin. The CPE increase skin permeability by reversibly altering the physicochemical nature of the stratum corneum, the outer most layer of skin, to reduce its diffusional resistance. These compounds increase skin permeability also by increasing the partition coefficient of the drug into the skin and by increasing the thermodynamic activity of the drug in the vehicle. This review compiles the various CPE used for the enhancement of TDD, the mechanism of action of different chemical enhancers and the structure-activity relationship of selected and extensively studied enhancers such as fatty acids, fatty alcohols and terpenes. Based on the chemical structure of penetration enhancers (such as chain length, polarity, level of unsaturation and presence of some special groups such as ketones), the interaction between the stratum corneum and penetration enhancers may vary which will result in significant differences in penetration enhancement. Our review also discusses the various factors to be considered in the selection of an appropriate penetration enhancer for the development of transdermal delivery systems.

The CHOICE study: effect of counselling on the selection of combined hormonal contraceptive methods in 11 countries.

PubMed

Bitzer, Johannes; Gemzell-Danielsson, Kristina; Roumen, Frans; Marintcheva-Petrova, Maya; van Bakel, Bas; Oddens, Björn J

2012-02-01

To encourage healthcare professionals to counsel women seeking combined hormonal contraceptives (CHCs) about alternative CHCs and to study the influence of counselling on women's selection of CHCs. Women (15-40 years old) in 11 countries who consulted HCPs about CHCs were counselled about the pill, transdermal patch, and vaginal ring. Both the HCPs and the women completed questionnaires. Of women who were counselled (n = 18,787), 47% selected another CHC method than originally planned. One in four who intended to use the pill chose another method (16% chose the patch; 65% chose the ring). In total, patch use increased from 5% -8% (difference = 3.7% [97.5% CI: 3.3-4.2]; p < 0.0001). Ring use nearly quadrupled from 8% -30% (difference = 21.7% [97.5% CI: 21.0-22.5]; p < 0.0001). Nearly all women who were undecided prior to counselling selected a method after counselling. Selection of the pill increased most in Russia (+ 11%) and Sweden (+ 5%); patch selection was greatest in Russia (+ 7%) and Israel (+ 6%); ring use increased most in Ukraine and in the Czech Republic and Slovakia (+ 36%). Counselling increases use of alternative CHCs, such as the patch and the ring. Considerable differences between countries were noted.

A rivastigmine patch for the treatment of Alzheimer's disease and Parkinson's disease dementia.

PubMed

Cummings, Jeffrey; Winblad, Bengt

2007-11-01

Rivastigmine patch is the first transdermal treatment to be approved for Alzheimer's disease (AD) and Parkinson's disease dementia in the USA and for AD in Europe. It provides smooth, continuous drug delivery, and has the potential to maintain rivastigmine concentrations within an optimal therapeutic window while avoiding the peaks and troughs associated with oral drug delivery. The target dose, rivastigmine 9.5 mg/24 h patch (a 10 cm(2) patch), is given once daily and requires a simple one-step dose titration to the therapeutic dose. In a 24-week study in 1195 AD patients, the rivastigmine 9.5 mg/24 h patch provided similar efficacy to the highest dose range of capsules, with approximately three-times fewer reports of nausea and vomiting. Patients in the 9.5 mg/24 h patch and 12 mg/day capsule groups evidenced significant improvements versus placebo on both primary outcome measures: the Alzheimer's Disease Assessment Scale-Cognitive subscale; and Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change; in addition to the following secondary outcome measures: Alzheimer's Disease Cooperative Study-Activities of Daily Living scale; Mini-Mental State Examination; and Trail Making Test Part A for assessment of attention, visual tracking and motor processing speed. Treatment differences on the Neuropsychiatric Inventory and Ten Point Clock-drawing Test did not reach statistical significance in this study. The patch may be the optimal way to treat dementia patients with rivastigmine.

Patient adherence to transdermal rivastigmine after switching from oral donepezil: a retrospective claims database study.

PubMed

Tian, Haijun; Abouzaid, Safiya; Chen, Wei; Kahler, Kristijan H; Kim, Edward

2013-01-01

To examine patient adherence before and after switching from donepezil to the rivastigmine patch. This retrospective cohort study used the MarketScan Commercial and Medicare data sets (2004 to 2009). Patients with a diagnosis of Alzheimer disease who were new donepezil users and were subsequently switched to the rivastigmine patch were included. The proportion of days covered (PDC) and PDC difference between donepezil and the rivastigmine patch were calculated from the time of initiation to the switch, capped at 1 year after the first respective claim. PDC was calculated as the number of days with drugs available divided by the number of days in the respective follow-up periods. The sample included 772 patients (mean age 77 y; 58% female). The mean time between switching from donepezil to the rivastigmine patch was 579 (SD=317.3) days. The mean PDC for the rivastigmine patch was highest among patients who switched within 3 months (80.4% vs. 90.7%; P=0.04) and within 7 to 9 months (61.3% vs. 71.0%; P=0.05) of initiating donepezil. When adherence was analyzed in increments of 1 year, patients who switched to the rivastigmine patch within the first year of treatment had significantly greater adherence to rivastigmine compared with those who were on donepezil (PDC 69.3% vs. 60.6%; P=0.0004). Switching from donepezil to the rivastigmine patch seems to be associated with increased adherence, especially in patients who switched within the first year of initiating donepezil.

Rotigotine polyoxazoline conjugate SER-214 provides robust and sustained antiparkinsonian benefit.

PubMed

Eskow Jaunarajs, Karen L; Standaert, David G; Viegas, Tacey X; Bentley, Michael D; Fang, Zhihao; Dizman, Bekir; Yoon, Kunsang; Weimer, Rebecca; Ravenscroft, Paula; Johnston, Tom H; Hill, Michael P; Brotchie, Jonathan M; Moreadith, Randall W

2013-10-01

Currently available dopaminergic drugs such as levodopa and dopamine (DA) receptor agonists impart considerable improvement in Parkinson's disease (PD) motor symptoms but often lead to significant motor complications including "wearing-off" and dyskinesia. Such complications are believed to stem from the pulsatile nature of dopaminergic stimulation with these agents. Continuous dopaminergic drug delivery using polyoxazoline (POZ) polymer conjugation may improve motor symptoms, while avoiding development of side effects. The purposes of the current study are to characterize the in vitro and in vivo pharmacokinetics of POZ conjugation of a U.S. Food and Drug Administration (FDA)-approved DA agonist, rotigotine, and to evaluate their effects in an established rat model of PD. After determination of release profiles of several POZ-conjugated constructs ("fast": SER-212; "moderate": SER-213; and "slow": SER-214) using in vitro hydrolysis, normal male Sprague-Dawley rats were used for determination of the pharmacokinetic profile of both acute and chronic exposure. Finally, a separate group of rats was rendered hemiparkinsonian using intracranial 6-hydroxydopamine (6-OHDA) infusions, treated acutely with POZ-rotigotine, and assessed for rotational behavior and antiparkinsonian benefit using the cylinder test. POZ-rotigotine formulations SER-213 and SER-214 led to substantial pharmacokinetic improvement compared to unconjugated rotigotine. In addition, SER-214 led to antiparkinsonian effects in DA-lesioned rats that persisted up to 5 days posttreatment. Repeated weekly dose administration of SER-214 to normal rats for up to 12 weeks demonstrated highly reproducible pharmacokinetic profiles. The continuous dopaminergic stimulation profile afforded by SER-214 could represent a significant advance in the treatment of PD, with potential to be a viable, once-per-week therapy for PD patients. © 2013 Movement Disorder Society.

Protection of MPTP-induced neuroinflammation and neurodegeneration by rotigotine-loaded microspheres.

PubMed

Yu, Xin; Yao, Jun-Yi; He, Jie; Tian, Jing-Wei

2015-03-01

The aim of the study is to evaluate the neuroprotective effects of continuous dopaminergic stimulation (CDS) by rotigotine-loaded microspheres (RoMS) in a mouse model of MPTP-induced Parkinson's disease (PD) and to elucidate the potential mechanism underlying these effects. Male C57BL/6 mice were treated either intramuscularly once with RoMS or twice daily for two weeks with rotigotine, and from the 9th day, MPTP (30 mg/kg, i.p.) was injected for the last 5 days. Following treatment, Parkinsonism scores were calculated and oxidative stress-related indicators in the striatum were performed. Neuroinflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) were detected in the striatum. Expression of apoptosis-related proteins B-cell leukemia/lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (BAX) was measured in the striatum by Western blot. Nigral tyrosine hydroxylase (TH)-positive neurons and microglial cell markers, i.e., ionized calcium binding adaptor molecule-1 (Iba-1) and neuronal synaptosomes, were quantified to assess the neuroprotective efficacy of RoMS. The administration of rotigotine significantly improved the Parkinsonism score, protected dopaminergic neurons with antioxidants, reduced microglial cell activation and the release of neuroinflammatory cytokines, and balanced the expression of Bcl-2 and Bax in MPTP-treated mice. Interestingly, the neuroprotective properties of rotigotine were remarkably amplified by CDS treatment with RoMS. These results suggest that CDS therapy can play a neuroprotective role in an MPTP mouse model. Neuroprotective disease-modifying therapy may have the potential benefits of early treatment by normalizing compensatory mechanisms and may also help to delay dyskinesia in the later stages of PD. Copyright © 2015 Elsevier Inc. All rights reserved.

Transdermal scopolamine: an alternative to ondansetron and droperidol for the prevention of postoperative and postdischarge emetic symptoms.

PubMed

White, Paul F; Tang, Jun; Song, Dajun; Coleman, Jayne E; Wender, Ronald H; Ogunnaike, Babatunde; Sloninsky, Alexander; Kapu, Rajani; Shah, Mary; Webb, Tom

2007-01-01

Given the controversy regarding the use of droperidol and the high cost of the 5-HT3 antagonists, a cost-effective alternative for routine use as a prophylactic antiemetic would be desirable. We designed two parallel, randomized, double-blind sham and placebo-controlled studies to compare the early and late antiemetic efficacy and adverse event profile of transdermal scopolamine (TDS) 1.5 mg, to ondansetron 4 mg IV, and droperidol 1.25 mg IV for antiemetic prophylaxis as part of a multimodal regimen in "at risk" surgical populations. A total of 150 patients undergoing major laparoscopic (n = 80) or plastic (n = 70) surgery procedures received either an active TDS patch (containing scopolamine 1.5 mg) or a similar appearing sham patch 60 min before entering the operating room. All patients received a standardized general anesthetic technique. A second study medication was administered in a 2-mL numbered syringe containing either saline (for the two active TDS groups), droperidol, 1.25 mg, or ondansetron, 4 mg (for the sham patch groups), and was administered IV near the end of the procedure. The occurrence of postoperative nausea and vomiting/retching, need for rescue antiemetics, and the complete response rates (i.e., absence of protracted nausea or repeated episodes of emesis requiring antiemetic rescue medication) was reported. In addition, complaints of visual disturbances, dry mouth, drowsiness, and restlessness were noted up to 72 h after surgery. There were no significant differences in any of the emetic outcomes or need for rescue antiemetics among the TDS, droperidol, and ondansetron groups in the first 72 h after surgery. The complete response rates varied from 41% to 51%, and did not significantly differ among the treatment groups. The overall incidence of dry mouth was significantly more frequent in the TDS groups than in the droperidol and ondansetron groups (21% vs 3%). Premedication with TDS was as effective as droperidol (1.25 mg) or ondansetron (4 mg) in preventing nausea and vomiting in the early and late postoperative periods. However, the use of a TDS patch is more likely to produce a dry mouth.

Early Postmenopausal Transdermal 17β-Estradiol Therapy and Amyloid-β Deposition.

PubMed

Kantarci, Kejal; Lowe, Val J; Lesnick, Timothy G; Tosakulwong, Nirubol; Bailey, Kent R; Fields, Julie A; Shuster, Lynne T; Zuk, Samantha M; Senjem, Matthew L; Mielke, Michelle M; Gleason, Carey; Jack, Clifford R; Rocca, Walter A; Miller, Virginia M

2016-05-07

It remains controversial whether hormone therapy in recently postmenopausal women modifies the risk of Alzheimer's disease (AD). To investigate the effects of hormone therapy on amyloid-β deposition in recently postmenopausal women. Participants within 5-36 months past menopause in the Kronos Early Estrogen Prevention Study, a randomized, double blinded placebo-controlled clinical trial, were randomized to: 1) 0.45 mg/day oral conjugated equine estrogens (CEE); 2) 50μg/day transdermal 17β-estradiol; or 3) placebo pills and patch for four years. Oral progesterone (200 mg/day) was given to active treatment groups for 12 days each month. 11C Pittsburgh compound B (PiB) PET imaging was performed in 68 of the 118 participants at Mayo Clinic approximately seven years post randomization and three years after stopping randomized treatment. PiB Standard unit value ratio (SUVR) was calculated. Women (age = 52-65) randomized to transdermal 17β-estradiol (n = 21) had lower PiB SUVR compared to placebo (n = 30) after adjusting for age [odds ratio (95% CI) = 0.31(0.11-0.83)]. In the APOEɛ4 carriers, transdermal 17β-estradiol treated women (n = 10) had lower PiB SUVR compared to either placebo (n = 5) [odds ratio (95% CI) = 0.04(0.004-0.44)], or the oral CEE treated group (n = 3) [odds ratio (95% CI) = 0.01(0.0006-0.23)] after adjusting for age. Hormone therapy was not associated with PiB SUVR in the APOEɛ4 non-carriers. In this pilot study, transdermal 17β-estradiol therapy in recently postmenopausal women was associated with a reduced amyloid-β deposition, particularly in APOEɛ4 carriers. This finding may have important implications for the prevention of AD in postmenopausal women, and needs to be confirmed in a larger sample.

Rotigotine: Unexpected Polymorphism with Predictable Overall Monotropic Behavior.

PubMed

Rietveld, Ivo B; Céolin, René

2015-12-01

Crystallization of polymorphs still has a touch of art, as even prior observations of polymorphs do not guarantee their crystallization. However, once crystals of various polymorphs have been obtained, their relative stabilities can be established with a straightforward thermodynamic approach even if the conclusion will depend on the quality of the experimental data. Rotigotine is an active pharmaceutical ingredient, which has suffered the same setback as Ritonavir: a sudden appearance of a more stable crystalline polymorph than the one used for the formulation. Although the cause of the defect in the formulation was quickly established, the interpretation of the phase behavior of rotigotine has been lacking in clarity. In the present paper, data published in the patents resulting from the discovery of the new polymorph have been used to establish the pressure-temperature phase diagram of the two known solid forms of rotigotine. The analysis clearly demonstrates that form II is the stable solid phase and form I is metastable in the entire pressure-temperature domain: form I is overall monotropic in relation to form II. Thus, it was a sensible decision of European Medicines Agency to ask for a reformulation, as the first formulation was metastable even if crystallization appeared to be very slow. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

Transdermal nitroglycerin as an adjuvant to patient-controlled morphine analgesia after total knee arthroplasty

PubMed Central

Orbach-Zinger, Sharon; Lenchinsky, Artium; Paul-Kesslin, Lesley; Velks, Steven; Salai, Moses; Eidelman, Leonid A

2009-01-01

BACKGROUND: Nitroglycerin (NTG) has been shown to be a useful adjunct for pain treatment without increasing adverse side effects. The effects of NTG on postoperative morphine consumption after knee replacement were evaluated. METHODS: After undergoing total knee replacement, patients receiving patient-controlled morphine analgesia were randomly assigned to receive either an NTG or a placebo patch. The blinded investigator assessed each patient using a visual analogue scale at rest and while moving, as well as the patient’s morphine requirements, sedation score, sleep quality, nausea and vomiting, vital signs and postoperative bleeding. RESULTS: Two of the patients in the NTG group suffered postoperative myocardial infarctions after removal of the patch. Because of these two serious adverse effects, the study was stopped prematurely. In the subset of patients studied, NTG conferred no advantage over placebo in pain control (visual analogue scale at rest or during movement) and in satisfaction scores. CONCLUSIONS: The use of NTG patches conferred no advantage over the use of placebo in patients receiving patient-controlled morphine analgesia after total knee replacement. Two myocardial infarcts occurred in this group. Therefore, the safety of postoperative NTG patch use for pain control must be questioned. PMID:19532851

Gateways to clinical trials.

PubMed

Bayes, M; Rabasseda, X; Prous, J R

2005-01-01

Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: (-)-Epigallocatechin gallate; ACP-103, Ad.Egr.TNF.11 D, adalimumab, AF-IL 12, AIDSVAX gp120 B/B, alefacept, alemtuzumab, a-Galactosylceramide, ALVAC vCP 1452, alvimopan hydrate, alvocidib hydrochloride, aminolevulinic acid hydrochloride, aminolevulinic acid methyl ester, anakinra, anidulafungin, antarelix, aprepitant, aripiprazole, arsenic sulfide, asoprisnil, atazanavir sulfate, atomoxetine hydrochloride; Bevacizumab, bimatoprost, BMS-184476, bortezomib, bosentan, botulinum toxin type B, BrachySil, brivudine; Caffeine, calcipotriol/betamethasone dipropionate, cannabidiol, capsaicin for injection, caspofungin acetate, CC-4047, cetuximab, CGP-36742, clofazimine, CpG-7909, Cypher; Darbepoetin alfa, dextromethorphan/quinidine sulfate, dimethylfumarate, dronabinol/cannabidiol, drotrecogin alfa (activated), duloxetine hydrochloride, dutasteride; Ecogramostim, efalizumab, eletriptan, emtricitabine, enfuvirtide, eplerenone, esomeprazole magnesium, estradiol acetate, eszopiclone, etoricoxib, exenatide, ezetimibe, ezetimibe/simvastatin; Fampridine, fondaparinux sodium, fosamprenavir calcium; Gefitinib, GPI-0100; hA 20, HTU-PA, human insulin, HuOKT 3 gamma 1(Ala 234-Ala 235), hyaluronic acid; Icatibant, imatinib mesylate, Indiplon, INKP-100, INKP-102, iodine (I131) tositumomab, istradefylline, IV gamma-globulin, ivabradine hydrochloride, ixabepilone; Lacosamide, landiolol, lanthanum carbonate, lasofoxifene tartrate, LB-80380, lenalidomide, lidocaine/tetracaine, linezolid, liposomal doxorubicin, liposomal vincristine sulfate, lopinavir, lopinavir/ritonavir, lumiracoxib, lurtotecan; Maribavir, morphine glucuronide, MVA-5 T 4; NBI-56418, NCX-4016, nesiritide, nicotine conjugate vaccine, NSC-330507; Oglufanide, omalizumab, oxipurinol; Palifermin, palonosetron hydrochloride, parecoxib sodium, PEG-filgrastim, peginterferon alfa-2a, peginterferon alfa-2b, peginterferon alfa-2b/ribavirin, PEGylated interferon alfacon-1, perospirone hydrochloride, pimecrolimus, pixantrone maleate, plerixafor hydrochloride, PowderJect lidocaine, pradefovir mesylate, prasterone, pregabalin, Prostvac VF, PT-141, PTC-124, pyridoxamine; QS-21, quercetin; R-126638, R-411, ralfinamide, rasagiline mesilate, rF-PSA, RG-2077, rhThrombin, rimonabant hydrochloride, rofecoxib, rosuvastatin calcium, rotigotine hydrochloride, rV-PSA; S-18886, S-303, seocalcitol, SGN-40, sitaxsentan sodium, SPP-301, St. John's Wort extract; Tadalafil, taxus, telithromycin, tenatoprazole, tenofovir disoproxil fumarate, testosterone MDTS, testosterone transdermal patch, tgAAC-09, TH-9507, thioacetazone, tipifarnib, TQ-1011, trabectedin, travoprost, trimethoprim; Valdecoxib, valganciclovir hydrochloride, valopicitabine, voriconazole; Xcellerated T cells. (c) 2005 Prous Science. All rights reserved.

Pharmacokinetics of Sustained-Release and Transdermal Buprenorphine in Göttingen Minipigs (Sus scrofa domestica)

PubMed Central

Thiede, Allison J; Garcia, Kelly D; Stolarik, DeAnne F; Ma, Junli; Jenkins, Gary J; Nunamaker, Elizabeth A

2014-01-01

The opioid buprenorphine has been shown to provide adequate postoperative analgesia in both companion and laboratory animals. However, its use is still hindered by the need for multiple parenteral injections to achieve continuous analgesia. The purpose of the current study was to conduct a pharmacokinetic analysis of 2 new long-acting formulations of buprenorphine—an injectable sustained-release buprenorphine (SRB) and a transdermal buprenorphine (TDB) patch—in healthy Göttingen minipigs by using liquid chromatography–electrospray ionization–tandem mass spectrometry. Administration of 0.18 mg/kg SC SRB and 30 μg/h TDB achieved AUC0-Tlast of 221.6 ± 26.8 and 25.2 ± 3.9 ng × h/mL, respectively, compared with 9.7 ± 1.4 ng*h/mL for 0.02 mg/kg IV buprenorphine. By using a hypothesized therapeutic plasma buprenorphine concentration threshold of 0.1 ng/mL, therapeutic concentrations were achieved at the first study time point (5 to 30 min) and lasted an average of 8.0 ± 1.3 h for intravenous buprenorphine and 264.0 ± 32.2 h for SRB. TDB achieved therapeutic concentrations in 12 to 24 h after patch application, which lasted until the patch was removed at 72 h. The results of this study suggest that SRB and TDB are long-acting alternatives for pain management, and their use could decrease animal handling and stress, thereby simplifying pain management and improving welfare in laboratory swine. PMID:25650977

3D printed microneedles for insulin skin delivery.

PubMed

Pere, Cristiane Patricia Pissinato; Economidou, Sophia N; Lall, Gurprit; Ziraud, Clémentine; Boateng, Joshua S; Alexander, Bruce D; Lamprou, Dimitrios A; Douroumis, Dennis

2018-06-15

In this study, polymeric microneedle patches were fabricated by stereolithography, a 3D printing technique, for the transdermal delivery of insulin. A biocompatible resin was photopolymerized to build pyramid and cone microneedle designs followed by inkjet print coating of insulin formulations. Trehalose, mannitol and xylitol were used as drug carriers with the aim to preserve insulin integrity and stability but also to facilitate rapid release rates. Circular dichroism and Raman analysis demonstrated that all carriers maintained the native form of insulin, with xylitol presenting the best performance. Franz cell release studies were used for in vitro determination of insulin release rates in porcine skin. Insulin was released rapidly within 30 min irrespectively of the microneedle design. 3D printing was proved an effective technology for the fabrication of biocompatible and scalable microneedle patches. Copyright © 2018 Elsevier B.V. All rights reserved.

Noninvasive Transdermal Vaccination Using Hyaluronan Nanocarriers and Laser Adjuvant

PubMed Central

Kim, Ki Su; Kim, Hyemin; Park, Yunji; Kong, Won Ho; Lee, Seung Woo; Kwok, Sheldon J. J.

2016-01-01

Vaccines are commonly administered by injection using needles. Although transdermal microneedles are less-invasive promising alternatives, needle-free topical vaccination without involving physical damage to the natural skin barrier is still sought after as it can further reduce needle-induced anxiety and simply administration. However, this long-standing goal has been elusive since the intact skin is impermeable to most macromolecules. Here, we show an efficient, non-invasive transdermal vaccination in mice by employing two key innovations: first, the use of hyaluronan (HA) as vaccine carriers and, second, non-ablative laser adjuvants. Conjugates of a model vaccine ovalbumin (OVA) and HA—HA-OVA conjugates—induced more effective maturation of dendritic cells in vitro, compared to OVA or HA alone, through synergistic HA receptor-mediated effects. Following topical administration in the back skin, HA-OVA conjugates penetrated into the epidermis and dermis in murine and porcine skins up to 30% of the total applied quantity, as revealed by intravital microscopy and quantitative fluorescence assay. Topical administration of HA-OVA conjugates significantly elevated both anti-OVA IgG antibody levels in serum and IgA antibody levels in bronchioalveolar lavage, with peak levels at 4 weeks, while OVA alone had a negligible effect. An OVA challenge at week 8 elicited strong immune-recall humoral responses. With pre-treatment of the skin using non-ablative fractional laser beams (1410 nm wavelength, 10 ms pulse duration, 0.2 mJ/pulse) as laser adjuvant, strong immunization was achieved with much reduced doses of HA-OVA (1 mg/kg OVA). Our results demonstrate the potential of the non-invasive patch-type transdermal vaccination platform. PMID:27833475

Comparison between transdermal nitroglycerin and sildenafil citrate in intrauterine growth restriction: effects on uterine, umbilical and fetal middle cerebral artery pulsatility indices.

PubMed

Trapani, A; Gonçalves, L F; Trapani, T F; Franco, M J; Galluzzo, R N; Pires, M M S

2016-07-01

To evaluate the effects of transdermal nitroglycerin (GTN) and sildenafil citrate on Doppler velocity waveforms of the uterine (UtA), umbilical (UA) and fetal middle cerebral (MCA) arteries in pregnancies with intrauterine growth restriction (IUGR). This was a prospective study of 35 singleton pregnancies (gestational age, 24-31 weeks) with IUGR and abnormal UtA and UA Doppler waveforms. We compared maternal arterial blood pressure and Z-scores of the pulsatility index (PI) of UtA, UA and fetal MCA before and after application of a transdermal GTN patch (average dose, 0.4 mg/h), oral sildenafil citrate (50 mg) or placebo. Statistical analysis was performed by ANOVA for paired samples. There was a significant decrease in UtA-PI after application of GTN (21.0%) and sildenafil citrate (20.4%). A significant reduction in UA-PI was also observed for both GTN (19.1%) and sildenafil citrate (18.2%). There was no difference in UtA- and UA-PI when the GTN and sildenafil groups were compared. No changes in Doppler velocimetry were observed in the placebo group and no significant change in MCA-PI was observed in any group. Maternal arterial blood pressure decreased with administration of both GTN and sildenafil citrate in those with pre-eclampsia. The use of transdermal GTN or sildenafil citrate in pregnancies with IUGR is associated with a significant reduction in both UtA and UA Doppler PI, as well as maternal arterial blood pressure. Neither drug affected the MCA-PI. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

Effects of Artcure Diffusional Patch application on pain and functional status in lumbar disc herniation patients: a prospective randomized controlled study.

PubMed

Uğurlu, Mahmut; Aksekili, Mehmet Atıf Erol; Alkan, Berat Meryem; Kara, Halil; Çağlar, Ceyhun

2017-06-12

The aim of this study was to assess the efficacy of the Artcure Diffusional Patch, which contains a mixture of 6 herbal oils (oleum thymi, oleum limonis, oleum nigra, oleum rosmarini, oleum chamomilla, oleum lauriexpressum) and has a hypoosmolar lipid structure, in the conservative treatment of lumbar disc herniation patients and to show the advantages and/or possibility of using this as an alternative method to surgery. Of the 120 patients enrolled, 79 clinically diagnosed patients were included in the study. Clinical evaluations were performed on patients who had findings of protrusion or extrusion in their magnetic resonance results. The treatment group was treated with the Artcure Diffusional Patch while the control group received a placebo transdermal diffusional patch. The functional state of patients was measured using the Oswestry Disability Index and pain intensity was measured with a visual analog scale as primary outcomes. Secondary outcomes of the study were Lasegue's sign, the femoral stretching test, and paravertebral muscle spasm. The treatment group showed a dramatic recovery in the first month following the application in regards to Oswestry Disability Index scores and visual analog scale values. The patients treated with the Artcure Diffusional Patch showed a statistically significant difference in recovery as compared to the control group. These findings suggest that the Artcure Diffusional Patch may be an alternative for the conservative treatment of lumbar disc herniation with radiculopathy.

Fabrication, Physicochemical Characterization, and Performance Evaluation of Biodegradable Polymeric Microneedle Patch System for Enhanced Transcutaneous Flux of High Molecular Weight Therapeutics.

PubMed

Shah, Viral; Choudhury, Bijaya Krushna

2017-11-01

A revolutionary paradigm shift is being observed currently, towards the use of therapeutic biologics for disease management. The present research was focused on designing an efficient dosage form for transdermal delivery of α-choriogonadotropin (high molecular weight biologic), through biodegradable polymeric microneedles. Polyvinylpyrrolidone-based biodegradable microneedle arrays loaded with high molecular weight polypeptide, α-choriogonadotropin, were fabricated for its systemic delivery via transdermal route. Varied process and formulation parameters were optimized for fabricating microneedle array, which in turn was expected to temporally rupture the stratum corneum layer of the skin, acting as a major barrier to drug delivery through transdermal route. The developed polymeric microneedles were optimized on the basis of quality attributes like mechanical strength, axial strength, insertion ratio, and insertion force analysis. The optimized polymeric microneedle arrays were characterized for in vitro drug release studies, ex vivo drug permeation studies, skin resealing studies, and in vivo pharmacokinetic studies. Results depicted that fabricated polymeric microneedle arrays with mechanical strength of above 5 N and good insertion ratio exhibited similar systemic bioavailability of α-choriogonadotropin in comparison to marketed subcutaneous injection formulation of α-choriogonadotropin. Thus, it was ultimately concluded that the designed drug delivery system can serve as an efficient tool for systemic delivery of therapeutic biologics, with an added benefit of overcoming the limitations of parenteral delivery, achieving better patient acceptability and compliance.

Transdermal delivery of alprazolam from a monolithic patch: formulation based on in vitro characterization.

PubMed

Soler, L I; Boix, A; Lauroba, J; Colom, H; Domenech, J

2012-10-01

Alprazolam, a benzodiazepine widely used for the treatment of psychiatric disorders, has been aimed to be formulated in a transdermal delivery system (TDS) prototype. A series of TDS prototypes dosed in all cases at 0.35 mg·cm(-2) of alprazolam were prepared as a monolithic drug in adhesive matrix using acrylic pressure-sensitive adhesives (PSA) of acrylate vinyl acetate (Duro-tack(®)). The effects of several permeation enhancers as azone, transcutol, propylene glycol, dodecyl alcohol, decyl alcohol, diethanolamine, N-methyl pyrrolidone and lauric acid were studied. Prototypes have been characterized based on adhesion parameters (peel adhesion and shear adhesion), in vitro human skin permeation and in vitro drug release according to European Pharmacopoeia for the selected prototype. Best results show that a combination of permeation enhancers from different chemical groups is able to provide almost a 33 fold increase in the transdermal alprazolam flux of an aqueous saturated dispersion (from 0.054 ± 0.019 to 1.76 ± 0.21 μg h.cm(-2)). Based on these in vitro flux data, a predictive simulation of the achievable plasmatic levels was performed assuming a constant systemic infusion of drug. In summary, it is possible to obtain a prototype of a TDS of alprazolam with adequate adhesive properties (peel adhesion and shear adhesion) and able to predict sustained therapeutic plasmatic levels.

Comparative evaluation of rivastigmine permeation from a transdermal system in the Franz cell using synthetic membranes and pig ear skin with in vivo-in vitro correlation.

PubMed

Simon, Alice; Amaro, Maria Inês; Healy, Anne Marie; Cabral, Lucio Mendes; de Sousa, Valeria Pereira

2016-10-15

In the present study, in vitro permeation experiments in a Franz diffusion cell were performed using different synthetic polymeric membranes and pig ear skin to evaluate a rivastigmine (RV) transdermal drug delivery system. In vitro-in vivo correlations (IVIVC) were examined to determine the best model membrane. In vitro permeation studies across different synthetic membranes and skin were performed for the Exelon(®) Patch (which contains RV), and the results were compared. Deconvolution of bioavailability data using the Wagner-Nelson method enabled the fraction of RV absorbed to be determined and a point-to-point IVIVC to be established. The synthetic membrane, Strat-M™, showed a RV permeation profile similar to that obtained with pig ear skin (R(2)=0.920). Studies with Strat-M™ resulted in a good and linear IVIVC (R(2)=0.991) when compared with other synthetic membranes that showed R(2) values less than 0.90. The R(2) for pig ear skin was 0.982. Strat-M™ membrane was the only synthetic membrane that adequately simulated skin barrier performance and therefore it can be considered to be a suitable alternative to human or animal skin in evaluating transdermal drug transport, potentially reducing the number of studies requiring human or animal samples. Copyright © 2016 Elsevier B.V. All rights reserved.

Effect of micropatterning induced surface hydrophobicity on drug release from electrospun cellulose acetate nanofibers

NASA Astrophysics Data System (ADS)

Adepu, Shivakalyani; Gaydhane, Mrunalini K.; Kakunuri, Manohar; Sharma, Chandra S.; Khandelwal, Mudrika; Eichhorn, Stephen J.

2017-12-01

Sustained release and prevention of burst release for low half-life drugs like Diclofenac sodium is crucial to prevent drug related toxicity. Electrospun nanofibers have emerged recently as potential carrier materials for controlled and sustained drug release. Here, we present a facile method to prevent burst release by tuning the surface wettability through template assisted micropatterning of drug loaded electrospun cellulose acetate (CA) nanofibers. A known amount of drug (Diclofenac sodium) was first mixed with CA and then electrospun in the form of a nanofabric. This as-spun network was hydrophilic in nature. However, when electrospinning was carried out through non-conducting templates, viz nylon meshes with 50 and 100 μm size openings, two kinds of hydrophobic micro-patterned CA nanofabrics were produced. In vitro transdermal testing of our nanofibrous mats was carried out; these tests were able to show that it would be possible to create a patch for transdermal drug release. Further, our results show that with optimized micro-patterned dimensions, a zero order sustained drug release of up to 12 h may be achieved for the transdermal system when compared to non-patterned samples. This patterning caused a change in the surface wettability, to a hydrophobic surface, resulting in a controlled diffusion of the hydrophilic drug. Patterning assisted in controlling the initial burst release, which is a significant finding especially for low half-life drugs.

Wearable/disposable sweat-based glucose monitoring device with multistage transdermal drug delivery module

PubMed Central

Lee, Hyunjae; Song, Changyeong; Hong, Yong Seok; Kim, Min Sung; Cho, Hye Rim; Kang, Taegyu; Shin, Kwangsoo; Choi, Seung Hong; Hyeon, Taeghwan; Kim, Dae-Hyeong

2017-01-01

Electrochemical analysis of sweat using soft bioelectronics on human skin provides a new route for noninvasive glucose monitoring without painful blood collection. However, sweat-based glucose sensing still faces many challenges, such as difficulty in sweat collection, activity variation of glucose oxidase due to lactic acid secretion and ambient temperature changes, and delamination of the enzyme when exposed to mechanical friction and skin deformation. Precise point-of-care therapy in response to the measured glucose levels is still very challenging. We present a wearable/disposable sweat-based glucose monitoring device integrated with a feedback transdermal drug delivery module. Careful multilayer patch design and miniaturization of sensors increase the efficiency of the sweat collection and sensing process. Multimodal glucose sensing, as well as its real-time correction based on pH, temperature, and humidity measurements, maximizes the accuracy of the sensing. The minimal layout design of the same sensors also enables a strip-type disposable device. Drugs for the feedback transdermal therapy are loaded on two different temperature-responsive phase change nanoparticles. These nanoparticles are embedded in hyaluronic acid hydrogel microneedles, which are additionally coated with phase change materials. This enables multistage, spatially patterned, and precisely controlled drug release in response to the patient’s glucose level. The system provides a novel closed-loop solution for the noninvasive sweat-based management of diabetes mellitus. PMID:28345030

Preclinical investigation of the topical administration of phenserine: transdermal flux, cholinesterase inhibition, and cognitive efficacy.

PubMed

Utsuki, Tadanobu; Uchimura, Nao; Irikura, Mitsuru; Moriuchi, Hiroshi; Holloway, Harold W; Yu, Qian-Sheng; Spangler, Edward L; Mamczarz, Jacek; Ingram, Donald K; Irie, Tetsumi; Greig, Nigel H

2007-04-01

Phenserine (PS) was designed as a selective acetylcholinesterase (AChE) inhibitor, with a tartrate form (PST) for oral administration in mild to moderate Alzheimer's disease (AD). Recent phase 3 trials of PST in Europe indicate that any clinically relevant activity of PST may be limited by its duration of action. Like many oral drugs, bioavailability and plasma concentrations of PST are regulated by hepatic and gastrointestinal first-pass effects. To minimize the kinetic limitations of first-pass metabolism, transdermal formulations of PS and PST (ointment/patch) were developed and characterized in vitro and in vivo. Initial in vitro kinetic characterization of PS or PST formulations used a diffusion cell chamber and skin samples isolated from hairless mice. Liquid paraffin and fatty alcohol/propylene glycol (FAPG) were found to be suitable vehicles for ointment formulation. Addition of a penetration enhancer, 1-[2-(decylthio)ethyl]-azacyclopentane-2-one (HPE-101), improved stratum corneum permeability. Application of the optimal formulation of PS/HPE-101/FAPG to the shaved back of rats resulted in significantly lowered plasma and brain AChE activities and improved cognitive performance in animals with scopolamine-induced cognitive impairment. These results suggest that the transdermal application of AChE inhibitors may represent an effective therapeutic strategy for AD. Particular benefits over oral therapies might include avoiding first-pass metabolic effects and improved dosing compliance.

Preparation of rotigotine-loaded microspheres and their combination use with L-DOPA to modify dyskinesias in 6-OHDA-lesioned rats.

PubMed

Wang, Aiping; Wang, Lexi; Sun, Kaoxiang; Liu, Wanhui; Sha, Chunjie; Li, Youxin

2012-09-01

To prepare rotigotine loaded microspheres (RoMS) to achieve continuous dopaminergic stimulation (CDS) for the treatment of Parkinson's disease (PD) and investigate both the therapeutic benefit and inducibility of AIMs of administration of RoMS combination with L-DOPA in 6-OHDA-leisioned rats. Rotigotine was encapsulated into poly(lactic-co-glycolic acid) (PLGA) microspheres by an oil-in-water emulsion solvent evaporation technique. In vitro characteristics and in vivo pharmacokinetics of RoMS either in rat blood or brain (by microdialysis) were investigated. Contraversive rotations and AIMs were observed to investigate the therapeutic benefit and the propensity to induce dyskinesia of RoMS or RoMS combination with L-DOPA in 6-OHDA-lesioned rats. RoMS displayed continuous-release characteristics of rotigotine in animals and exhibited a steady efficacy lasted for 2 weeks in 6-OHDA-lesioned rats. No significant difference of the therapeutic benefit between the treatment of RoMS and pulsatile L-DOPA combination and mono L-DOPA was found. While the dyskinesia was significantly decreased with the treatment of RoMS and pulsatile L-DOPA combination compared to mono L-DOPA. RoMS could supply an alternative of CDS for the treatment of PD and the study indicates a potential advantage of RoMS for the treatment of mild and advanced PD patient in combination with L-DOPA.

Bleeding pattern and cycle control of a low-dose transdermal contraceptive patch compared with a combined oral contraceptive: a randomized study.

PubMed

Merz, M; Kroll, R; Lynen, R; Bangerter, K

2015-02-01

The aim of this study was to investigate the bleeding pattern and cycle control of a contraceptive patch containing 0.55 mg ethinyl estradiol (EE) and 2.1 mg gestodene (GSD) compared with a combined oral contraceptive (COC) containing 0.02 mg EE and 0.1 mg levonorgestrel (LNG). In this phase III, randomized, controlled, double-blind, double-dummy, multicenter trial, healthy women aged 18-45 years (smokers aged 18-35 years) received either the EE/GSD patch and a placebo tablet (n=171), or a placebo patch and the COC (n=175) for seven 28-day cycles. Bleeding control was assessed in two 90-day reference periods. Mean number of bleeding/spotting days was comparable across treatment groups in both reference periods (p>.05). Mean number of bleeding/spotting episodes was also comparable in reference period 1; however, there were fewer bleeding/spotting episodes for COC in reference period 2 (3.4 versus 3.1; p=.01). Mean length of bleeding/spotting episodes was comparable across treatment groups for both reference periods (p>.05). Withdrawal bleeding occurred consistently in both groups over the entire treatment period, but its absence was more common in the COC group in cycles 4 and 6 of reference period 2 (p<.01). Intracyclic bleeding was comparable between groups. Bleeding pattern and cycle control with the EE/GSD patch was comparable to an EE/LNG-containing COC. The findings suggest that bleeding patterns with the EE/GSD patch are similar to an EE/LNG-containing COC, except for absence of withdrawal bleeding, which was less common in patch users. The EE/GSD patch may constitute an additional contraceptive option for women. Copyright © 2015 Elsevier Inc. All rights reserved.

Novel Non-Intrusive Trans-Dermal Remote Wireless Micro-Fluidic Monitoring System Applied to Continuous Glucose and Lactate Assays for Casualty Care and Combat Readiness Assessment

DTIC Science & Technology

2004-09-01

identification of the lettered features. 2.2 BFIT Sampling Chip The BFIT sampling chip is a flexible patch-like chip with a multilayer polymeric metal...PPy) and glucose oxidase (GOD). The BFIT fabrication process uses SU8 as a principal structural material consisting of five steps (Figure 2). This...process is a subset of an earlier technology developed for the polymer material PDMS.11,12,13,14,15 The first step was the deposition of a Teflon

Perceived competence and contraceptive use during adolescence.

PubMed

Hillman, Jennifer B; Negriff, Sonya; Dorn, Lorah D

2010-03-01

Little is known about psychosocial correlates of different contraceptive methods in adolescence. Cross-sectional analyses of 209 postmenarcheal girls [mean age (years)+/-SD=15.68+/-1.74], primarily Caucasian (62.8%) or African American (32.8%). Competence (activities and social) and rule-breaking behavior were assessed by the Youth Self Report (YSR; adolescent) and the Child Behavior Checklist (CBCL; parent). Three contraceptive-use groups were created: no hormonal contraceptive (n=142), combined oral contraceptives or the transdermal patch (COCs/patch, n=41), and depot medroxyprogesterone acetate (DMPA, n=20). There was a significant effect of contraceptive-use group on competence (p=.003). The DMPA group had lower competence (CBCL activities and social; YSR social) than the no-hormonal-contraceptive and COCs/patch groups. The COCs/patch group scored lower than the no-hormonal-contraceptive group on YSR activities competence, but was not different from the DMPA group. Lastly, there was an effect of contraceptive-use group on CBCL (but not YSR) rule-breaking behavior (p=.029) with the DMPA group having higher rule-breaking behavior than the other groups. Type of contraceptive method was associated with parent and adolescent's perceived competence. For rule-breaking behavior, parental perception may be more relevant to contraceptive use. Copyright (c) 2010 Elsevier Inc. All rights reserved.

Transdermal Delivery of Functional Collagen Via Polyvinylpyrrolidone Microneedles

PubMed Central

Sun, Wenchao; Inayathullah, Mohammed; Manoukian, Martin A. C.; Malkovskiy, Andrey V.; Manickam, Sathish; Marinkovich, M. Peter; Lane, Alfred T.; Tayebi, Lobat; Seifalian, Alexander M.; Rajadas, Jayakumar

2017-01-01

Collagen makes up a large proportion of the human body, particularly the skin. As the body ages, collagen content decreases, resulting in wrinkled skin and decreased wound healing capabilities. This paper presents a method of delivering type I collagen into porcine and human skin utilizing a polyvinylpyrrolidone microneedle delivery system. The microneedle patches were made with concentrations of 1, 2, 4, and 8% type I collagen (w/w). Microneedle structures and the distribution of collagen were characterized using scanning electron microscopy and confocal microscopy. Patches were then applied on the porcine and human skin, and their effectiveness was examined using fluorescence microscopy. The results illustrate that this microneedle delivery system is effective in delivering collagen I into the epidermis and dermis of porcine and human skin. Since the technique presented in this paper is quick, safe, effective and easy, it can be considered as a new collagen delivery method for cosmetic and therapeutic applications. PMID:26066056

State of the art systematic review of bone disease in anorexia nervosa.

PubMed

Misra, Madhusmita; Golden, Neville H; Katzman, Debra K

2016-03-01

Low bone mineral density (BMD) is a known consequence of anorexia nervosa (AN) and is particularly concerning during adolescence, a critical time for bone accrual. A comprehensive synthesis of available data regarding impaired bone health, its determinants, and associated management strategies in AN is currently lacking. This systematic review aims to synthesize information from key physiologic and prospective studies and trials, and provide a thorough understanding of impaired bone health in AN and its management. Search terms included "anorexia nervosa" AND "bone density" for the period 1995-2015, limited to articles in English. Papers were screened manually based on journal impact factor, sample size, age of participants, and inclusion of a control group. When necessary, we included seminal papers published before 1995. AN leads to low BMD, impaired bone quality and increased fracture risk. Important determinants are low lean mass, hypogonadism, IGF-1 deficiency, and alterations in other hormones that impact bone health. Weight gain and menses restoration are critical for improving bone outcomes in AN. Physiologic estrogen replacement as the transdermal patch was shown to increase bone accrual in one study in adolescent females with AN; however, residual deficits persist. Bisphosphonates are potentially useful in adults with AN. To date, evidence suggests that the safest and most effective strategy to improve bone health in AN is normalization of weight with restoration of menses. Pharmacotherapies that show promise include physiologic estradiol replacement (as the transdermal estradiol patch), and in adults, bisphosphonates. Further studies are necessary to determine the best strategies to normalize BMD in AN. © 2015 Wiley Periodicals, Inc.

Reliability of postmortem fentanyl concentrations in determining the cause of death.

PubMed

Gill, James R; Lin, Peter T; Nelson, Lewis

2013-03-01

Transdermal fentanyl, an opioid used for management of marked pain, also is abused and may cause death. We reviewed medical examiner reports of 92 decedents who had one or more fentanyl transdermal patches on their body and had fentanyl detected in their postmortem toxicology analysis. The manners of death included 40 accidents, 36 natural, 8 suicides, 5 therapeutic complications, and 3 undetermined deaths. Among the accidental fentanyl intoxication deaths, 32 of 37 involved substance abuse. The majority (95 %) of the 37 accidental deaths involving fentanyl were multi-drug intoxications. The substance abuse deaths had a mean fentanyl blood concentration (26.4 ng/ml or μg/L) that was over twice that of the natural group (11.8 ng/ml). Our analysis suggests a relationship between total patch dosage and mean postmortem fentanyl concentration up to the 100-μg/h dose. The very wide and overlapping ranges of postmortem fentanyl concentrations effectively nullify the utility of correlating the dose and expected postmortem concentration for any particular death. Based on the variable relationship between dose and blood concentration, the antemortem dose cannot be reliably predicted based on the postmortem concentration. This does not, however, render the medical examiner/coroner unable to determine the cause and manner of death because the toxicology results are only one datum point among several that are considered. Although there was a weakly positive relationship between body mass index and fentanyl concentration, further research is needed to determine whether adipose tissue represents a significant depot for postmortem release of fentanyl.

State of the Art Systematic Review of Bone Disease in Anorexia Nervosa

PubMed Central

Misra, Madhusmita; Golden, Neville H.; Katzman, Debra K.

2016-01-01

Objective Low bone mineral density (BMD) is a known consequence of anorexia nervosa (AN) and is particularly concerning during adolescence, a critical time for bone accrual. A comprehensive synthesis of available data regarding impaired bone health, its determinants, and associated management strategies in AN is currently lacking. This systematic review aims to synthesize information from key physiologic and prospective studies and trials, and provide a thorough understanding of impaired bone health in AN and its management. Method Search terms included “anorexia nervosa” AND “bone density” for the period 1995–2015, limited to articles in English. Papers were screened manually based on journal impact factor, sample size, age of participants, and inclusion of a control group. When necessary, we included seminal papers published before 1995. Results AN leads to low BMD, impaired bone quality and increased fracture risk. Important determinants are low lean mass, hypogonadism, IGF-1 deficiency, and alterations in other hormones that impact bone health. Weight gain and menses restoration are critical for improving bone outcomes in AN. Physiologic estrogen replacement as the transdermal patch was shown to increase bone accrual in one study in adolescent females with AN; however, residual deficits persist. Bisphosphonates are potentially useful in adults with AN. Discussion To date, evidence suggests that the safest and most effective strategy to improve bone health in AN is normalization of weight with restoration of menses. Pharmacotherapies that show promise include physiologic estradiol replacement (as the transdermal estradiol patch), and in adults, bisphosphonates. Further studies are necessary to determine the best strategies to normalize BMD in AN. PMID:26311400

Separate and Combined Effects of Very Low Nicotine Cigarettes and Nicotine Replacement in Smokers with Schizophrenia and Controls

PubMed Central

Rohsenow, Damaris J.; Kaplan, Gary B.; Swift, Robert M.; AhnAllen, Christopher G.

2013-01-01

Introduction: The prevalence of smoking among people with schizophrenia in the United States is about 3 times that of the general population. Novel approaches are needed to reduce rates of smoking-related morbidity and mortality among these smokers. Methods: This study used a within-subjects design to investigate the separate and combined effects of sensorimotor replacement for smoking (very low nicotine content [VLNC] cigarettes vs. no cigarettes) and transdermal nicotine replacement (42 mg nicotine [NIC] vs. placebo [PLA] patches) in smokers with schizophrenia (SS; n = 30) and control smokers without psychiatric illness (CS; n = 26). Each session contained a 5-hr controlled administration period in which participants underwent the following conditions, in counterbalanced order: VLNC + NIC, VLNC + PLA, no cigarettes + NIC, no cigarettes + PLA, usual-brand cigarettes + no patches. Next, participants completed measures of cigarette craving, nicotine withdrawal, smoking habit withdrawal, and cigarette subjective effects, followed by a 90-min period of ad libitum usual-brand smoking. Results: Smoking VLNC cigarettes during the controlled administration periods reduced cigarette craving, nicotine withdrawal symptoms, habit withdrawal symptoms, and usual-brand smoking in SS and CS relative to the no cigarette conditions. VLNC cigarettes were well accepted by both groups and did not affect psychiatric symptom levels in SS. Transdermal nicotine significantly reduced cigarette craving but did not affect usual-brand smoking. Conclusions: These findings suggest that reducing the nicotine content of cigarettes to nonaddictive levels may be a promising approach for reducing nicotine dependence among people with schizophrenia. PMID:22517190

MAOIs and transdermal delivery.

PubMed

Vandenberg, Chad M

2012-09-01

Although not currently considered a first-line treatment for depression due to safety and tolerability concerns, MAOIs are effective antidepressants, particularly for atypical or treatment-resistant depression. FDA-approved oral MAOIs inhibit both MAO-A and MAO-B; inhibition of MAO-A in the brain is required for an antidepressant effect, but inhibition in the intestinal tract can allow excessive absorption of tyramine, which can lead to hypertensive crisis. A transdermal formulation of selegiline delivers the medication directly into the circulatory system, bypassing the first-pass metabolism of the GI system and substantially reducing the risk for tyramine-related adverse events. The skin patch allows for a lower dose of the drug to achieve an antidepressant effect, maintains a steady dose of the medication over 24 hours, and avoids the need for dietary restrictions at the minimum effective dose of 6 mg/24 hours. MAOIs are useful treatment options for patients who have not responded to first-line treatments, and understanding their mechanism of action can help clinicians to accurately and safely prescribe these medications. © Copyright 2012 Physicians Postgraduate Press, Inc.

Design and physicochemical characterisation of novel dissolving polymeric microneedle arrays for transdermal delivery of high dose, low molecular weight drugs

PubMed Central

McCrudden, Maelíosa T.C.; Alkilani, Ahlam Zaid; McCrudden, Cian M.; McAlister, Emma; McCarthy, Helen O.; Woolfson, A. David; Donnelly, Ryan F.

2014-01-01

We describe formulation and evaluation of novel dissolving polymeric microneedle (MN) arrays for the facilitated delivery of low molecular weight, high dose drugs. Ibuprofen sodium was used as the model here and was successfully formulated at approximately 50% w/w in the dry state using the copolymer poly(methylvinylether/maleic acid). These MNs were robust and effectively penetrated skin in vitro, dissolving rapidly to deliver the incorporated drug. The delivery of 1.5 mg ibuprofen sodium, the theoretical mass of ibuprofen sodium contained within the dry MN alone, was vastly exceeded, indicating extensive delivery of the drug loaded into the baseplates. Indeed in in vitro transdermal delivery studies, approximately 33 mg (90%) of the drug initially loaded into the arrays was delivered over 24 h. Iontophoresis produced no meaningful increase in delivery. Biocompatibility studies and in vivo rat skin tolerance experiments raised no concerns. The blood plasma ibuprofen sodium concentrations achieved in rats (263 μg ml− 1 at the 24 h time point) were approximately 20 times greater than the human therapeutic plasma level. By simplistic extrapolation of average weights from rats to humans, a MN patch design of no greater than 10 cm2 could cautiously be estimated to deliver therapeutically-relevant concentrations of ibuprofen sodium in humans. This work, therefore, represents a significant progression in exploitation of MN for successful transdermal delivery of a much wider range of drugs. PMID:24556420

Transdermal diffusion of xenon in vitro using diffusion cells

NASA Astrophysics Data System (ADS)

Verkhovsky, A.; Petrov, E.

2015-11-01

The aim of this research was to study the diffusion rate of xenon through guinea pig skin and how viscosity of cosmetic component capryl/capric triglyceride (CCT) facilitates to deliver xenon to surface of skin patches. They were placed in Franz cell for 24 hours and diffusion rate and permeability of xenon were calculated. Thus diffusion rate was 0.031 mg/hour*cm2 and permeability was 0.003 cm/hour. Using Brookfield viscometer it was shown that viscosity of CCT decreased upon increasing xenon concentration. Obtained results can be utilized in developing of new xenon containing drugs for topical administration.

[Dose-finding for treatment with a transdermal fentanyl patch : Titration with oral transmucosal fentanyl citrate and morphine sulfate].

PubMed

Mücke, M; Conrad, R; Marinova, M; Cuhls, H; Elsner, F; Rolke, R; Radbruch, L

2016-12-01

To date, no studies investigating titration with oral transmucosal fentanyl for the dose-finding of transdermal fentanyl treatment have been published. In an open randomized study 60 patients with chronic malignant (n = 39) or nonmalignant pain (n = 21), who required opioid therapy according to step three of the guidelines of the World Health Organization (WHO), were investigated. In two groups of 30 patients each titration with immediate release morphine (IRM) or oral transmucosal fentanyl citrate (OTFC) was undertaken. For measurement purposes the Brief Pain Inventory (BPI) and Minimal Documentation System (MIDOS) were used. After a 24-h titration phase, in which patients documented the intensity of pain, nausea, and tiredness, treatment with transdermal fentanyl was evaluated over a 10-day period by means of the necessary dose adaptation (responder ≤ 1 dose adaptation; conversion formula 1:1 [OTFC group] vs 100:1 [IRM group]).The pain reduction over the first 24 h (titration phase) did not differ significantly between the groups. The number of responders (17 OTFC vs. 21 IRM) over the 10-day period did not show any difference either. In both groups there was a significant reduction in pain intensity (p < 0.001). Over the course of the study, there were significantly more drop-outs because of adverse effects in the OTFC group than in the IRM group (8 vs 1, p = 0.028).Oral transmucosal fentanyl citrate can be applied for the titration of transdermal fentanyl, but it does not show any clinically relevant advantage. For example, the risk of side effects-induced drop-outs was greater in the present study. Whether the unnecessary opioid switching to treat chronic pain and breakthrough pain is advantageous with regard to minimizing conversion errors cannot be definitively answered within the scope of this study.

Microneedle Array Design Determines the Induction of Protective Memory CD8+ T Cell Responses Induced by a Recombinant Live Malaria Vaccine in Mice

PubMed Central

Carey, John B.; Pearson, Frances E.; Vrdoljak, Anto; McGrath, Marie G.; Crean, Abina M.; Walsh, Patrick T.; Doody, Timothy; O'Mahony, Conor; Hill, Adrian V. S.; Moore, Anne C.

2011-01-01

Background Vaccine delivery into the skin has received renewed interest due to ease of access to the immune system and microvasculature, however the stratum corneum (SC), must be breached for successful vaccination. This has been achieved by removing the SC by abrasion or scarification or by delivering the vaccine intradermally (ID) with traditional needle-and-syringes or with long microneedle devices. Microneedle patch-based transdermal vaccine studies have predominantly focused on antibody induction by inactivated or subunit vaccines. Here, our principal aim is to determine if the design of a microneedle patch affects the CD8+ T cell responses to a malaria antigen induced by a live vaccine. Methodology and Findings Recombinant modified vaccinia virus Ankara (MVA) expressing a malaria antigen was percutaneously administered to mice using a range of silicon microneedle patches, termed ImmuPatch, that differed in microneedle height, density, patch area and total pore volume. We demonstrate that microneedle arrays that have small total pore volumes induce a significantly greater proportion of central memory T cells that vigorously expand to secondary immunization. Microneedle-mediated vaccine priming induced significantly greater T cell immunity post-boost and equivalent protection against malaria challenge compared to ID vaccination. Notably, unlike ID administration, ImmuPatch-mediated vaccination did not induce inflammatory responses at the site of immunization or in draining lymph nodes. Conclusions/Significance This study demonstrates that the design of microneedle patches significantly influences the magnitude and memory of vaccine-induced CD8+ T cell responses and can be optimised for the induction of desired immune responses. Furthermore, ImmuPatch-mediated delivery may be of benefit to reducing unwanted vaccine reactogenicity. In addition to the advantages of low cost and lack of pain, the development of optimised microneedle array designs for the induction of T cell responses by live vaccines aids the development of solutions to current obstacles of immunization programmes. PMID:21799855

Continuous transdermal nitroglycerin therapy for menopausal hot flashes: a single-arm, dose-escalation trial.

PubMed

Huang, Alison J; Cummings, Steven R; Schembri, Michael; Vittinghoff, Eric; Ganz, Peter; Grady, Deborah

2016-03-01

To describe the efficacy and tolerability of continuous nitroglycerin for treatment of hot flashes. Perimenopausal and postmenopausal women reporting at least seven hot flashes per day were recruited into a single-arm, dose-escalation trial of continuous transdermal nitroglycerin. Participants were started on a generic 0.1 mg/hour nitroglycerin patch applied daily without patch-free periods. During 4 weeks, participants escalated dosage weekly to 0.2, 0.4, or 0.6 mg/hour as tolerated, then discontinued nitroglycerin during the final week. Changes in hot flash frequency and severity were assessed using symptom diaries. Paired t tests examined change in outcomes between baseline and maximal-dose therapy and after discontinuation of nitroglycerin. Of the 19 participants, mean age was 51.4 (±4.3) years. Women reported an average 10.6 (±3.0) hot flashes and 7.1 (±3.8) moderate-to-severe hot flashes per day at baseline. Eleven women escalated to 0.6 mg/hour, three to 0.4 mg/hour, two to 0.2 mg/hour, and one remained on 0.1 mg/hour nitroglycerin. Two discontinued nitroglycerin before the first outcomes assessment. Among the remaining 17 women, the average daily frequency of hot flashes decreased by 54% and the average frequency of moderate-to-severe hot flashes decreased by 69% from baseline to maximum-dose therapy (P < 0.001 for both). After discontinuing nitroglycerin, participants reported an average 23% increase in frequency of any hot flashes (P = 0.041) and 96% increase in moderate-to-severe hot flashes (P < 0.001). Continuous nitroglycerin may substantially and reversibly decrease hot flash frequency and severity. If confirmed in a randomized blinded trial, it may offer a novel nonhormonal hot flash treatment.

Continuous Transdermal Nitroglycerin Therapy for Menopausal Hot Flashes: A Single-Arm Dose-Escalation Trial

PubMed Central

Huang, Alison J.; Cummings, Steven R.; Schembri, Michael; Vittinghoff, Eric; Ganz, Peter; Grady, Deborah

2015-01-01

Objective To describe the efficacy and tolerability of continuous nitroglycerin for treatment of hot flashes. Methods Peri- and postmenopausal women reporting at least 7 hot flashes per day were recruited into a single-arm, dose-escalation trial of continuous transdermal nitroglycerin. Participants were started on a generic 0.1 mg/hr nitroglycerin patch applied daily without patch-free periods. Over four weeks, participants escalated dosage weekly to 0.2, 0.4, or 0.6 mg/hr as tolerated, then discontinued nitroglycerin during the final week. Changes in hot flash frequency and severity were assessed using symptom diaries. Paired t-tests examined change in outcomes between baseline and maximal-dose therapy as well as after discontinuation of nitroglycerin. Results Of the 19 participants, mean age was 51.4 (±4.3) years. Women reported an average 10.6 (±3.0) hot flashes and 7.1 (±3.8) moderate-to-severe hot flashes per day at baseline. Eleven women escalated to 0.6 mg/hr, three to 0.4 mg/hr, two to 0.2 mg/hr, and one remained on 0.1 mg/hr nitroglycerin. Two discontinued nitroglycerin before the first outcomes assessment. Among the remaining 17 women, the average daily frequency of hot flashes decreased by 54% and the average frequency of moderate-to-severe hot flashes decreased by 69% from baseline to maximum-dose therapy (P<0.001 for both). After discontinuing nitroglycerin, participants reported an average 23% increase in frequency of any hot flashes (P=0.041) and 96% increase in moderate-to-severe hot flashes (P<0.001). Conclusions Continuous nitroglycerin may substantially and reversibly decrease hot flash frequency and severity. If confirmed in a randomized blinded trial, it may offer a novel non-hormonal hot flash treatment. PMID:26263283

Comparative study of the efficacy of transdermal buprenorphine patches and prolonged-release tramadol tablets for postoperative pain control after spinal fusion surgery: a prospective, randomized controlled non-inferiority trial.

PubMed

Kim, Ho-Joong; Ahn, Hyo Sae; Nam, Yunjin; Chang, Bong-Soon; Lee, Choon-Ki; Yeom, Jin S

2017-11-01

To compare the efficacy of a transdermal buprenorphine patch (5, 10, 15, and 20 μg/h) with that of oral tramadol (150, 200, 250, and 300 mg) for postoperative pain control after single level spinal fusion surgery. The present study (ClinicalTrials.gov, number NCT02416804) was a prospective, randomized controlled non-inferiority trial designed to determine the efficacy of buprenorphine TDS for alleviating postoperative pain following patient controlled analgesia (PCA) in persons underwent a single level posterior lumbar interbody fusion surgery through 1:1 allocation. The primary outcome was the Visual Analog Pain Scale (VAS) score for postoperative back pain at 7 days after surgery. The non-inferior margin of the VAS was set at δ = 1.5 points. The VAS score (primary outcome) for postoperative back pain at 7 days after surgery in the Buprenorphine group was not inferior compared to the Tramadol group. The overall changes in VAS scores for postoperative pain during follow-up assessments over a 2-week period did not differ between both groups. However, the VAS scores for postoperative pain significantly improved with time after surgery in both groups. The patterns of changes in the VAS scores for postoperative pain during the follow-up period were not significantly different between the both groups. The efficacy of buprenorphine TDS was not inferior to that of oral tramadol medication for alleviating postoperative pain in the subacute period from 72 h after surgery, following PCA administration. In addition, adverse events were similar between both groups.

Absolute bioavailability and safety of a novel rivastigmine nasal spray in healthy elderly individuals.

PubMed

Morgan, Timothy M; Soh, Bob

2017-03-01

To test the feasibility of a novel rivastigmine nasal spray as prospective treatment for dementia. A single dose, crossover absolute bioavailability and safety study was conducted with rivastigmine intravenous solution (1 mg) and nasal spray (3.126 mg) in eight healthy elderly individuals, aged 58-75 years. Absolute bioavailability (F) of the nasal spray was significant at 0.62 (0.15) for F > 0 (P < 0.001, n = 8). The systemic dose absorbed was 2.0 (0.6) mg, time to maximum plasma concentration was 1.1 (0.5) h and maximum plasma concentration was 6.9 (2.0) ng ml -1 . The NAP226-90 to rivastigmine AUC 0-∞ ratio was 0.78 (0.19). The single dose safety was good with two of five mild adverse events related to the nasal spray. Nasal and throat irritation were perceived as mild and transient, and both had resolved at 20 min post-nasal dose. An estimated dose of two or three sprays twice-daily with nasal spray would deliver comparable rivastigmine exposure and efficacy as a 6-9.7 mg day -1 oral dose and a 10 cm 2 transdermal patch, respectively. The rivastigmine nasal spray had superior absolute bioavailability compared to historical values for oral capsule and transdermal patch determined by other researchers. It had rapid onset of action, low NAP226-90 to rivastigmine exposure ratio and a favourable safety and tolerability profile. The ability to achieve adjustable, individual, twice-daily dosing during waking hours has good potential to minimise undesirable cholinergic burden and sleep disturbances whilst delivering an effective dose for the treatment of dementia associated with Alzheimer's and Parkinson's disease. © 2016 The British Pharmacological Society.

Escalating doses of transdermal nicotine in heavy smokers: effects on smoking behavior and craving.

PubMed

Selby, Peter; Andriash, Katherine; Zawertailo, Laurie; Persad, Desmond; Zack, Martin; Busto, Usoa E

2013-10-01

Fixed-dose nicotine replacement therapy (NRT) is efficacious for smoking cessation in the general population of smokers. However, it is less effective in populations with psychiatric comorbidities and/or severe tobacco dependence where the percent nicotine replacement is suboptimal. The objective of this pilot study was to determine the effectiveness of nicotine patch dose titration in response to continued smoking in heavily dependent smokers with psychiatric comorbidity. In a single-arm, open-label study adult smokers (mean cigarettes per day, 25.4 ± 13.4; range, 14-43; n = 12) willing to quit were treated with escalating doses of transdermal nicotine and brief counseling intervention if they continued to smoke over a 9-week treatment period. Plasma nicotine and cotinine, along with expired carbon monoxide levels, and the subjective effects of smoking, urge to smoke, demand elasticity, and mood symptoms were also assessed. The mean NRT dose was 32.7 (SD, 16.4) mg/d (range, 7-56 mg/d). Smokers reported significant reductions in both cigarettes per day (mean decrease, 18.4 ± 11.5) confirmed by expired carbon monoxide (mean decrease, 13.5 ± 13.0) with no significant changes in plasma nicotine concentrations during the course of NRT dose titration. There were significant effects on the subjective effects of smoking and measures of smoking behavior. Most commonly reported adverse events were respiratory infections, skin irritation at patch site, nausea, and sleep disturbances, which were generally mild and transient. Titrating doses of NRT to effect with brief intervention hold promise as an effective clinical strategy to assist heavily dependent psychiatrically ill smokers to change their smoking behavior.

Smoking Topography Characteristics of Very Low Nicotine Content Cigarettes, With and Without Nicotine Replacement, in Smokers With Schizophrenia and Controls

PubMed Central

Cassidy, Rachel N.; Miller, Mollie E.

2016-01-01

Introduction: Reducing the nicotine content of cigarettes to a minimally addictive level has been proposed as a regulatory strategy for reducing tobacco dependence. However, smokers with schizophrenia (SS) may be prone to changing their smoking topography in efforts to compensate for the reduction in nicotine content. The aims of this study were to compare smoking topography characteristics of usual-brand and very low nicotine content (VLNC) cigarettes in SS and control smokers without psychiatric illness (CS), and to determine whether nicotine replacement reversed any changes in topography produced by VLNC cigarettes. Methods: Using a within-subjects, counter-balanced design, SS (n = 27) and CS (n = 23) smoked usual brand cigarettes, VLNC cigarettes while wearing placebo patches (VLNC + PLA), or VLNC cigarettes while wearing transdermal nicotine patches totaling 42mg (VLNC + NIC) during 5-hour ad libitum smoking sessions. Cigarettes were smoked through topography measurement devices. Results: Across conditions, SS smoked more puffs per session and per cigarette, had higher cigarette volumes, and had shorter inter-puff intervals than CS (Ps < .01). During VLNC cigarette sessions, puff duration increased and time between puffs decreased, but participants smoked fewer puffs, resulting in a net decrease in cigarette and total session volume (Ps < .001). There were no significant interactions between group and condition. Conclusions: These findings indicate that acute use of VLNC cigarettes does not increase intensity of smoking in SS, and support the feasibility of a nicotine reduction policy. Implications: Reducing the nicotine in cigarettes to a minimally addictive level has been proposed as a means of reducing tobacco dependence. However, smokers, particularly those with schizophrenia (SS) may alter their puffing in an attempt to extract more nicotine from VLNC cigarettes. This study compared smoking topography of usual brand versus VLNC cigarettes, combined with placebo or transdermal nicotine patches, in SS and controls. Although some changes in topography were indicative of compensatory smoking, total puffs and total cigarette volume were reduced with VLNC cigarettes, indicating that acute VLNC cigarette use does not increase smoking in SS. PMID:26995794

Use of nicotine patches in breast-feeding mothers: transfer of nicotine and cotinine into human milk.

PubMed

Ilett, Kenneth F; Hale, Thomas W; Page-Sharp, Madhu; Kristensen, Judith H; Kohan, Rolland; Hackett, L Peter

2003-12-01

Our objective was to assess the extent of exposure to nicotine and cotinine in breast-fed infants during maternal smoking and later during maternal use of the nicotine transdermal patch to achieve smoking cessation. Fifteen lactating women (mean age, 32 years; mean weight, 72 kg) who were smokers (mean of 17 cigarettes per day) participated in a trial of the nicotine patch to assist in smoking cessation. Serial milk samples were collected from the women over sequential 24-hour periods when they were smoking and when they were stabilized on the 21-mg/d, 14-mg/d, and 7-mg/d nicotine patches. Nicotine and cotinine in milk were quantified by HPLC, and infant dose was calculated. Plasma concentrations of nicotine in the breast-fed infants were assessed, and the infants were also clinically assessed. Nicotine and cotinine concentrations in milk were not significantly different between smoking (mean of 17 cigarettes per day) and the 21-mg/d patch, but concentrations were significantly lower (P <.05) when patients were using the 14-mg/d and 7-mg/d patches than when smoking. There was also a downward trend in absolute infant dose (nicotine equivalents) from smoking or the 21-mg patch through to the 14-mg and 7-mg patches (P <.05 at both 14-mg and 7-mg doses, compared with smoking). Milk intake (shown as median and 25th to 75th percentile) by the breast-fed infants was similar while their mothers were smoking (585 mL/d [507-755 mL/d]) and subsequently when their mothers were using the 21-mg (717 mL/d [504-776 mL/d]), 14-mg (731 mL/d [535-864 mL/d]), and 7-mg (619 mL/d [520-706 mL/d]) patches (chi(2) = 3.19, P =.364). We conclude that the absolute infant dose of nicotine and its metabolite cotinine decreases by about 70% from when subjects were smoking or using the 21-mg patch to when they were using the 7-mg patch. In addition, use of the nicotine patch had no significant influence on the milk intake by the breast-fed infant. Undertaking maternal smoking cessation with the nicotine patch is, therefore, a safer option than continued smoking.

Limonene enhances the in vitro and in vivo permeation of trimetazidine across a membrane-controlled transdermal therapeutic system.

PubMed

Krishnaiah, Yellela S; Al-Saidan, Saleh M

2008-01-01

The objective of the study was to design membrane-controlled transdermal therapeutic system (TTS) for trimetazidine. The optimization of (i) concentration of ethanol-water solvent system, (ii) HPMC concentration of drug reservoir and (iii) limonene concentration in 2% w/v HPMC gel was done based on the in vitro permeation of trimetazidine across excised rat epidermis. A limonene-based membrane-controlled TTS of trimetazidine was fabricated and evaluated for its in vivo drug release in rabbit model. The in vitro permeation of trimetazidine from water, ethanol and selected concentrations (25, 50 and 75% v/v) of ethanol-water co-solvent systems showed that 50% v/v of ethanol-water solvent system provided an optimal transdermal flux of 233.1+/-3.8 microg/cm(2.)h. The flux of the drug decreased to 194.1+/-7.4 microg/cm(2.)h on adding 2% w/v of HPMC to ethanolic (50% v/v ethanol-water) solution of trimetazidine. However, on adding selected concentrations of limonene (0, 2, 4, 6 and 8% w/v) to 2% w/v HPMC gel drug reservoir, the flux of the drug increased to 365.5+/-7.1 microg/cm(2.)h. Based on these results, 2% w/v HPMC gel drug reservoir containing 6% w/v of limonene was chosen as an optimal formulation for studying the influence of rate-controlling EVA2825 membrane and adhesive-coated EVA2825 membrane. The flux of the drug across EVA2825 membrane (mean thickness 31.2 microm) decreased to 285.8+/-2.2 microg/cm(2.)h indicating that the chosen membrane was effective as rate-controlling membrane. On applying an adhesive coat (mean thickness 10.2 microm) to EVA2825 membrane, the drug flux further decreased to 212.4+/-2.6 microg/cm(2.)h. However, the flux of the drug across adhesive-coated EVA2825 membrane-rat epidermis composite was 185.9+/-2.9 microg/cm(2.)h, which is about 2-times higher than the desired flux. The fabricated limonene-based TTS patch of trimetazidine showed a mean steady state plasma concentration of 71.5 ng/mL for about 14 h with minimal fluctuation when tested in rabbits. It was concluded from the investigation that the limonene-based TTS patch of trimetazidine provided constant drug delivery across the skin in rabbit model.

Effect of microneedles on transdermal permeation enhancement of amlodipine.

PubMed

Nalluri, Buchi N; Uppuluri, Chandrateja; Devineni, Jyothirmayee; Nayak, Atul; Nair, Karthik J; Whiteside, Benjamin R; Das, Diganta B

2017-06-01

The present study aimed to investigate the effect of microneedle (MN) geometry parameters like length, density, shape and type on transdermal permeation enhancement of amlodipine (AMLO). Two types of MN devices viz. AdminPatch® arrays (ADM) (0.6, 1.2 and 1.5 mm lengths) and laboratory-fabricated polymeric MNs (PM) of 0.6 mm length were employed. In the case of PMs, arrays were applied thrice at different places within a 1.77-cm 2 skin area (PM-3) to maintain the MN density closer to 0.6 mm ADM. Scaling analyses were done using dimensionless parameters like concentration of AMLO (C t /C s ), thickness (h/L) and surface area of the skin (Sa/L 2 ). Microinjection moulding technique was employed to fabricate PM. Histological studies revealed that the PM, owing to their geometry/design, formed wider and deeper microconduits when compared to ADM of similar length. Approximately 6.84- and 6.11-fold increase in the cumulative amount (48 h) of AMLO permeated was observed with 1.5 mm ADM and PM-3 treatments respectively, when compared to passive permeation amounts. Good correlations (R 2  > 0.89) were observed between different dimensionless parameters with scaling analyses. The enhancement in AMLO permeation was found to be in the order of 1.5 mm ADM ≥ PM-3 > 1.2 mm ADM > 0.6 mm ADM ≥PM-1 > passive. The study suggests that MN application enhances the AMLO transdermal permeation and the geometrical parameters of MNs play an important role in the degree of such enhancement.

Effect of PEG6000 on the in vitro and in vivo transdermal permeation of ondansetron hydrochloride from EVA1802 membranes.

PubMed

Krishnaiah, Yellela S R; Rama, Bukka; Raghumurthy, Vanambattina; Ramanamurthy, Kolapalli V; Satyanarayana, Vemulapalli

2009-01-01

The objective was to evaluate ethylene vinyl acetate (EVA) copolymer membranes with vinyl acetate content of 18% w/w (EVA1802) for transdermal delivery of ondansetron hydrochloride. The EVA1802 membranes containing selected concentrations (0, 5, 10 and 15% w/w) of PEG6000 were prepared, and subjected to in vitro permeation studies from a nerodilol-based drug reservoir. Flux of ondansetron from EVA1802 membranes without PEG6000 was 64.1 +/- 0.6 microg/cm(2.)h, and with 10%w/w of PEG6000 (EVA1802-PEG6000-10) it increased to 194.9 +/- 4.6 microg/cm(2.)h. However, with 15%w/w of PEG6000, EVA1802 membranes produced a burst release of drug which in turn decreased drug flux. The EVA1802-PEG6000-10 membrane was coated with an adhesive emulsion, applied to rat epidermis and subjected to in vitro permeation studies against controls. Flux of ondansetron from transdermal patch across rat epidermis was 111.7 +/- 1.3 microg/cm(2.)h, which is about 1.3 times the required flux. A TTS was fabricated using adhesive-coated EVA1802-PEG6000-10 membrane and other TTS components, and subjected to in vivo delivery in human volunteers against a control. It was concluded from the comparative pharmacokinetic study that TTS of ondansetron, prepared with EVA1802-PEG6000-10 membrane, provided average steady-state plasma concentration on par with multiple-dosed oral tablets, but with a low percent of peak-to-trough fluctuation.

Reduction of nicotine self-administration by chronic nicotine infusion with H1 histamine blockade in female rats.

PubMed

Levin, Edward D; Hall, Brandon J; Chattopadhyay, Autri; Slade, Susan; Wells, Corinne; Rezvani, Amir H; Rose, Jed E

2016-08-01

Chronic nicotine infusion via transdermal patches has been widely shown to assist with smoking cessation. In particular, transdermal nicotine treatment prior to quitting smoking helps reduce ad libitum smoking and aids cessation Rose et al. (Nicotine Tob Res 11:1067-75, 2009). However, despite this success, the majority of smokers who use transdermal nicotine fail to permanently quit smoking. Additional treatments are needed. Tobacco addiction does not just depend on nicotinic receptor systems; a variety of neural systems are involved, including dopamine, norepinepherine, serotonin, and histamine. Given the involvement of a variety of neural systems in the circuits of addiction, combination therapy may offer improved efficacy for successful smoking cessation beyond single treatments alone. We have found that pyrilamine, an H1 histamine antagonist, significantly decreases nicotine self-administration in rats. The current study was conducted to confirm the effect of chronic nicotine infusion on ongoing nicotine self-administration and resumed access after enforced abstinence and to determine the interaction of chronic nicotine with an H1 antagonist treatment. Chronic nicotine infusion via osmotic minipump (2.5 and 5 mg/kg/day for 28 days) significantly reduced nicotine self-administration in a dose-dependent manner. Chronic nicotine infusion also reduced the resumption of nicotine self-administration after enforced abstinence. Chronic pyrilamine infusion (25 mg/kg/day for 14 days) also significantly reduced nicotine self-administration. The combination of chronic nicotine and pyrilamine reduced nicotine self-administration to a greater extent than treatment with either drug alone.

Cross-Linked Hydrogel for Pharmaceutical Applications: A Review

PubMed Central

2017-01-01

Hydrogels are promising biomaterials because of their important qualities such as biocompatibility, biodegradability, hydrophilicity and non-toxicity. These qualities make hydrogels suitable for application in medical and pharmaceutical field. Recently, a tremendous growth of hydrogel application is seen, especially as gel and patch form, in transdermal drug delivery. This review mainly focuses on the types of hydrogels based on cross-linking and; secondly to describe the possible synthesis methods to design hydrogels for different pharmaceutical applications. The synthesis and chemistry of these hydrogels are discussed using specific pharmaceutical examples. The structure and water content in a typical hydrogel have also been discussed. PMID:29399542

Toxic leukoencephalopathy due to transdermal fentanyl overdose.

PubMed

Foy, Lindsey; Seeyave, Desiree M; Bradin, Stuart A

2011-09-01

Children with altered mental status who present to the emergency department have a broad differential diagnosis. We report a case of a 19-month-old girl who presented in coma and who was later found to have a fentanyl patch adhered to her back. She was found to have changes on brain magnetic resonance imaging consistent with a toxic spongiform leukoencephalopathy but had a good neurologic outcome. This case report illustrates the importance of a thorough physical examination in children in coma and a rarely reported magnetic resonance imaging finding that has been seen in opioid intoxication and is usually associated with severe morbidity and mortality.

Transdermal granisetron versus palonosetron for prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: a multicenter, randomized, open-label, cross-over, active-controlled, and phase IV study.

PubMed

Seol, Young Mi; Kim, Hyo Jeong; Choi, Young Jin; Lee, Eun Mi; Kim, Yang Soo; Oh, Sung Yong; Koh, Su Jin; Baek, Jin Ho; Lee, Won Sik; Joo, Young Don; Lee, Hyun Gi; Yun, Eun Young; Chung, Joo Seop

2016-02-01

Palonosetron is the second-generation 5-hydroxytryptamine 3 receptor antagonist (5-HT3RA) that has shown better efficacy than the first-generation 5-HT3RA for prevention of chemotherapy-induced nausea and vomiting (CINV) in patients receiving moderately emetogenic chemotherapy (MEC). Granisetron transdermal delivery system (GTDS), a novel transdermal formulation, was developed to deliver granisetron continuously over 7 days. This study compared the efficacy and tolerability of the GTDS to palonosetron for the control of CINV following MEC. A total of 196 patients were randomized to GP or PG group. In this multicenter, randomized, open-label, cross-over, active-controlled, Phase IV study, GP group was assigned to receive transdermal granisetron (one GTDS patch, 7 days) in the first chemotherapy cycle, palonosetron (iv 0.25 mg/day, 1 days) in the second chemotherapy cycle before receiving MEC, and PG group was assigned to receive palonosetron in the first cycle and GTDS in the second cycle. Primary endpoint was the percentage of chemotherapy cycles achieving complete response (CR; defined as no emetic episodes and no rescue medication use) during the acute phase (0-24 h in post-chemotherapy; non-inferiority comparison with palonosetron). Total 333 cycles (165 in GTDS and 168 in palonosetron) were included in the per protocol analysis. The GTDS cycles showed non-inferiority to palonosetron cycles during the acute phase: CR was achieved by 124 (75.2 %) patients in the GTDS cycles and 134 (79.8 %) patients in the palonosetron cycles (treatment difference, -4.6 %; 95 % confidence interval, -13.6-4.4). There was no significant difference in CR rate during acute phase after the end of the first and second chemotherapy cycle between GP and PG group (p = 0.405, p = 0.074). Patients' satisfaction, assessed using Functional Living Index-Emesis (FLI-E), GTDS cycle were higher than those of palonosetron cycle in GP group (FLI-E score; median 1549.5 in GTDS cycle, median 1670.0 in palonosetron cycle). Both treatments were well tolerated and safe. Transdermal granisetron is a good alternative therapeutic option to palonosetron for preventing CINV after MEC.

Evaluation of the maternal-fetal transfer of granisetron in an ex vivo placenta perfusion model.

PubMed

Julius, Justin M; Tindall, Andrew; Moise, Kenneth J; Refuerzo, Jerrie S; Berens, Pamela D; Smith, Judith A

2014-11-01

The objective of this study was to estimate maternal-fetal transplacental passage of granisetron in an ex vivo placental perfusion model. Term human placentas (N=8) were collected immediately after delivery. A single cotyledon from each placenta was perfused granisetron concentration to mimic systemic maternal peak plasma concentrations following either IV (50ng/mL) or transdermal administration (5ng/mL). To assess drug transfer and accumulation, samples were collected from maternal and fetal compartments. In the 50ng/mL open model, the mean transport fraction was 0.21±0.08 with clearance index of 0.53±0.66. Fetal peak concentrations achieved was 5.6±6.6ng/mL with mean accumulation of 5.35±6.4ng/mL. No drug was detected in the fetal compartment with the 5ng/mL models. Transplacental passage of granisetron was inconsistent at the 50ng/mL concentration that achieved with IV dosing. However, there consistently was no detectable passage in all the placentas evaluated of the granisetron at 5ng/mL concentration that would be achieved after transdermal patch administration. Copyright © 2014 Elsevier Inc. All rights reserved.

Assisted suicide by fentanyl intoxication due to excessive transdermal application.

PubMed

Juebner, Martin; Fietzke, Mathias; Beike, Justus; Rothschild, Markus A; Bender, Katja

2014-11-01

Herein, we report a case of an assisted suicide committed by application of 34 matrix-based fentanyl-containing transdermal therapeutic systems (TTS) with different release rates. The TTS were supplied by the husband but administered by the deceased herself. Besides routine systematic toxicological analysis (STA), the concentrations of fentanyl and norfentanyl were determined in the blood (femoral and heart), urine, stomach content, brain, lung tissue, musculus iliopsoas, liver, kidney, bile and in some of the used TTS by LC-MS/MS. Blood levels of fentanyl were 60.6 μg/L in femoral blood and 94.1 μg/L in heart blood. These concentrations are in good concordance with levels described in cases with accidental or lethal suicidal fentanyl patch application. The organ distribution indicates an influence of post-mortem redistribution. The levels of residual fentanyl in the TTS were also determined. STA furthermore revealed supratherapeutic levels of bromazepam. Thus, the cause of death was a combination of fentanyl and bromazepam intoxication. However, considering the determined levels of fentanyl and norfentanyl in the entire set of specimens and the high toxicity in comparison to bromazepam, fentanyl was the leading toxic noxa.

Comparison of the Efficacy of Different Drugs on Non-Motor Symptoms of Parkinson's Disease: a Network Meta-Analysis.

PubMed

Li, Bao-Dong; Cui, Jing-Jun; Song, Jia; Qi, Ce; Ma, Pei-Feng; Wang, Ya-Rong; Bai, Jing

2018-01-01

A network meta-analysis is used to compare the efficacy of ropinirole, rasagiline, rotigotine, entacapone, apomorphine, pramipexole, sumanirole, bromocriptine, piribedil and levodopa, with placebo as a control, for non-motor symptoms in Parkinson's disease (PD). PubMed, Embase and the Cochrane Library were searched from their establishment dates up to January 2017 for randomized controlled trials (RCTs) investigating the efficacy of the above ten drugs on the non-motor symptoms of PD. A network meta-analysis combined the evidence from direct comparisons and indirect comparisons and evaluated the pooled weighted mean difference (WMD) values and surfaces under the cumulative ranking curves (SUCRA). The network meta-analysis included 21 RCTs. The analysis results indicated that, using the United Parkinson's Disease Rating Scale (UPDRS) III, the efficacies of placebo, ropinirole, rasagiline, rotigotine, entacapone, pramipexole, sumanirole and levodopa in treating PD were lower than that of apomorphine (WMD = -10.90, 95% CI = -16.12∼-5.48; WMD = -11.85, 95% CI = -17.31∼-6.16; WMD = -11.15, 95% CI = -16.64∼-5.04; WMD = -11.70, 95% CI = -16.98∼-5.60; WMD = -11.04, 95% CI = -16.97∼-5.34; WMD = -13.27, 95% CI = -19.22∼-7.40; WMD = -10.25, 95% CI = -15.66∼-4.32; and WMD = -11.60, 95% CI = -17.89∼-5.57, respectively). Treatment with ropinirole, rasagiline, rotigotine, entacapone, pramipexole, sumanirole, bromocriptine, piribedil or levodopa, with placebo as a control, on PD exhibited no significant differences on PD symptoms when the UPDRS II was used for evaluation. Moreover, using the UPDRS III, the SUCRA values indicated that a pomorphine had the best efficacy on the non-motor symptoms of PD (99.0%). Using the UPDRS II, the SUCRA values for ropinirole, rasagiline, rotigotine, entacapone, pramipexole, sumanirole, bromocriptine, piribedil and levodopa treatments, with placebo as a control, indicated that bromocriptine showed the best efficacy on the non-motor symptoms of PD (75.6%). Among ropinirole, rasagiline, rotigotine, entacapone, apomorphine, pramipexole, sumanirole, bromocriptine, piribedil and levodopa, with placebo as a control, apomorphine may be the most efficacious drug for therapy in treating the non-motor symptoms of PD. © 2018 The Author(s). Published by S. Karger AG, Basel.

Fatal overdose due to prescription fentanyl patches in a patient with sickle cell/beta-thalassemia and acute chest syndrome: A case report and review of the literature.

PubMed

Biedrzycki, Olaf J; Bevan, David; Lucas, Sebastian

2009-06-01

Introduced into clinical practice in the 1960s, the analgesic fentanyl is 100 times more potent than morphine. Various methods of administration exist including the transdermal Duragesic patch system, widely used in chronic pain and palliative care settings. Numerous, often imaginative methods of abuse of fentanyl patches have been reported; the majority of fatal fentanyl overdose cases resulting from deliberate abuse or suicide. We describe the accidental overdose of a young black male with sickle cell/beta-thalassemia who had been using the Duragesic system for almost 2 years.At autopsy the macroscopic findings were of nonspecific opiate overdose with congested heavy lungs. Histopathological examination revealed severe sickling of red blood cells in the lungs (acute chest syndrome). Toxicological examination revealed blood and urine fentanyl levels of 40 microg/L and 400 microg/L (10 fold and 100 fold higher than therapeutic levels). The mast cell tryptase was also significantly elevated at 76 microg/L, (Normal 2-14 microg/L). We discuss the relevance of these findings with regard to the cause of death, and stress the need to consider fentanyl when confronted with nonspecific signs of opiate overdose as it is not detected in routine toxicological drug screens.

Comparison of skin permeability for three diclofenac topical formulations: an in vitro study.

PubMed

Folzer, E; Gonzalez, D; Singh, R; Derendorf, H

2014-01-01

Diclofenac is a hydrophilic non-steroidal anti-inflammatory drug (NSAID) widely used in humans and animals. There are limited published studies evaluating diclofenac's skin permeation following topical administration. The aim of our study was to evaluate and compare the in vitro permeation of three different diclofenac-containing formulations (patch, gel, solution) over 24 hours. These formulations were applied (n = 6 per formulation) to pig skin sandwiched between the two chambers in a static Franz diffusion cell and aliquots from the receptor medium were sampled at pre-defined time points. An HPLC method with UV detection was developed and validated with the aim of characterizing the transepidermal penetration in the in vitro system. Using this assay to determine the permeation parameters, results at 24 hours showed that the Flector patch released the highest drug amount (54.6%), whereas a lower drug amount was delivered with the Voltaren Emulgel (38.2%) and the solution (34.4%). The commercial gel showed the highest flux (39.9 +/- 0.9 microg/cm2/h) and the shortest lag-time (1.97 +/- 0.02 h). Based on these in vitro results using pig skin, the transdermal patch resulted in a long-lasting controlled release of diclofenac, while the gel had the shortest lag-time.

Differential Efficacy of Nicotine Replacement Among Overweight and Obese Women Smokers.

PubMed

Strong, David R; David, Sean P; Johnstone, Elaine C; Aveyard, Paul; Murphy, Michael F; Munafò, Marcus R

2015-07-01

Rates of obesity are higher among more dependent smokers and 37%-65% of smokers seeking cessation treatment are overweight or obese. Overweight or obese smokers may possess metabolic and neurobiological features that contribute to difficulty achieving cessation using front-line nicotine replacement products. Attention to factors that facilitate effective cessation treatment in this vulnerable population is needed to significantly reduce mortality risk among overweight and obese smokers. This secondary analysis of 2 large trials of transdermal nicotine replacement in general medical practices evaluated the hypothesis that higher body mass index (BMI) would moderate the efficacy of the nicotine patch. We examined the potential for gender to further moderate the relationship between BMI and treatment efficacy. In the placebo controlled trial (N = 1,621), 21-mg patch was no more effective than placebo for assisting biochemically verified point prevalence abstinence up to 1 year after quitting for women with higher BMI, but appeared to be effective for men at normal or high BMI (gender × BMI beta = -0.22, p = .004). We did not find differential long-term cessation outcomes among male or female smokers in the 15-mg patch trial (n = 705). However, we observed significantly higher rates of early lapse among women with higher BMI treated with nicotine patch across both trials. These results suggest that increased BMI may affect the efficacy of nicotine patch on reducing risk of early lapse in women. Additional research is needed to explore mechanisms of risk for decreased efficacy of this commonly used cessation aid. © The Author 2014. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Rivastigmine transdermal patch and capsule in Alzheimer's disease: influence of disease stage on response to therapy.

PubMed

Farlow, Martin R; Grossberg, George T; Meng, Xiangyi; Olin, Jason; Somogyi, Monique

2011-12-01

The cholinesterase inhibitor rivastigmine is approved for the symptomatic treatment of mild to moderate Alzheimer's disease (AD). This exploratory, hypothesis-forming analysis assessed response to rivastigmine according to severity of dementia at baseline. This was a retrospective analysis of a large randomized, placebo-controlled trial (ENA713D2320). AD patients treated with 9.5 mg/24 h rivastigmine patch, 17.4 mg/24 h rivastigmine patch, rivastigmine capsule (12 mg/day), or placebo were stratified according to baseline Mini-Mental State Examination (MMSE) scores: ≥7 to ≤12 (severe disease), ≥13 to ≤15 (moderately severe), ≥16 to ≤18 (moderate), or ≥19 to ≤25 (mild to moderate). Changes from baseline at Week 24 on Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC), and Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) were assessed. Based on baseline MMSE scores, 141, 228, 333, and 348 patients had severe, moderately severe, moderate, and mild to moderate dementia. Worsening of ADAS-cog, ADCS-CGIC, and ADCS-ADL scores in patients receiving placebo were greater in patients with more severe dementia. Significant improvements versus placebo were seen with rivastigmine patch and/or capsule on ADAS-cog, ADCS-CGIC, and ADCS-ADL scores in patients with severe, moderately severe, and moderate AD (all p < 0.05). However, no significant improvements were seen in rivastigmine-treated patients with mild to moderate AD. Rivastigmine benefits AD patients across dementia stages. Similar to previous cholinesterase inhibitor studies, greatest treatment effects with rivastigmine patch and capsule were seen in patients with more advanced dementia, most likely driven by greater placebo decline in this population. Copyright © 2010 John Wiley & Sons, Ltd.

Postoperative fentanyl patch versus subacromial bupivacaine infusion in arthroscopic shoulder surgery.

PubMed

Merivirta, Riika; Äärimaa, Ville; Aantaa, Riku; Koivisto, Mari; Leino, Kari; Liukas, Antti; Kuusniemi, Kristiina

2013-07-01

The purpose of our study was to compare the effectiveness of subacromial bupivacaine infusion and a transdermal fentanyl patch in the treatment of postoperative pain after arthroscopic shoulder surgery. Sixty patients with rotator cuff disease scheduled for elective arthroscopic shoulder surgery were enrolled in the study. For the treatment of postoperative pain, 30 patients constituted group F and received a 12.0-μg/h fentanyl patch for 72 hours and saline solution infusion in a subacromial manner at the rate of 4 mL/h. The remaining 30 patients constituted group B and received a placebo patch and an infusion of 2.5-mg/mL bupivacaine in a subacromial manner for 72 hours. The primary outcome measure was the postoperative numerical rating scale pain score. The consumption of opioids, ibuprofen, and acetaminophen was also recorded. The Constant scores and general recovery were followed up until the 90th postoperative day. There was no statistically significant difference in the numerical rating scale scores (P = .60) between the groups. No differences in the use of rescue analgesic were observed except that the patients receiving bupivacaine used more ibuprofen (median, 1,200 mg v 600 mg) during the day of surgery (P = .042). No difference was found in general recovery between the groups. A fentanyl patch delivering 12-μg/h fentanyl offers an easy and safe treatment option as a part of multimodal analgesia with few adverse effects in the treatment of postoperative pain in a carefully selected patient group after arthroscopic shoulder surgery. Level I, randomized controlled trial. Copyright © 2013 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.

Efficacy of higher-dose 13.3 mg/24 h (15 cm2) rivastigmine patch on the Alzheimer's Disease Assessment Scale-cognitive subscale: domain and individual item analysis.

PubMed

Alva, Gustavo; Isaacson, Richard; Sadowsky, Carl; Grossberg, George; Meng, Xiangyi; Somogyi, Monique

2014-09-01

Rivastigmine displays dose-dependent efficacy on cognition in patients with Alzheimer's disease (AD), as measured by the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog). Subanalysis of the OPTIMA (OPtimising Transdermal Exelon In Mild-to-moderate Alzheimer's disease) study aimed to define ADAS-cog domains by factor analysis of individual items. Efficacy of 13.3 mg/24 h versus 9.5 mg/24 h rivastigmine patch on individual items and newly derived domains was assessed. OPTIMA was a 48-week, double-blind (DB) study in patients with mild-to-moderate AD. Patients meeting pre-defined decline criteria during open-label treatment with 9.5 mg/24 h patch were randomized in the DB phase to 13.3 mg/24 h (n = 280) or 9.5 mg/24 h (n = 287) patch. ADAS-cog change from baseline was a co-primary outcome measure. Factor analysis categorized ADAS-cog items into newly derived domains. Change from DB-baseline was calculated for domains and individual items. Numerically, less decline was displayed with 13.3 mg/24 h versus 9.5 mg/24 h patch in the total ADAS-cog score at all time points (significant at Week 24, p = 0.027). Factor analysis identified two domains: memory and language. Significantly, less decline was observed on the memory domain with 13.3 mg/24 h versus 9.5 mg/24 h patch at Weeks 12, 24, and 48 (p < 0.05; observed cases). Three items (following commands, orientation, and word recognition) displayed numerically less decline with 13.3 mg/24 h versus 9.5 mg/24 h patch at all time points. No significant between-group differences were observed on the language domain. Results suggest that the greater cognitive efficacy of 13.3 mg/24 h versus 9.5 mg/24 h rivastigmine patch is driven primarily by effects on memory, particularly in the areas of following commands, orientation, and word recognition. Copyright © 2014 John Wiley & Sons, Ltd.

Transdermal granisetron for the prevention of nausea and vomiting following moderately or highly emetogenic chemotherapy in Chinese patients: a randomized, double-blind, phase III study.

PubMed

Yang, Liu-Qing; Sun, Xin-Chen; Qin, Shu-Kui; Chen, Ying-Xia; Zhang, He-Long; Cheng, Ying; Chen, Zhen-Dong; Shi, Jian-Hua; Wu, Qiong; Bai, Yu-Xian; Han, Bao-Hui; Liu, Wei; Ouyang, Xue-Nong; Liu, Ji-Wei; Zhang, Zhi-Hui; Li, Yong-Qiang; Xu, Jian-Ming; Yu, Shi-Ying

2016-12-01

The granisetron transdermal delivery system (GTDS) has been demonstrated effectiveness in the control of chemotherapy-induced nausea and vomiting (CINV) in previous studies. This is the first phase III study to evaluate the efficacy and tolerability of GTDS in patients receiving moderately emetogenic chemotherapy (MEC) or highly emetogenic chemotherapy (HEC) in China. A total of 313 patients were randomized into the GTDS group (one transdermal granisetron patch, 7 days) or the oral granisetron group (granisetron oral 2 mg/day, ≥2 days). The primary endpoint was the percentage of patients achieving complete control (CC) from chemotherapy initiation until 24 h after final administration (PEEP). Chi-square test and Fisher's exact test were used for statistical analysis. Two hundred eighty-one patients were included in the per protocol analysis. During PEEP, CC was achieved by 67 (47.52%) patients in the GTDS group and 83 (59.29%) patients in the oral granisetron group. There was no statistical significance between the groups (P=0.0559). However, the difference of the CC percentage mainly occurred on the first day of chemotherapy between the groups. The CC was 70.13% on day 1 in the GTDS group, which was significantly lower than that of 91.03% in the oral granisetron group in the full analysis set. In the following days of chemotherapy, the CC was similar between the groups. In terms of cisplatin-contained regimen and female, there was statistical significance between the groups. Both treatments were well tolerated and safe. The most common adverse event was constipation. GTDS provided effective and well-tolerated control of CINV in Chinese patients, especially to non-cisplatin-contained regimen.

The direct analysis of drug distribution of rotigotine-loaded microspheres from tissue sections by LESA coupled with tandem mass spectrometry.

PubMed

Xu, Li-Xiao; Wang, Tian-Tian; Geng, Yin-Yin; Wang, Wen-Yan; Li, Yin; Duan, Xiao-Kun; Xu, Bin; Liu, Charles C; Liu, Wan-Hui

2017-09-01

The direct analysis of drug distribution of rotigotine-loaded microspheres (RoMS) from tissue sections by liquid extraction surface analysis (LESA) coupled with tandem mass spectrometry (MS/MS) was demonstrated. The RoMS distribution in rat tissues assessed by the ambient LESA-MS/MS approach without extensive or tedious sample pretreatment was compared with that obtained by a conventional liquid chromatography tandem mass spectrometry (LC-MS/MS) method in which organ excision and subsequent solvent extraction were commonly employed before analysis. Results obtained from the two were well correlated for a majority of the organs, such as muscle, liver, stomach, and hippocampus. The distribution of RoMS in the brain, however, was found to be mainly focused in the hippocampus and striatum regions as shown by the LESA-imaged profiles. The LESA approach we developed is sensitive enough, with an estimated LLOQ at 0.05 ng/mL of rotigotine in brain tissue, and information-rich with minimal sample preparation, suitable, and promising in assisting the development of new drug delivery systems for controlled drug release and protection. Graphical abstract Workflow for the LESA-MS/MS imaging of brain tissue section after intramuscular RoMS administration.

Responder analysis of a randomized comparison of the 13.3 mg/24 h and 9.5 mg/24 h rivastigmine patch.

PubMed

Molinuevo, José L; Frölich, Lutz; Grossberg, George T; Galvin, James E; Cummings, Jeffrey L; Krahnke, Tillmann; Strohmaier, Christine

2015-01-01

OPtimizing Transdermal Exelon In Mild-to-moderate Alzheimer's disease (OPTIMA) was a randomized, double-blind comparison of 13.3 mg/24 h versus 9.5 mg/24 h rivastigmine patch in patients with mild-to-moderate Alzheimer's disease who declined despite open-label treatment with 9.5 mg/24 h patch. Over 48 weeks of double-blind treatment, high-dose patch produced greater functional and cognitive benefits compared with 9.5 mg/24 h patch. Using OPTIMA data, a post-hoc responder analysis was performed to firstly, compare the proportion of patients demonstrating improvement or absence of decline with 13.3 mg/24 h versus 9.5 mg/24 h patch; and secondly, identify predictors of improvement or absence of decline. 'Improvers' were patients who improved on the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) by ≥4 points from baseline, and did not decline on the instrumental domain of the Alzheimer's Disease Cooperative Study-Activities of Daily Living scale (ADCS-IADL). 'Non-decliners' were patients who did not decline on either scale. Overall, 265 patients randomized to 13.3 mg/24 h and 271 to 9.5 mg/24 h patch met the criteria for inclusion in the intention-to-treat population and were included in the analyses. Significantly more patients were 'improvers' with 13.3 mg/24 h compared with 9.5 mg/24 h patch at Weeks 24 (44 (16.6%) versus 19 (7.0%); P < 0.001) and 48 (21 (7.9%) versus 10 (3.7%); P = 0.023). A significantly greater proportion of patients were 'non-decliners' with 13.3 mg/24 h compared with 9.5 mg/24 h patch at Week 24 (71 (26.8%) versus 44 (16.2%); P = 0.002). At Week 48, there was a trend in favor of 13.3 mg/24 h patch. Functional and cognitive assessment scores at double-blind baseline did not consistently predict effects at Weeks 24 or 48. More patients with mild-to-moderate Alzheimer's disease who are titrated to 13.3 mg/24 h rivastigmine patch at time of decline are 'improvers' or 'non-decliners' i.e. show responses on cognition and activities of daily living compared with patients remaining on 9.5 mg/24 h patch. Clinicaltrials.gov identifier: NCT00506415; registered July 20, 2007.

Smoking Topography Characteristics of Very Low Nicotine Content Cigarettes, With and Without Nicotine Replacement, in Smokers With Schizophrenia and Controls.

PubMed

Tidey, Jennifer W; Cassidy, Rachel N; Miller, Mollie E

2016-09-01

Reducing the nicotine content of cigarettes to a minimally addictive level has been proposed as a regulatory strategy for reducing tobacco dependence. However, smokers with schizophrenia (SS) may be prone to changing their smoking topography in efforts to compensate for the reduction in nicotine content. The aims of this study were to compare smoking topography characteristics of usual-brand and very low nicotine content (VLNC) cigarettes in SS and control smokers without psychiatric illness (CS), and to determine whether nicotine replacement reversed any changes in topography produced by VLNC cigarettes. Using a within-subjects, counter-balanced design, SS (n = 27) and CS (n = 23) smoked usual brand cigarettes, VLNC cigarettes while wearing placebo patches (VLNC + PLA), or VLNC cigarettes while wearing transdermal nicotine patches totaling 42mg (VLNC + NIC) during 5-hour ad libitum smoking sessions. Cigarettes were smoked through topography measurement devices. Across conditions, SS smoked more puffs per session and per cigarette, had higher cigarette volumes, and had shorter inter-puff intervals than CS (Ps < .01). During VLNC cigarette sessions, puff duration increased and time between puffs decreased, but participants smoked fewer puffs, resulting in a net decrease in cigarette and total session volume (Ps < .001). There were no significant interactions between group and condition. These findings indicate that acute use of VLNC cigarettes does not increase intensity of smoking in SS, and support the feasibility of a nicotine reduction policy. Reducing the nicotine in cigarettes to a minimally addictive level has been proposed as a means of reducing tobacco dependence. However, smokers, particularly those with schizophrenia (SS) may alter their puffing in an attempt to extract more nicotine from VLNC cigarettes. This study compared smoking topography of usual brand versus VLNC cigarettes, combined with placebo or transdermal nicotine patches, in SS and controls. Although some changes in topography were indicative of compensatory smoking, total puffs and total cigarette volume were reduced with VLNC cigarettes, indicating that acute VLNC cigarette use does not increase smoking in SS. © The Author 2016. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Understanding prescription adherence: Pharmacy claims data from the Contraceptive CHOICE Project

PubMed Central

Pittman, Meredith E.; Secura, Gina M.; Allsworth, Jenifer E.; Homco, Juell B.; Madden, Tessa; Peipert, Jeffrey F.

2010-01-01

BACKGROUND We examined prescription adherence rates by contraceptive method among women who used oral contraceptive pills (OCP), transdermal patch, or vaginal ring. STUDY DESIGN Women in the St. Louis area were provided their choice of OCP, patch, or ring at no cost and followed for 18 months. Time between monthly refills was obtained from pharmacy data and analyzed as a marker of adherence. Risk factors for initial nonadherence were estimated using Cox proportional hazards; predictors for repeated nonadherence were analyzed using Poisson regression with robust error variance. RESULTS Overall, 619 participants filled 6,435 contraceptive prescriptions with a median of 10 refills per participant. Only 30% of women (n=187) obtained all refills on time. In the time-to-failure analysis, use of vaginal ring and increased parity were predictors of early nonadherence (p<0.05). In the multivariable analysis, use of the vaginal ring and history of abortion were risk factors for repeated nonadherence (p<0.01). CONCLUSIONS Even with financial barriers removed, pharmacy data show that many women inconsistently refill their contraception and may be at risk for unintended pregnancy. PMID:21397092

Lidocaine-loaded fish scale-nanocellulose biopolymer composite microneedles.

PubMed

Medhi, Pangkhi; Olatunji, Ololade; Nayak, Atul; Uppuluri, Chandra Teja; Olsson, Richard T; Nalluri, Buchi N; Das, Diganta B

2017-07-01

Microneedle (MN) technology has emerged as an effective drug delivery system, and it has tremendous potential as a patient friendly substitute for conventional methods for transdermal drug delivery (TDD). In this paper, we report on the preparation of lidocaine-loaded biodegradable microneedles, which are manufactured from fish scale-derived collagen. Lidocaine, a common tissue numbing anaesthetic, is loaded in these microneedles with an aim of delivering the drug with controlled skin permeation. Evaluation of lidocaine permeation in porcine skin has been successfully performed using Franz diffusion cell (FDC) which has shown that the drug permeation rate increases from 2.5 to 7.5% w/w after 36 h and pseudo steady state profile is observed from 5.0 to 10.0% w/w lidocaine-loaded microneedle. Swelling experiments have suggested that the microneedles have negligible swellability which implies that the patch would stick to the tissue when inserted. The experiments on MN dissolution have depicted that the lidocaine loaded in the patch is lower than the theoretical loading, which is expected as there can be losses of the drug during initial process manufacture.

[Tobacco reduction in a prison of France].

PubMed

Harcouët, L; Balanger, S; Meunier, N; Mourgues, A; Grabar, S; Haouili, B; Guillevin, L

2008-05-01

Little is known about free nicotine transdermal patch efficacy on tobacco reduction in prisoners. The objective is to study this efficacy in prison as well as motivations to reduce and influence of socioeconomic conditions and other addictions in prisoners' aspiration to stop smoking. A prospective study was proposed to prisoners candidate to tobacco cessation. Assessment was made by questionnaires and visits to physicians working at the prison. Nicotinic patches were systematically proposed to patients with a starting 15 mg/16 h dose (or 10 mg/16 h if the dependence was low), followed by a 10 and 5 mg/16 h dose reduction. Prisoners motivated to smoking cessation (N=73) generally had multiaddictive behaviours and precarious socioeconomic profile. Thirty percent of prisoners self-reported a reduction of 50% of their cigarettes consumption until they left prison. Median duration of this successful treatment was 45 days. Median duration of treatment response for patients who relapsed in prison (15 %) was 75 days. No predictive factor of success was found. Tobacco reduction is possible in prison even if living conditions are not favourable.

The Efficacy of Systemic Lidocaine in the Management of Chronic Pain: A Literature Review.

PubMed

Yousefshahi, Fardin; Predescu, Oana; Francisco Asenjo, Juan

2017-06-01

Despite recent advances in the understanding of the chronic pain concept, its diagnosis and management remains a daily challenge for clinicians and patients. Based on the published literature, this review discusses and tries to organize the current knowledge and the up-to-date clinical experience about the efficacy and safety of the use of intravenous lidocaine in treatment and prevention of chronic pain. To prepare this narrative review, we performed an in depth literature review using the PubMed searching engine. We extracted all relevant articles published in English, up to April 2016. Lidocaine, administered as transdermal patch or intravenous lidocaine, is a safe and effective modality in the treatment of post-herpetic neuralgia (PHN), complex regional pain syndrome, as well and for prevention of chronic pain. It may be effective in the management of neuropathic pain syndromes, chronic pain, post-operative pain, and refractory cancer pain. Intravenous lidocaine and lidocaine patch are effective and safe for the treatment of several chronic or neuropathic pain syndromes. The use of lidocaine during surgery could prevent the development of some chronic post-surgical pain syndromes.

Longitudinal Changes in Smoking Abstinence Symptoms and Alternative Reinforcers Predict Long-term Smoking Cessation Outcomes

PubMed Central

Schnoll, Robert A.; Hitsman, Brian; Blazekovic, Sonja; Veluz-Wilkins, Anna; Wileyto, E. Paul; Leone, Frank T.; Audrain-McGovern, Janet E.

2016-01-01

Background Transdermal nicotine, with behavioral counseling, is among the most popular approaches used to quit smoking. Yet, 6-month cessation rates rarely exceed 20–25%. Identifying factors associated with cessation success may help researchers and clinicians develop enhanced interventions that can improve quit rates. This study examined longitudinal changes in withdrawal, craving, depression and anxiety symptoms, and alternative reinforcers, from a baseline assessment to a 6-month outcome, as predictors of 6-month smoking cessation outcomes following 8 weeks of nicotine patch treatment and counseling. Methods A sample of 180 smokers, who completed an effectiveness trial that provided counseling and 8 weeks of 21mg nicotine patches, was analyzed. Generalized estimating equations evaluated changes in withdrawal and craving, depression and anxiety symptoms, and alternative reinforcers over time, between participants who were smoking at 6-months and participants who were abstinent (confirmed with carbon monoxide) at 6-months. Multiple logistic regression assessed changes in these variables as predictors of relapse. Results Controlling for covariates associated with cessation (i.e., nicotine dependence, patch adherence, and rate of nicotine metabolism), participants who were abstinent at 6 months showed significantly lower craving and withdrawal and significantly higher substitute reinforcers from baseline to 6 months, vs. those who were smoking at 6 months (p < .001). An increase in craving predicted relapse to smoking (p < .05). Conclusions These results support continued efforts to strengthen interventions that reduce withdrawal and craving and the development of interventions to address alternative reinforcers in order to promote long-term smoking abstinence following nicotine patch treatment. PMID:27372219

An Overview of Clinical and Commercial Impact of Drug Delivery Systems

PubMed Central

Anselmo, Aaron C.; Mitragotri, Samir

2014-01-01

Drug delivery systems are widely researched and developed to improve the delivery of pharmaceutical compounds and molecules. The last few decades have seen a marked growth of the field fueled by increased number of researchers, research funding, venture capital and the number of start-ups. Collectively, the growth has led to novel systems that make use of micro/nano-particles, transdermal patches, inhalers, drug reservoir implants and antibody-drug conjugates. While the increased research activity is clearly an indication of proliferation of the field, clinical and commercial translation of early-stage research ideas is critically important for future growth and interest in the field. Here, we will highlight some of the examples of novel drug delivery systems that have undergone such translation. Specifically, we will discuss the developments, advantages, limitations and lessons learned from: (i) microparticle-based depot formulations, (ii) nanoparticle-based cancer drugs, (iii) transdermal systems, (iv) oral drug delivery systems, (v) pulmonary drug delivery, (vi) implants and (vii) antibody-drug conjugates. These systems have impacted treatment of many prevalent diseases including diabetes, cancer and cardiovascular diseases, among others. At the same time, these systems are integral and enabling components of products that collectively generate annual revenues exceeding US $100 billion. These examples provide strong evidence of the clinical and commercial impact of drug delivery systems. PMID:24747160

Diclofenac delays micropore closure following microneedle treatment in human subjects.

PubMed

Brogden, Nicole K; Milewski, Mikolaj; Ghosh, Priyanka; Hardi, Lucia; Crofford, Leslie J; Stinchcomb, Audra L

2012-10-28

Drugs absorbed poorly through the skin are commonly delivered via injection with a hypodermic needle, which is painful and increases the risk of transmitting infectious diseases. Microneedles (MNs) selectively and painlessly permeabilize the outermost skin layer, allowing otherwise skin-impermeable drugs to cross the skin through micron-sized pores and reach therapeutic concentrations. However, rapid healing of the micropores prevents further drug delivery, blunting the clinical utility of this unique transdermal technique. We present the first human study demonstrating that micropore lifetime can be extended following MN treatment. Subjects received one-time MN treatment and daily topical application of diclofenac sodium. Micropore closure was measured with impedance spectroscopy, and area under the admittance-time curve (AUC) was calculated. AUC was significantly higher at MN+diclofenac sodium sites vs. placebo, suggesting slower rates of micropore healing. Colorimetry measurements confirmed the absence of local erythema and irritation. This mechanistic human proof-of-concept study demonstrates that micropore lifetime can be prolonged with simple topical administration of a non-specific cyclooxygenase inhibitor, suggesting the involvement of subclinical inflammation in micropore healing. These results will allow for longer patch wear time with MN-enhanced delivery, thus increasing patient compliance and expanding the transdermal field to a wider variety of clinical conditions. Copyright © 2012 Elsevier B.V. All rights reserved.

Diclofenac delays micropore closure following microneedle treatment in human subjects

PubMed Central

Brogden, Nicole K.; Milewski, Mikolaj; Ghosh, Priyanka; Hardi, Lucia; Crofford, Leslie J.; Stinchcomb, Audra L.

2013-01-01

Drugs absorbed poorly through the skin are commonly delivered via injection with a hypodermic needle, which is painful and increases the risk of transmitting infectious diseases. Microneedles (MNs) selectively and painlessly permeabilize the outermost skin layer, allowing otherwise skin-impermeable drugs to cross the skin through micron-sized pores and reach therapeutic concentrations. However, rapid healing of the micropores prevents further drug delivery, blunting the clinical utility of this unique transdermal technique. We present the first human study demonstrating that micropore lifetime can be extended following MN treatment. Subjects received one-time MN treatment and daily topical application of diclofenac sodium. Micropore closure was measured with impedance spectroscopy, and area under the admittance–time curve (AUC) was calculated. AUC was significantly higher at MN + diclofenac sodium sites vs. placebo, suggesting slower rates of micropore healing. Colorimetry measurements confirmed the absence of local erythema and irritation. This mechanistic human proof-of-concept study demonstrates that micropore lifetime can be prolonged with simple topical administration of a non-specific cyclooxygenase inhibitor, suggesting the involvement of subclinical inflammation in micropore healing. These results will allow for longer patch wear time with MN-enhanced delivery, thus increasing patient compliance and expanding the transdermal field to a wider variety of clinical conditions. PMID:22929967

Consumption of three strong opioids (morphine, oxycodone and fentanyl) in seven European countries during seven years (2003-2009).

PubMed

Hudec, R; Tisonova, J; Foltan, V; Kristova, V

2013-01-01

The aim was to analyse the consumption of selected strong opioid analgesics during a seven-year period of 2003-2009 in order to compare Slovak consumption with that in six other European countries and to determine our position. Drug consumption data from the State Institute for Drug Control in Slovak Republic were used. As to the data from other countries, annual health statistics published on websites were used in comparison. Obviously the consumption of one of studied opioid drugs with transdermal aplication route, particularly fentanyl, tended to increase in all countries during the observed period. Oxycodone tends to yield a rapid increase in consumption as well. As opposed to the latter drugs, the consumption of morphine was decreasing throughout the observed period. The consumption of these drugs in Slovakia remains low (except for that of fentanyl). Our analysis confirmed a clear shift from oral to transdermal therapy as well as usage of newer drugs. Drug consumption data are a relatively new source of information for health research. Our analysis showed increasing trends in fentanyl (patch opioid) consumption in all compared countries as well as an increasing consumption of oxycodone and decreasing consumption of morphine (Fig. 3, Ref. 17).

It is feasible and effective to help patients with severe mental disorders to quit smoking: An ecological pragmatic clinical trial with transdermal nicotine patches and varenicline.

PubMed

Garcia-Portilla, Maria P; Garcia-Alvarez, Leticia; Sarramea, Fernando; Galvan, Gonzalo; Diaz-Mesa, Eva; Bobes-Bascaran, Teresa; Al-Halabi, Susana; Elizagarate, Edorta; Iglesias, Celso; Saiz Martínez, Pilar A; Bobes, Julio

2016-10-01

Despite the proven association between smoking and high rates of medical morbidity and reduced life expectancy in people with severe mental disorders (SMD), their smoking rates do not decline as they do in the general population. We carried out a non-randomized, open-label, prospective, 9-month follow-up multicentre trial to investigate the clinical efficacy, safety and tolerability of a 12-week smoking cessation programme for patients with SMD in the community under real-world clinical conditions. Eighty-two adult outpatients with schizophrenic/bipolar disorder smoking ≥15 cigarettes/day were assigned by shared decision between doctors and patients to transdermal nicotine patches (TNP) [36(46.2%)] or varenicline [39(50%)]. Short-term efficacy: The 12-week 7-day smoking cessation (self-reported cigarettes/day=0 and breath carbon monoxide levels≤9ppm) prevalence was 49.3%, without statistically significant differences between medications (TNP 50.0% vs varenicline 48.6%, chi-square=0.015, p=1.000). Long-term efficacy: At weeks 24 and 36, 41.3 and 37.3% of patients were abstinent, with no statistically significant differences between treatments. Safety and Tolerability: no patients made suicide attempts/required hospitalization. There was no worsening on the psychometric scales. Patients significantly increased weight [TNP 1.1(2.8) vs varenicline 2.5(3.3), p=0.063], without significant changes in vital signs/laboratory results, except significant decreases in alkaline phosphatase and low-density lipoprotein-cholesterol levels in the varenicline group. Patients under varenicline more frequently presented nausea/vomiting (p<0.0005), patients under TNP experienced skin reactions more frequently (p=0.002). Three patients under varenicline had elevated liver enzymes. In conclusion, we have demonstrated that in real-world clinical settings it is feasible and safe to help patients with stabilized severe mental disorders to quit smoking. Copyright © 2016 Elsevier B.V. All rights reserved.

Absolute bioavailability and safety of a novel rivastigmine nasal spray in healthy elderly individuals

PubMed Central

Soh, Bob

2016-01-01

Aims To test the feasibility of a novel rivastigmine nasal spray as prospective treatment for dementia. Methods A single dose, crossover absolute bioavailability and safety study was conducted with rivastigmine intravenous solution (1 mg) and nasal spray (3.126 mg) in eight healthy elderly individuals, aged 58–75 years. Results Absolute bioavailability (F) of the nasal spray was significant at 0.62 (0.15) for F > 0 (P < 0.001, n = 8). The systemic dose absorbed was 2.0 (0.6) mg, time to maximum plasma concentration was 1.1 (0.5) h and maximum plasma concentration was 6.9 (2.0) ng ml−1. The NAP226–90 to rivastigmine AUC0–∞ ratio was 0.78 (0.19). The single dose safety was good with two of five mild adverse events related to the nasal spray. Nasal and throat irritation were perceived as mild and transient, and both had resolved at 20 min post‐nasal dose. An estimated dose of two or three sprays twice‐daily with nasal spray would deliver comparable rivastigmine exposure and efficacy as a 6–9.7 mg day–1 oral dose and a 10 cm2 transdermal patch, respectively. Conclusions The rivastigmine nasal spray had superior absolute bioavailability compared to historical values for oral capsule and transdermal patch determined by other researchers. It had rapid onset of action, low NAP226–90 to rivastigmine exposure ratio and a favourable safety and tolerability profile. The ability to achieve adjustable, individual, twice‐daily dosing during waking hours has good potential to minimise undesirable cholinergic burden and sleep disturbances whilst delivering an effective dose for the treatment of dementia associated with Alzheimer's and Parkinson's disease. PMID:27639640

A pilot randomized controlled trial evaluating an integrated treatment of rivastigmine transdermal patch and cognitive stimulation in patients with Alzheimer's disease.

PubMed

D'Onofrio, Grazia; Sancarlo, Daniele; Addante, Filomena; Ciccone, Filomena; Cascavilla, Leandro; Paris, Francesco; Elia, Anna Chiara; Nuzzaci, Claudia; Picoco, Michele; Greco, Antonio; Panza, Francesco; Pilotto, Alberto

2015-09-01

To evaluate in a pilot single-blind randomized controlled clinical trial the efficacy of an integrated treatment with rivastigmine transdermal patch (RTP) and cognitive stimulation (CS) in Alzheimer's disease (AD) patients at 6-month follow-up. We enrolled 90 patients with an age ≥65 years admitted to the outpatient Alzheimer's Evaluation Unit with diagnosis of AD. Patients were randomized to enter in the Group-1 (RTP + CS) or in the Group-2 (RTP). All patients at baseline and after 6 months were evaluated with the following tools: Mini Mental State Examination (MMSE), Clinical Dementia Rating (CDR), Hamilton Rating Scale for Depression (HAM-D), Geriatric Depression Scale (GDS-15), Neuropsychiatric Inventory (NPI), Neuropsychiatric Inventory-Distress (NPI-D), and a standardized Comprehensive Geriatric Assessment, including also activities of daily living (ADL), instrumental activities of daily living (IADL), and the Mini Nutritional Assessment (MNA). Mortality risk was assessed using the Multidimensional Prognostic Index (MPI). At baseline no significant difference was shown between the two groups. After 6 months of follow-up, there were significant differences between Group-1 and Group-2 in: MMSE: +6.39% vs. +2.69%, CDR: +6.92% vs. +1.54%, HDRS-D = -60.7% vs. -45.8%, GDS: -60.9% vs. -7.3%, NPI: -55.2% vs. -32.7%%, NPI-D: -55.1% vs. -18.6%, ADL: +13.88% vs. +5.95%, IADL: +67.59% vs. +18.28%, MNA: +12.02% vs. +5.91%, and MPI: -29.03% vs. -12.90%. The integrated treatment of RTP with CS in AD patients for 6 months improved significantly cognition, depressive and neuropsychiatric symptoms, functional status, and mortality risk in comparison with a group of AD patients receiving only RTP. Copyright © 2014 John Wiley & Sons, Ltd.

Effects of smoking cessation on heart rate variability among long-term male smokers.

PubMed

Harte, Christopher B; Meston, Cindy M

2014-04-01

Cigarette smoking has been shown to adversely affect heart rate variability (HRV), suggesting dysregulation of cardiac autonomic function. Conversely, smoking cessation is posited to improve cardiac regulation. The aim of the present study was to examine the effects of smoking cessation on HRV among a community sample of chronic smokers. Sixty-two healthy male smokers enrolled in an 8-week smoking cessation program involving a nicotine transdermal patch treatment. Participants were assessed at baseline (while smoking regularly), at mid-treatment (while using a high-dose patch), and at follow-up, 4 weeks after patch discontinuation. Both time-domain (standard deviation of normal-to-normal (NN) intervals (SDNN), square root of the mean squared difference of successive NN intervals (RMSSD), and percent of NN intervals for which successive heartbeat intervals differed by at least 50 ms (pNN50)) and frequency-domain (low frequency (LF), high frequency (HF), LF/HF ratio) parameters of HRV were assessed at each visit. Successful quitters (n = 20), compared to those who relapsed (n = 42), displayed significantly higher SDNN, RMSSD, pNN50, LF, and HF at follow-up, when both nicotine and smoke free. Smoking cessation significantly enhances HRV in chronic male smokers, indicating improved autonomic modulation of the heart. Results suggest that these findings may be primarily attributable to nicotine discontinuation rather than tobacco smoke discontinuation alone.

New Initiation of Long-Acting Opioids in Long-Stay Nursing Home Residents

PubMed Central

Pimentel, Camilla B.; Gurwitz, Jerry H.; Tjia, Jennifer; Hume, Anne L.; Lapane, Kate L.

2016-01-01

BACKGROUND Despite known risks of overdose and respiratory depression when treating opioid-naïve individuals with long-acting opioids, use of these potent agents may be common in nursing homes. OBJECTIVES To estimate prevalence of new initiation of long-acting opioids since national efforts to increase prescriber and public awareness on safe use of transdermal fentanyl patches. DESIGN Cross-sectional. SETTING US nursing homes. PARTICIPANTS 22,253 Medicare-enrolled long-stay nursing home residents. MEASUREMENTS The Minimum Data Set 3.0 linked with Medicare enrollment, hospital claims, and prescription drug transaction data (January–December 2011) were used to determine the prevalence of new initiation among nursing home residents who were prescribed a long-acting opioid in the nursing home. RESULTS Of nursing home residents who were prescribed a long-acting opioid within 30 days of a nursing home admission (n = 12,278), 9.4% (95% confidence interval [CI]: 8.9–9.9%) lacked a prescription drug claim for a short-acting opioid in the previous 60 days. The most common initial prescriptions of long-acting opioids were fentanyl patch (51.9% of opioid-naïve nursing home residents), morphine sulfate (28.1%), and oxycodone (17.2%). CONCLUSION New initiation of long-acting opioids—especially fentanyl patches that have been the subject of safety communications—persists in nursing homes. PMID:27487158

Application of Ultrasound Energy as a New Drug Delivery System

NASA Astrophysics Data System (ADS)

Tachibana, Katsuro; Tachibana, Shunro

1999-05-01

Ultrasound has been in use for the last three decades as amodality for diagnostic imaging in medicine. Recently, there have beennumerous reports on the application of nonthermal ultrasound energyfor targeting or controlling drug release. This new concept oftherapeutic ultrasound combined with drugs has led to much excitementin various medical fields. Ultrasound energy can enhance the effectsof thrombolytic agents such as urokinase. Therapeutic ultrasoundcatheters are currently being developed for treatment ofcardiovascular diseases. Devices with ultrasound transducers implantedin transdermal drug patches are also being evaluated for possibledelivery of insulin through the skin. Chemical activation of drugs byultrasound energy for treatment of cancers is another new fieldrecently termed “Sonodynamic Therapy”. Various examples of ultrasoundapplication are under investigation which could lead to revolutionarydrug delivery systems in the future.

An industry update: the latest developments in Therapeutic delivery.

PubMed

Steinbach, Oliver C

2018-05-01

The present industry update covers the period of 1 January-31 January 2018, with information sourced from company press releases, regulatory and patent agencies as well as scientific literature. Several public offerings (Gecko, Insmed), licensing (Foresee) and commercialization agreements (Alnylam, Collegium Pharmaceutical) as well as patent filings (Elute) continue to prove the sustained investments in the drug delivery market. In increasing numbers, more effective ways to deliver the active ingredient to the right location and the right dose through devices (Boehringer Ingelheim's Respimat, Medtronics' SynchroMedII) or improved compound properties through formulation (Aquestive Therapeutics' PharmFilm, Noven Pharmaceuticals' transdermal patch) are reaching the market. Furthering biologics and gene delivery (Avacta, Bracco) proves that novel drug delivery technologies are successfully addressing more challenging drug formats.

Post-mortem review of fentanyl-related overdose deaths among identified drug users in Southern Bavaria, Germany, 2005-2014.

PubMed

Sinicina, Inga; Sachs, Hans; Keil, Wolfgang

2017-11-01

Two decades ago, there were only single case reports on deaths in Europe following the consumption of illicitly manufactured fentanyl by problem drug users. Today, lethal fentanyl intoxication is now no longer a rarity. Since 2005, a rapid increase of lethal fentanyl-related intoxications in the drug scene has been observed at the Institute of Legal Medicine, Ludwig Maximilians University, Munich. We hypothesized that this rise is the result of the launch of fentanyl matrix patches in Germany in 2004, their broad acceptance, their diversion from the regulated supply chain, and incautious prescription by medical care providers. Post-mortem toxicological reports were reviewed for lethal fentanyl-related intoxications between 2004 und 2014. Blood and tissue samples were tested by GC/MS or LC-MS/MS. The results of police investigations, autopsy reports, and the database of the Institute of Legal Medicine, LMU, were analysed to identify problem drug users and to detect the source of fentanyl as well as the routes of administration. Between 2005 and 2014, 242 overdose victims with post-mortem toxicological detection of fentanyl were found. In the majority of cases, fentanyl matrix patches were the source of fentanyl. The onset of fentanyl-related deaths coincided with the launch of transdermal fentanyl matrix patches in Germany in 2004. Several approaches, such as providing drug users with information on the possible risks of fentanyl consumption, education of medical caregivers, and also monitoring of the prescription of fentanyl patches, are required to reduce the number of fentanyl-related deaths in drug addicts. Copyright © 2017 Elsevier B.V. All rights reserved.

Craving control using nicotine replacement therapy in a teaching hospital.

PubMed

Jones, T E; Williams, J

2012-03-01

A period of hospitalisation is perhaps the longest period of enforced 'temporary abstinence' smokers have to endure and hence many crave during their admission. Cravings may result in patients' smoking on hospital premises. Nicotine replacement may reduce cravings, decrease smoking on hospital grounds and increase interest in quitting post-discharge. The aim of this study was to compare the efficacy of two nicotine formulations in controlling inpatient cravings and enthusiasm for quitting post-discharge. Inpatients who were smokers were randomised to nicotine patch or inhaler on alternating days. Patients selected their preferred formulation, which was then used for the duration of the hospital stay. Craving control and formulation preference were assessed by visual analogue scales (VAS), and interest in quitting on a 3-point scale. Abstinence was confirmed by exhaled breath CO monitoring. Patches were preferred by 64% of the 367 subjects. Fewer patients went outside to smoke after either formulation (37% before, 5% after enrolment). Cravings were reduced by both nicotine formulations (mean VAS score fell from 7.5 to 1.7). Interest in quitting post-discharge increased. Estimated mean exposure to nicotine was 5 mg/day (inhaler), 15 mg/day (transdermal patch) compared with 30 mg/day (cigarettes) before hospitalisation. Many smokers crave and some smoke outside during a hospital admission. While the patch was the preferred formulation of nicotine replacement therapy, both were effective in reducing cravings, increasing motivation for quitting post-discharge and improving Hospital 'image' by reducing smoking on campus. Nicotine replacement therapy should be made available to inpatients in all hospitals and other places of enforced prolonged abstinence. © 2010 The Authors. Journal compilation © 2010 Royal Australasian College of Physicians.

Guidelines for the first-line treatment of restless legs syndrome/Willis-Ekbom disease, prevention and treatment of dopaminergic augmentation: a combined task force of the IRLSSG, EURLSSG, and the RLS-foundation.

PubMed

Garcia-Borreguero, Diego; Silber, Michael H; Winkelman, John W; Högl, Birgit; Bainbridge, Jacquelyn; Buchfuhrer, Mark; Hadjigeorgiou, Georgios; Inoue, Yuichi; Manconi, Mauro; Oertel, Wolfgang; Ondo, William; Winkelmann, Juliane; Allen, Richard P

2016-05-01

A Task Force was established by the International Restless Legs Syndrome Study Group (IRLSSG) in conjunction with the European Restless Legs Syndrome Study Group (EURLSSG) and the RLS Foundation (RLS-F) to develop evidence-based and consensus-based recommendations for the prevention and treatment of long-term pharmacologic treatment of dopaminergic-induced augmentation in restless legs syndrome/Willis-Ekbom disease (RLS/WED). The Task Force made the following prevention and treatment recommendations: As a means to prevent augmentation, medications such as α2δ ligands may be considered for initial RLS/WED treatment; these drugs are effective and have little risk of augmentation. Alternatively, if dopaminergic drugs are elected as initial treatment, then the daily dose should be as low as possible and not exceed that recommended for RLS/WED treatment. However, the physician should be aware that even low dose dopaminergics can cause augmentation. Patients with low iron stores should be given appropriate iron supplementation. Daily treatment by either medication should start only when symptoms have a significant impact on quality of life in terms of frequency and severity; intermittent treatment might be considered in intermediate cases. Treatment of existing augmentation should be initiated, where possible, with the elimination/correction of extrinsic exacerbating factors (iron levels, antidepressants, antihistamines, etc.). In cases of mild augmentation, dopamine agonist therapy can be continued by dividing or advancing the dose, or increasing the dose if there are breakthrough night-time symptoms. Alternatively, the patient can be switched to an α2δ ligand or rotigotine. For severe augmentation the patient can be switched either to an α2δ ligand or rotigotine, noting that rotigotine may also produce augmentation at higher doses with long-term use. In more severe cases of augmentation an opioid may be considered, bypassing α2δ ligands and rotigotine. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

[Comparative study on transdermal osmosis in vitro of Aconitum brachypodium liniment, gel and patcher].

PubMed

Lin, Ya-ping; Zhao, Ying; Zhang, Yong-ping; Liang, Guang-yi

2007-02-01

To study the transdermal osmosis process of Aconitum brachypodum's liniment, gel and patcher to provide basis for selecting dosage form and controlling the quality. Taking the cumulate rate of transdermal as index, a imitated Fick's diffusion device was used for the investigating the transdermal osmosis course of the three preparations. The best transdermal mathematics models are obtained and the relations between the transdermal course and the release course are analysed. The three preparations have different characteristics of transdermal osmosis course. The liniment meets dynamics 0 order process, the gel and the patcher meet dynamic 0 order process of non-corroded drug system. And the relation is good cubic equation between their transdermal course and release course. The transdermal osmosis experiment in vitro for three preparations can provide basis for selecting dosage form and the quality control in future studies.

LC-MS/MS analysis of fentanyl and norfentanyl in a fatality due to application of multiple Durogesic transdermal therapeutic systems.

PubMed

Coopman, Vera; Cordonnier, Jan; Pien, Karen; Van Varenbergh, Dirk

2007-07-04

Fentanyl is a potent synthetic narcotic analgesic administered in the form of a transdermal patch for the management of chronic pain. A 78-year-old woman with a history of cancer was found dead in bed. She was lying on her back. The external examination revealed 10 Durogesic transdermal therapeutic systems (100 microg/h fentanyl) on the body. Liquid-liquid extraction and liquid chromatography tandem mass spectrometry with electrospray source in positive ionization mode was applied for the quantitation of fentanyl and its major metabolite norfentanyl in the post-mortem samples. Fentanyl-d5 and norfentanyl-d5 were used as internal standards. Multiple reaction monitoring was used for specific detection. Calibration was performed by addition of standard solutions to drug-free matrix (blood, urine and liver) prior to extraction. The method showed good linearity for fentanyl and norfentanyl over a concentration range of 5-150 microg/L in reconstituted extracts with coefficients of determination equal or greater than 0.998. Percent mean within-day precision and accuracy of 0.9-1.0% and 99.4-101.1% for fentanyl and 2.0-4.5% and 93.1-101.0% for norfentanyl were obtained. Mean extraction recoveries varied between 95.5% and 100.3% for fentanyl and 39.2-57.4% for norfentanyl. The following fentanyl (norfentanyl) concentration in the post-mortem samples were measured; 28.6 microg/L (3.0 microg/L) in right and 28.2 microg/L (3.5 microg/L) in left subclavian blood, 21.3 microg/L (<2 microg/L) in right and 20.9 microg/L (<2 microg/L) in left femoral blood, 37.6 microg/L (4.2 microg/L) in right and 33.9 microg/L (4.4 microg/L) in left ventricular blood, 282.9 microg/L (121.2 microg/L) in urine, 688.2 microg/L in stomach contents, 122.5 microg/L (25.4 microg/L) in bile, 19.5 microg/L (< 2 microg/L) in vitreous humour, 203.0 microg/kg (26.6 microg/kg) in liver and 78.6 microg/kg (46.3 microg/kg) in kidney. We concluded that the woman's death was caused by acute intoxication with fentanyl. The manner of death was presumed to be suicide due to excessive administered Durogesic transdermal therapeutic systems.

Impact of a women's counselling programme on combined hormonal contraception in Portugal--the IMAGINE Study.

PubMed

Costa, Ana Rosa R; Palma, Fátima; Sá, José Luís; Vicente, Lisa; Bombas, Teresa; Nogueira, Ana Maria; Rocha, Pedro

2011-12-01

The aim of this health education project was to measure the impact of counselling about combined hormonal contraceptive (CHC) methods on the subsequent choice of method by Portuguese women. This was a multi-centre study with a representative population, at the national and regional levels, of 2951 Portuguese women≥16 years of age visiting the gynaecologist. Counselling on available CHC methods was provided using a single leaflet, and their CHC choice was assessed before and after counselling. A combined oral contraceptive (COC) was the method preferred by the majority of the women prior to counselling. After counselling, 35% of women who initially had chosen the pill, switched to either the vaginal ring or the transdermal patch, and the difference was statistically significant. Ease of use was the major reason for choosing the COC, while a lower probability of omission was the reason for choosing the vaginal ring and the patch. The implementation of a counselling programme significantly affected contraceptive choices leading in a number of cases to the selection of alternatives better suited to women's lifestyle. Age and educational level are socio-demographic factors which play an important role.

The Efficacy of Systemic Lidocaine in the Management of Chronic Pain: A Literature Review

PubMed Central

Yousefshahi, Fardin; Predescu, Oana; Francisco Asenjo, Juan

2017-01-01

Context Despite recent advances in the understanding of the chronic pain concept, its diagnosis and management remains a daily challenge for clinicians and patients. Based on the published literature, this review discusses and tries to organize the current knowledge and the up-to-date clinical experience about the efficacy and safety of the use of intravenous lidocaine in treatment and prevention of chronic pain. Evidence Acquisition To prepare this narrative review, we performed an in depth literature review using the PubMed searching engine. We extracted all relevant articles published in English, up to April 2016. Results Lidocaine, administered as transdermal patch or intravenous lidocaine, is a safe and effective modality in the treatment of post-herpetic neuralgia (PHN), complex regional pain syndrome, as well and for prevention of chronic pain. It may be effective in the management of neuropathic pain syndromes, chronic pain, post-operative pain, and refractory cancer pain. Conclusions Intravenous lidocaine and lidocaine patch are effective and safe for the treatment of several chronic or neuropathic pain syndromes. The use of lidocaine during surgery could prevent the development of some chronic post-surgical pain syndromes. PMID:28856112

Release of chemical permeation enhancers from drug-in-adhesive transdermal patches.

PubMed

Qvist, Michael H; Hoeck, Ulla; Kreilgaard, Bo; Madsen, Flemming; Frokjaer, Sven

2002-01-14

There is only limited knowledge of how chemical permeation enhancers release from transdermal drug delivery systems of the drug-in-adhesive type. In this study, the release of eight commonly known enhancers from eight types of polymer adhesives was evaluated using Franz diffusion cells. It was shown that all the enhancers released completely from the adhesives and followed a square root of time kinetic (Higuchi law). Using a statistical analysis it was shown that the release rate was more dependent on the type of enhancer than on the type of polymers. The mean release rates were in the range from 2.2 to 11.1%/ radical t for the slowest and fastest releasing enhancers, which correspond to a 50% release within 500 and 20 min, respectively. Furthermore, the release rates were inversely proportional to the cube root of the molal volumes of the enhancers and to their logarithmic partition coefficients between the polymer adhesive and the receptor fluid. It was found that the observed release rates were probably due to a high diffusion coefficient of the enhancers rather than due to an inhomogeneous embedment of the enhancers in the adhesives. The type of adhesive showed minor influence on the release rate, especially among the acrylic polymers no difference was seen. However, compared to the acrylic adhesives, the polyisobutylene adhesive showed slower release rates, while the silicone adhesive showed slightly faster release rates.

Local transdermal delivery of phenylephrine to the anal sphincter muscle using microneedles

PubMed Central

Baek, Changyoon; Han, MeeRee; Min, Junghong; Prausnitz, Mark R.; Park, Jung-Hwan; Park, Jungho

2014-01-01

We propose pretreatment using microneedles to increase perianal skin permeability for locally targeted delivery of phenylephrine (PE), a drug that increases resting anal sphincter pressure to treat fecal incontinence. Microneedle patches were fabricated by micromolding poly-lactic-acid. Pre-treatment of human cadaver skin with microneedles increased PE delivery across the skin by up to 10-fold in vitro. In vivo delivery was assessed in rats receiving treatment with or without use of microneedles and with or without PE. Resting anal sphincter pressure was then measured over time using water-perfused anorectal manometry. For rats pretreated with microneedles, topical application of 30% PE gel rapidly increased the mean resting anal sphincter pressure from 7 ± 2 cm H2O to a peak value of 43 ± 17 cm H2O after 1 h, which was significantly greater than rats receiving PE gel without microneedle pretreatment. Additional safety studies showed that topically applied green fluorescent protein–expressing E. coli penetrated skin pierced with 23- and 26-gauge hypodermic needles, but E. coli was not detected in skin pretreated with microneedles, which suggests that microneedle-treated skin may not be especially susceptible to infection. In conclusion, this study demonstrates local transdermal delivery of PE to the anal sphincter muscle using microneedles, which may provide a novel treatment for fecal incontinence. PMID:21586307

An overview of clinical and commercial impact of drug delivery systems.

PubMed

Anselmo, Aaron C; Mitragotri, Samir

2014-09-28

Drug delivery systems are widely researched and developed to improve the delivery of pharmaceutical compounds and molecules. The last few decades have seen a marked growth of the field fueled by increased number of researchers, research funding, venture capital and the number of start-ups. Collectively, the growth has led to novel systems that make use of micro/nano-particles, transdermal patches, inhalers, drug reservoir implants and antibody-drug conjugates. While the increased research activity is clearly an indication of proliferation of the field, clinical and commercial translation of early-stage research ideas is critically important for future growth and interest in the field. Here, we will highlight some of the examples of novel drug delivery systems that have undergone such translation. Specifically, we will discuss the developments, advantages, limitations and lessons learned from: (i) microparticle-based depot formulations, (ii) nanoparticle-based cancer drugs, (iii) transdermal systems, (iv) oral drug delivery systems, (v) pulmonary drug delivery, (vi) implants and (vii) antibody-drug conjugates. These systems have impacted treatment of many prevalent diseases including diabetes, cancer and cardiovascular diseases, among others. At the same time, these systems are integral and enabling components of products that collectively generate annual revenues exceeding US $100 billion. These examples provide strong evidence of the clinical and commercial impact of drug delivery systems. Copyright © 2013 Elsevier B.V. All rights reserved.

Coping with space motion sickness in Spacelab missions

NASA Astrophysics Data System (ADS)

Graybiel, Ashton

A substantial number of persons, around 75%, making their first transition into orbital flight will need to adapt to this unique environment. The two most powerful instruments in the prevention of space motion sickness reside in the selection process and in acquiring adaptation-prelaunch. Today, neither of these means is practical. One logical alternative is to administer preventative medication to all or none. One candidate drug is a high-potency transdermal therapeutic system (TTS)-scopolamine. This is marketed in the nature of a patch that is affixed to the skin behind the ear 12 hr before need and delivers scopolamine into the blood stream for three days. We are systematically evaluating all claims for its high potency and low side effects. We are also evaluating new antimotion sickness remedies and new combinations of homergic drugs.

Teaching Caregivers to Administer Eye Drops, Transdermal Patches, and Suppositories.

PubMed

Lindauer, Allison; Sexson, Kathryn; Harvath, Theresa A

2017-01-01

This article is the third in a series, Supporting Family Caregivers: No Longer Home Alone, published in collaboration with the AARP Public Policy Institute. Results of focus groups conducted as part of the AARP Public Policy Institute's No Longer Home Alone video project supported evidence that family caregivers aren't being given the information they need to manage the complex care regimens of their family members. This series of articles and accompanying videos aims to help nurses provide caregivers with the tools they need to manage their family member's medications. Each article explains the principles nurses should consider and reinforce with caregivers and is accompanied by a video for the caregiver to watch. The third video can be accessed at http://links.lww.com/AJN/A76.

Teaching Caregivers to Administer Eye Drops, Transdermal Patches, and Suppositories.

PubMed

Lindauer, Allison; Sexson, Kathryn; Harvath, Theresa A

2017-05-01

: This article is the third in a series, Supporting Family Caregivers: No Longer Home Alone, published in collaboration with the AARP Public Policy Institute. Results of focus groups conducted as part of the AARP Public Policy Institute's No Longer Home Alone video project supported evidence that family caregivers aren't being given the information they need to manage the complex care regimens of their family members. This series of articles and accompanying videos aims to help nurses provide caregivers with the tools they need to manage their family member's medications. Each article explains the principles nurses should consider and reinforce with caregivers and is accompanied by a video for the caregiver to watch. The third video can be accessed at http://links.lww.com/AJN/A76.

Challenges and opportunities in dermal/transdermal delivery

PubMed Central

Paudel, Kalpana S; Milewski, Mikolaj; Swadley, Courtney L; Brogden, Nicole K; Ghosh, Priyanka; Stinchcomb, Audra L

2010-01-01

Transdermal drug delivery is an exciting and challenging area. There are numerous transdermal delivery systems currently available on the market. However, the transdermal market still remains limited to a narrow range of drugs. Further advances in transdermal delivery depend on the ability to overcome the challenges faced regarding the permeation and skin irritation of the drug molecules. Emergence of novel techniques for skin permeation enhancement and development of methods to lessen skin irritation would widen the transdermal market for hydrophilic compounds, macromolecules and conventional drugs for new therapeutic indications. As evident from the ongoing clinical trials of a wide variety of drugs for various clinical conditions, there is a great future for transdermal delivery of drugs. PMID:21132122

Minimization of CYP2D6 Polymorphic Differences and Improved Bioavailability via Transdermal Administration: Latrepirdine Example.

PubMed

Chew, Marci L; Mordenti, Joyce; Yeoh, Thean; Ranade, Gautam; Qiu, Ruolun; Fang, Juanzhi; Liang, Yali; Corrigan, Brian

2016-08-01

Transdermal delivery has the potential to offer improved bioavailability by circumventing first-pass gut and hepatic metabolism. This study evaluated the pharmacokinetics of oral immediate release and transdermal latrepirdine in extensive and poor CYP2D6 metabolizers (EM/PM). Latrepirdine transdermal solution was prepared extemporaneously. The solution was applied with occlusive dressing to upper or middle back for 24 h. Each subject received a single dose of 8.14 mg oral, 5 mg transdermal, and 10 mg transdermal (EMs only) latrepirdine free base in a fixed sequence. Twelve EMs and 7 PMs (50-79 years) enrolled and completed the study. Latrepirdine was well tolerated following both routes of administration. Dose-normalized latrepirdine total exposures were approximately 11-fold and 1.5-fold higher in EMs and PMs, respectively following administration of transdermal relative to oral. Differences between EM and PM latrepirdine exposures were decreased, with PMs having 1.9- and 2.7-fold higher peak and total exposures, respectively, following transdermal administration compared to 11- and 20-fold higher exposures, respectively, following oral administration. Transdermal delivery can potentially mitigate the large intersubject differences observed with compounds metabolized primarily by CYP2D6. Transdermal delivery was readily accomplished in the clinic using an extemporaneously prepared solution [NCT00990613].

New screening methodology for selection of polymeric materials for transdermal drug delivery devices

NASA Astrophysics Data System (ADS)

Falcone, Roberto P.

As medical advances extend the human lifespan, the level of chronic illnesses will increase and thus straining the needs of the health care system that, as a result, governments will need to balance expenses without upsetting national budgets. Therefore, the selection of a precise and affordable drug delivery technology is seen as the most practical solution for governments, health care professionals, and consumers. Transdermal drug delivery patches (TDDP) are one of the best economical technologies that are favored by pharmaceutical companies and physicians alike because it offers fewer complications when compared to other delivery technologies. TDDP provides increased efficiency, safety and convenience for the patient. The TDDP segment within the US and Global drug delivery markets were valued at 5.6 and 12.7 billion respectively in 2009. TDDP is forecasted to reach $31.5 billion in 2015. The present TDDP technology involves the fabrication of a patch that consists of a drug embedded in a polymeric matrix. The diffusion coefficient is determined from the slope of the cumulative drug release versus time. It is a trial and error method that is time and labor consuming. With all the advantages that TDDPs can offer, the methodology used to achieve the so-called optimum design has resulted in several incidents where the safety and design have been put to question in recent times (e.g. Fentanyl). A more logical screening methodology is needed. This work shows the use of a modified Duda Zielinsky equation (DZE). Experimental release curves from commercial are evaluated. The experimental and theoretical Diffusion Coefficient values are found to be within the limits specified in the patent literature. One interesting finding is that the accuracy of the DZE is closer to experimental values when the type of Molecular Shape and Radius are used. This work shows that the modified DZE could be used as an excellent screening tool to determine the optimal polymeric matrices that will yield the desired Diffusion Coefficient and thus effectively decreasing the amount of time and labor when developing TDDPs.

Practice guideline summary: Treatment of restless legs syndrome in adults

PubMed Central

Winkelman, John W.; Armstrong, Melissa J.; Allen, Richard P.; Chaudhuri, K. Ray; Ondo, William; Trenkwalder, Claudia; Zee, Phyllis C.; Gronseth, Gary S.; Gloss, David; Zesiewicz, Theresa

2016-01-01

Objective: To make evidence-based recommendations regarding restless legs syndrome (RLS) management in adults. Methods: Articles were classified per the 2004 American Academy of Neurology evidence rating scheme. Recommendations were tied to evidence strength. Results and recommendations: In moderate to severe primary RLS, clinicians should consider prescribing medication to reduce RLS symptoms. Strong evidence supports pramipexole, rotigotine, cabergoline, and gabapentin enacarbil use (Level A); moderate evidence supports ropinirole, pregabalin, and IV ferric carboxymaltose use (Level B). Clinicians may consider prescribing levodopa (Level C). Few head-to-head comparisons exist to suggest agents preferentially. Cabergoline is rarely used (cardiac valvulopathy risks). Augmentation risks with dopaminergic agents should be considered. When treating periodic limb movements of sleep, clinicians should consider prescribing ropinirole (Level A) or pramipexole, rotigotine, cabergoline, or pregabalin (Level B). For subjective sleep measures, clinicians should consider prescribing cabergoline or gabapentin enacarbil (Level A), or ropinirole, pramipexole, rotigotine, or pregabalin (Level B). For patients failing other treatments for RLS symptoms, clinicians may consider prescribing prolonged-release oxycodone/naloxone where available (Level C). In patients with RLS with ferritin ≤75 μg/L, clinicians should consider prescribing ferrous sulfate with vitamin C (Level B). When nonpharmacologic approaches are desired, clinicians should consider prescribing pneumatic compression (Level B) and may consider prescribing near-infrared spectroscopy or transcranial magnetic stimulation (Level C). Clinicians may consider prescribing vibrating pads to improve subjective sleep (Level C). In patients on hemodialysis with secondary RLS, clinicians should consider prescribing vitamin C and E supplementation (Level B) and may consider prescribing ropinirole, levodopa, or exercise (Level C). PMID:27856776

An update on the application of physical technologies to enhance intradermal and transdermal drug delivery.

PubMed

Herwadkar, Anushree; Banga, Ajay K

2012-03-01

A large number of biopharmaceuticals and other macromolecules are being developed for therapeutic applications. Conventional oral delivery is not always possible due to first-pass metabolism and degradation in the GI tract. Parenteral delivery is invasive and has poor patient compliance. Transdermal delivery provides one attractive route of administration. Transdermal administration can achieve the continuous and non-invasive delivery of drugs. However, passive transdermal delivery is restricted to small lipophilic molecules. Active physical-enhancement technologies are being investigated to increase the scope of transdermal delivery to hydrophilic molecules and macromolecules. Recent developments in transdermal technologies, such as microporation, iontophoresis and sonophoresis can enable therapeutic delivery of many drug molecules, biopharmaceuticals, cosmeceuticals and vaccines. This review provides an update of recent developments in transdermal delivery focusing on physical-enhancement technologies.

A commentary on transdermal drug delivery systems in clinical trials.

PubMed

Watkinson, Adam C

2013-09-01

The number of drugs available as marketed transdermal products is limited to those that exhibit the correct physicochemical and pharmacokinetic properties that enable their effective delivery across the skin. In this respect, there are less than 20 drugs that are currently marketed in the US and EU as products that deliver systemic levels of their active ingredients. An analysis of clinical trials conducted in the transdermal sector shows a similar picture with only nine drugs accounting for approximately 80% of all transdermal clinical trials listed on ClinicalTrials.gov. Those drugs for which there are very few transdermal trials listed consist mostly of molecules that are inherently unsuitable for transdermal delivery and serve as a clear warning to drug developers that the science that governs transdermal drug delivery is well reflected by the successes and failures of drugs in development as well as those that make it to the market. Copyright © 2013 Wiley Periodicals, Inc.

Postoperative Anticholinergic Poisoning: Concealed Complications of a Commonly Used Medication.

PubMed

Zhang, Xiao Chi; Farrell, Natalija; Haronian, Thomas; Hack, Jason

2017-10-01

Scopolamine is a potent anticholinergic compound used commonly for the prevention of postoperative nausea and vomiting. Scopolamine can cause atypical anticholinergic syndromes due to its prominent central antimuscarinic effects. A 47-year-old female presented to the emergency department (ED) 20 h after hospital discharge for a right-knee meniscectomy, with altered mental status (AMS) and dystonic extremity movements that began 12 h after her procedure. Her vital signs were normal and physical examination revealed mydriasis, visual hallucinations, hyperreflexia, and dystonic movements. Laboratory data, lumbar puncture, and computed tomography were unrevealing. The sustained AMS prompted a re-evaluation that revealed urinary overflow with 500 mL of retained urine discovered on ultrasound and a scopolamine patch hidden behind her ear. Her mental status improved shortly after patch removal and physostigmine, with complete resolution after 24 h with discharge diagnosis of scopolamine-induced anticholinergic toxicity. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Although therapeutically dosed scopolamine transdermal patches rarely cause complications, incomplete toxidromes can be insidiously common in polypharmacy settings. Providers should thoroughly evaluate the skin of intoxicated patients for additional adherent medications that may result in a delay in ED diagnosis and curative therapies. Our case, as well as rare case reports of therapeutic scopolamine-induced anticholinergic toxicity, demonstrates that peripheral anticholinergic effects, such as tachycardia, dry mucous membranes, and hyperpyrexia are often not present, and incremental doses of physostigmine may be required to reverse scopolamine's long duration of action. This further complicates identification of the anticholinergic toxidrome and diagnosis. Published by Elsevier Inc.

Impact of newer pharmacological treatments on quality of life in patients with Parkinson's disease.

PubMed

Gallagher, David A; Schrag, Anette

2008-01-01

Parkinson's disease is a common progressive neurodegenerative condition with multiple motor and nonmotor features contributing to impairment of health-related quality of life (HR-QOL). Pharmacological treatments have been directed primarily at dopamine replacement with levodopa and agents to improve its bioavailability, including DOPA decarboxylase inhibitors, catechol-O-methyltransferase (COMT) inhibitors and monoamine oxidase B (MAO-B) inhibitors, as well as synthetic dopamine agonists. These treatments to restore motor function are often very successful in early Parkinson's disease, with objective improvement and concomitant improvement in subjective HR-QOL scores. However, as the disease progresses, motor complications and nonmotor symptoms predominate and are often refractory to therapeutic interventions. Antiparkinsonian medications have been shown to improve motor severity and motor complications of advancing disease, and there is increasing evidence that this can be translated into subjective improvement of HR-QOL from a patient's point of view. However, the degree of improvement is less marked on HR-QOL scores than on motor scores, and some studies do not show improvement of HR-QOL in parallel to motor improvements. A number of explanations are possible, including limitations of the scales used, trial designs and lack of clinical improvement from the patients' point of view. This review concentrates on clinical trials with an index of HR-QOL as an outcome measure, with particular emphasis on well designed, randomized, double-blind, placebo-controlled or active comparator-controlled methodology. Drugs that have been more recently added to the armamentarium of Parkinson's disease, including the oral (pramipexole, ropinirole and piribedil) and transdermal (rotigotine) non-ergotamine-derived dopamine agonists, the novel MAO-B inhibitor rasagiline and the COMT inhibitors tolcapone and entacapone, were included. The effect of each of these agents on overall HR-QOL and depression, a factor that has been shown to significantly contribute to HR-QOL in several multivariate analyses, is discussed.Overall, the literature search revealed 14 double-blind, placebo- or active comparator-controlled trials with an index of HR-QOL as an outcome measure. Entacapone resulted in HR-QOL improvement in nonfluctuating patients (one study) but not clearly in those with motor fluctuations (two studies). Tolcapone was only tested in patients with motor fluctuations and resulted in significant improvement in two of four studies using HR-QOL as an outcome measure. Rasagiline improved HR-QOL as monotherapy in early Parkinson's disease (one study), but not clearly in more advanced disease (one study). Rotigotine improved HR-QOL in both early Parkinson's disease (one study) and more advanced disease with motor fluctuations (one study). The impact of ropinirole and pramipexole on HR-QOL as monotherapy in early Parkinson's disease versus placebo has not been assessed, but both agents have resulted in improved HR-QOL in patients with motor fluctuations (ropinirole one study, pramipexole one study). The evidence for antidepressant efficacy of antiparkinsonian medications is limited.

Future of the transdermal drug delivery market--have we barely touched the surface?

PubMed

Watkinson, Adam C; Kearney, Mary-Carmel; Quinn, Helen L; Courtenay, Aaron J; Donnelly, Ryan F

2016-01-01

Transdermal drug delivery is the movement of drugs across the skin for absorption into the systemic circulation. Transfer of the drug can occur via passive or active means; passive transdermal products do not disrupt the stratum corneum to facilitate delivery whereas active technologies do. Due to the very specific physicochemical properties necessary for successful passive transdermal drug delivery, this sector of the pharmaceutical industry is relatively small. There are many well-documented benefits of this delivery route however, and as a result there is great interest in increasing the number of therapeutic substances that can be delivered transdermally. This review discusses the various transdermal products that are currently/have been marketed, and the paths that led to their success, or lack of. Both passive and active transdermal technologies are considered with the advantages and limitations of each highlighted. In addition to marketed products, technologies that are in the investigative stages by various pharmaceutical companies are reviewed. Passive transdermal drug delivery has made limited progress in recent years, however with the ongoing intense research into active technologies, there is great potential for growth within the transdermal delivery market. A number of active technologies have already been translated into marketed products, with other platforms including microneedles, rapidly progressing towards commercialisation.

TRANSDERMAL NITROGLYCERIN FOR THE TREATMENT OF PRETERM LABOR: A SYSTEMATIC REVIEW AND META-ANALYSIS

PubMed Central

CONDE-AGUDELO, Agustín; ROMERO, Roberto

2014-01-01

OBJECTIVE To evaluate the efficacy and safety of transdermal nitroglycerin as tocolytic agent in women with preterm labor. STUDY DESIGN Systematic review and meta-analysis of randomized controlled trials. RESULTS Thirteen studies (1302 women) were included. Two studies evaluated transdermal nitroglycerin versus placebo (N=186), 9 evaluated transdermal nitroglycerin versus β2-adrenergic-receptor agonists (N=1024), and 1 each evaluated transdermal nitroglycerin versus nifedipine (N=50) and transdermal nitroglycerin versus magnesium sulfate (N=42). There were no significant differences between transdermal nitroglycerin and placebo for delivery within 48 hours of initiation of treatment or before 28, 34 or 37 weeks’ gestation, adverse neonatal outcomes, and neurodevelopmental status at 24 months of age. Nevertheless, one study found a marginally significant reduction in the risk of a composite outcome of significant neonatal morbidity and perinatal mortality (3/74 [4.1%] versus 11/79 [13.9%]; relative risk 0.29, 95% confidence interval 0.08–1.00). When compared with β2-adrenergic-receptor agonists, transdermal nitroglycerin was associated with a significant reduction in the risk of preterm birth <34 and <37 weeks’ gestation, admission to the neonatal intensive care unit, use of mechanical ventilation, and maternal side effects. There were no significant differences between transdermal nitroglycerin and nifedipine and magnesium sulfate in delivery within 48 hours of treatment and pregnancy prolongation, respectively. Overall, women receiving transdermal nitroglycerin had a higher risk of headache. CONCLUSION Although transdermal nitroglycerin appears to be more effective than β 2-adrenergic-receptor agonists, the current evidence does not support its routine use as tocolytic agent for the treatment of preterm labor. Further additional double-blind placebo-controlled trials are needed. PMID:23891631

The value of oxybutynin in transdermal patches for treating overactive bladder.

PubMed

Salinas-Casado, J; Esteban-Fuertes, M; Serrano, O; Galván, J

2015-12-01

There is currently a broad therapeutic arsenal of drugs for treating overactive bladder syndrome (OAB). However, there is still a need for new compounds and for improving known drugs in terms of efficacy, compliance and tolerability. To report the scientific evidence on the safety and efficacy of transdermal oxybutynin (OXY-TDS) for treating OAB. A systematic review without time restrictions was conducted until May 2015 in the MEDLINE/PubMed database. We also performed a manual review of abstracts published in international urogynaecology congresses. The evaluated studies show that patients treated with OXY-TDS experience a significant reduction in urinary incontinence episodes compared with placebo, which is comparable to that observed in patients treated with oral oxybutynin or with tolterodine. In all of the studies, we observed improvements in symptoms from the second or third week of treatment and in a sustained manner until the end of treatment (6, 12 or 24 weeks). The clinical practice study also showed improved quality of life, achieving benefits in numerous patient profiles, with an efficacy independent of previous treatments. The safety of the drug was demonstrated in the various patient profiles. OXY-TDS represents an effective alternative for the symptomatic treatment of adult patients with OAB, which, thanks to its pharmacokinetic profile, better tolerability, different administration method and dosage, could represent an added value in treating special populations. Copyright © 2015 AEU. Publicado por Elsevier España, S.L.U. All rights reserved.

Effect of acute transdermal estrogen administration on basal, mental stress and cold pressor-induced sympathetic responses in postmenopausal women.

PubMed

Sofowora, Gbemiga G; Singh, Iqbal; He, Huai B; Wood, Alastair J J; Stein, C Michael

2005-06-01

Administration of estrogen has vascular effects through poorly defined mechanisms that may include sympathetic withdrawal. To define the effects of acute estrogen administration on sympathetic responses, nineteen healthy postmenopausal women (age 54+/-2 years) were studied after application of a placebo or estrogen patch for 36 hours, in random order. A p-value, adjusted for multiple comparisons, of <0.017 was used to determine statistical significance. Heart rate, blood pressure, and norepinephrine spillover were measured at rest, during mental stress (Stroop test), and during a cold pressor test. Estrogen did not attenuate basal or stimulated hemodynamic responses significantly. The increase in mean arterial pressure after the Stroop test (5.9+/-1.2mm/ Hg on placebo vs 6.1+/-1.6mm/Hg on estrogen, p=0.9) and after the cold pressor test (12.6+/-2.4mm/Hg on placebo vs 13.0+/-2.2 mm/Hg on estrogen, p=0.8) did not differ. Basal, mental stress and cold pressor-stimulated norepinephrine spillover were not significantly affected by short-term estrogen administration. Norepinephrine spillover tended to be higher after estrogen (1296.2+/-238 ng/min) than placebo (832.5+/-129 ng/min) (p=0.02) at baseline and after the Stroop test (1881.1+/-330 ng/min vs 1014.6+/-249 ng/min) (p=0.02). Acute transdermal estrogen administration did not attenuate norepinephrine spillover or sympathetically mediated hemodynamic responses.

Intention to use a combined contraceptive method and decision after counselling in Switzerland--Swiss data from the European CHOICE study.

PubMed

Merki-Feld, Gabriele S; Gruber, Isabel M L

2012-04-01

Considering the advantages of parenteral routes of administration of combined hormonal contraceptives (CHCs), their low prevalence of use in Europe is surprising. The Contraceptive health research of informed choice experience (CHOICE) study involved 11 European countries. It aimed at evaluating the influence of counselling on users' choice between three modalities of CHC administration (the pill, the transdermal patch, and the vaginal ring). We report here the results for Switzerland. Women (N = 2629) with a need for contraception received extended counselling. Questionnaires were used to collect data about the women's preferred method before and after counselling, and the reasons for their ultimate decision. After counselling, 40% of the women chose a contraceptive method that was different from the one initially intended. The number of vaginal ring users (28% vs. 11% intended) and patch users (7% vs. 4% intended) increased (p < 0.0001). Of the initially undecided women, 93% chose a contraceptive method after counselling. However, although information was provided on the risks, side effects and benefits associated with the different contraceptive methods, surprisingly few women retained this knowledge. The provision of balanced information on all CHCs influenced women's decisions to a great extent. Unlike the pill, non-oral methods were significantly more often chosen.

Follicular synchronization using transdermal estradiol patch and GnRH antagonists in the luteal phase; does it increase oocyte yield in poor responders to gonadotropin stimulation for in vitro fertilization (IVF)? A comparative study with microdose flare-up protocol.

PubMed

Ata, Baris; Zeng, Xing; Son, Weon Y; Holzer, Hananel; Tan, Seang L

2011-11-01

The aim of this retrospective study was to compare the oocyte yield with the luteal estradiol patch (LPA) - GnRH antagonist and microdose (MD) flare-up protocols in anticipated poor responders. Fifty-seven women who underwent IVF treatment following stimulation with LPA or MD protocols at McGill Reproductive Centre were matched for age and markers of ovarian reserve. Numbers of oocytes collected (6 vs 7), mature oocytes collected (5 vs 5), and oocyte maturation rates (72% vs 74%) were similar. The numbers of good quality embryos available (2 vs 1) and embryos transferred (3 vs 3) were likewise similar. Embryo implantation rate of 16.7% and clinical pregnancy rate of 38.9% achieved in the LPA group were almost 50% higher than the corresponding figures at 10.3% and 22.2% in the MD group; however, the differences were not statistically significant (p > 0.05 for all comparisons). Although the results do not suggest an increased oocyte yield or follicular synchronization with the LPA protocol, the observed trend toward higher embryo implantation and clinical pregnancy rates requires further research.

Double blind, randomized, placebo controlled clinical trial for the treatment of diabetic foot ulcers, using a nitric oxide releasing patch: PATHON

PubMed Central

Silva, Sandra Y; Rueda, Ligia C; Márquez, Gustavo A; López, Marcos; Smith, Daniel J; Calderón, Carlos A; Castillo, Juan C; Matute, Jaime; Rueda-Clausen, Christian F; Orduz, Arturo; Silva, Federico A; Kampeerapappun, Piyaporn; Bhide, Mahesh; López-Jaramillo, Patricio

2007-01-01

Background Diabetes Mellitus constitutes one of the most important public health problems due to its high prevalence and enormous social and economic consequences. Diabetic foot ulcers are one of the chronic complications of diabetes mellitus and constitute the most important cause of non-traumatic amputation of inferior limbs. It is estimated that 15% of the diabetic population will develop an ulcer sometime in their lives. Although novel therapies have been proposed, there is no effective treatment for this pathology. Naturally produced nitric oxide participates in the wound healing process by stimulating the synthesis of collagen, triggering the release of chemotactic cytokines, increasing blood vessels permeability, promoting angiogenic activity, stimulating the release of epidermical growth factors, and by interfering with the bacterial mitochondrial respiratory chain. Topically administered nitric oxide has demonstrated to be effective and safe for the treatment of chronic ulcers secondary to cutaneous leishmaniasis. However, due to their unstable nitric oxide release, the topical donors needed to be applied frequently, diminishing the adherence to the treatment. This difficulty has led to the development of a multilayer polymeric transdermal patch produced by electrospinning technique that guarantees a constant nitric oxide release. The main objective of this study is to evaluate the effectiveness and safety of this novel nitric oxide releasing wound dressing for the treatment of diabetic foot ulcers. Methods and design A double-blind, placebo-controlled clinical trial, including 100 diabetic patients was designed. At the time of enrollment, a complete medical evaluation and laboratory tests will be performed, and those patients who meet the inclusion criteria randomly assigned to one of two groups. Over the course of 90 days group 1 will receive active patches and group 2 placebo patches. The patients will be seen by the research group at least every two weeks until the healing of the ulcer or the end of the treatment. During each visit the healing process of the ulcer, the patient's health status and the presence of adverse events will be assessed. Should the effectiveness of the patches be demonstrated an alternative treatment would then be available to patients. Trial registration NCT00428727. PMID:17897470

Pharmacokinetics and adhesion of the Agile transdermal contraceptive patch (AG200-15) during daily exposure to external conditions of heat, humidity and exercise.

PubMed

Archer, David F; Stanczyk, Frank Z; Rubin, Arkady; Foegh, Marie

2013-02-01

This study compares the pharmacokinetic profile, adhesion and safety of the AG200-15 Agile Patch (AP), a novel contraceptive patch releasing low-dose ethinyl estradiol (EE) and levonorgestrel (LNG), during wear under external conditions of heat, humidity and exercise versus normal activities. This open-label, three-period, five-treatment, crossover study randomized 24 healthy women to one of six external condition sequences. Each sequence included one normal wear and two external conditions periods. Participants wore the AP for 7 days under normal conditions or conditions of daily sauna, treadmill, whirlpool or cool water immersion, with a 7-day washout between treatments. Blood samples were collected for pharmacokinetic evaluations. Twenty-four subjects completed the study. For EE, the mean maximum concentration level (Cmax), area under the plasma concentration-time curve from time 0 to 168 h (AUC(0-168)) and area under the plasma concentration-time curve from time 0 to infinity (AUC(0-inf)) were higher during normal conditions compared with all external conditions (geometric means ratio range: 80%-93%), except cool water. Mean steady-state concentrations (C(ss)) of EE were highest under normal conditions, followed by cool water, sauna, whirlpool and treadmill. The LNG mean C(max), AUC(0-168), AUC(0-inf) and C(ss) were higher under normal wear versus all other conditions (geometric means ratios: 75%-82%), with the exception of AUC(0-168), AUC(0-inf) and C(ss) for cold water. Median times to maximum concentration (Tmax) for EE and LNG were comparable across conditions. Patch adhesion was excellent under all conditions. Adverse events were mild, with none serious or leading to discontinuation. Although slightly lower mean drug concentration levels were observed for whirlpool, treadmill and sauna, drug concentrations under all conditions were well within therapeutic ranges established for the AP during normal wear and within ranges reported for low-dose combination oral contraceptives. Patch adhesion was excellent; the AP was safe and well tolerated under all conditions. Copyright © 2013 Elsevier Inc. All rights reserved.

Treatment with subcutaneous and transdermal fentanyl: results from a population pharmacokinetic study in cancer patients.

PubMed

Oosten, Astrid W; Abrantes, João A; Jönsson, Siv; de Bruijn, Peter; Kuip, Evelien J M; Falcão, Amílcar; van der Rijt, Carin C D; Mathijssen, Ron H J

2016-04-01

Transdermal fentanyl is effective for the treatment of moderate to severe cancer-related pain but is unsuitable for fast titration. In this setting, continuous subcutaneous fentanyl may be used. As data on the pharmacokinetics of continuous subcutaneous fentanyl are lacking, we studied the pharmacokinetics of subcutaneous and transdermal fentanyl. Furthermore, we evaluated rotations from the subcutaneous to the transdermal route. Fifty-two patients treated with subcutaneous and/or transdermal fentanyl for moderate to severe cancer-related pain participated. A population pharmacokinetic model was developed and evaluated using non-linear mixed-effects modelling. For rotations from subcutaneous to transdermal fentanyl, a 1:1 dose conversion ratio was used while the subcutaneous infusion was continued for 12 h (with a 50 % tapering after 6 h). A 6-h scheme with 50 % tapering after 3 h was simulated using the final model. A one-compartment model with first-order elimination and separate first-order absorption processes for each route adequately described the data. The estimated apparent clearance of fentanyl was 49.6 L/h; the absorption rate constant for subcutaneous and transdermal fentanyl was 0.0358 and 0.0135 h(-1), respectively. Moderate to large inter-individual and inter-occasion variability was found. Around rotation from subcutaneous to transdermal fentanyl, measured and simulated plasma fentanyl concentrations rose and increasing side effects were observed. We describe the pharmacokinetics of subcutaneous and transdermal fentanyl in one patient cohort and report several findings that are relevant for clinical practice. Further research is warranted to study the optimal scheme for rotations from the subcutaneous to the transdermal route.

Advanced Drug Delivery Systems for Transdermal Delivery of Non-Steroidal Anti-Inflammatory Drugs: A Review.

PubMed

Kumar, Lalit; Verma, Shivani; Singh, Mehakjot; Tamanna, Tamanna; Utreja, Puneet

2018-06-04

Transdermal route of delivery of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) has several advantages over other routes like reduced adverse effects, less systemic absorption, and avoidance of first pass effect and degradation in the gastrointestinal tract (GIT). Transdermal route is also beneficial for drugs having a narrow therapeutic index. The skin acts as the primary barrier for transdermal delivery of various therapeutic molecules. Various advanced nanocarrier systems offer several advantages like improved dermal penetration along with an extended drug release profile due to their smaller size and high surface area. Various nanocarrier explored for transdermal delivery of NSAIDs are liposomes, niosomes, ethosomes, polymeric nanoparticles (NPs), solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), dendrimers, nanosuspensions/nanoemulsion, and nanofibers Objectives: In the present review, our major aim was to explore the therapeutic potential of advanced nanocarrier systems enlisted above for transdermal delivery of NSAIDs. All literature search regarding advanced nanocarrier systems for transdermal delivery of NSAIDs was done using Google Scholar and Pubmed. Advanced nanocarrier have shown various advantages like reduced side effect, low dosing frequency, high skin permeation, and ease of application over conventional transdermal delivery systems of NSAIDs in various preclinical studies. However, clinical exploration of advanced nanocarrier systems for transdermal delivery of NSAIDs is still a challenge. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Machine learning study for the prediction of transdermal peptide

NASA Astrophysics Data System (ADS)

Jung, Eunkyoung; Choi, Seung-Hoon; Lee, Nam Kyung; Kang, Sang-Kee; Choi, Yun-Jaie; Shin, Jae-Min; Choi, Kihang; Jung, Dong Hyun

2011-04-01

In order to develop a computational method to rapidly evaluate transdermal peptides, we report approaches for predicting the transdermal activity of peptides on the basis of peptide sequence information using Artificial Neural Network (ANN), Partial Least Squares (PLS) and Support Vector Machine (SVM). We identified 269 transdermal peptides by the phage display technique and use them as the positive controls to develop and test machine learning models. Combinations of three descriptors with neural network architectures, the number of latent variables and the kernel functions are tried in training to make appropriate predictions. The capacity of models is evaluated by means of statistical indicators including sensitivity, specificity, and the area under the receiver operating characteristic curve (ROC score). In the ROC score-based comparison, three methods proved capable of providing a reasonable prediction of transdermal peptide. The best result is obtained by SVM model with a radial basis function and VHSE descriptors. The results indicate that it is possible to discriminate between transdermal peptides and random sequences using our models. We anticipate that our models will be applicable to prediction of transdermal peptide for large peptide database for facilitating efficient transdermal drug delivery through intact skin.

Feline Transdermal Formulation Considerations.

PubMed

Forsythe, Lauren Eichstadt

2017-01-01

Transdermal delivery of drugs is comparatively new in feline patients. However, transdermal formulations can be a desirable option for treating feline patients that are not willing participants to medication administration. However, achieving drug penetration across the skin is not always easy, and there are a wide variety of variables that can further affect penetration. This, coupled with a lack of studies, make transdermal administration an unknown with regards to efficacy and safety for many drugs. This article focuses on drugs that are administered transdermally with the intent of producing systemic effects. Copyright© by International Journal of Pharmaceutical Compounding, Inc.

Drugs in development for Parkinson's disease.

PubMed

Johnston, Tom H; Brotchie, Jonathan M

2004-07-01

Pharmacological treatment of Parkinson's disease (PD) is entering a new and exciting era. Real promise now exists for the clinical application of a large range of molecules in development that will combat different aspects and stages of the condition. These include methyl- and ethyl-esterified forms of L-dopa (etilevodopa and melevodopa), inhibitors of enzymes such as monoamine oxidase type-B (eg, rasagiline), catechol-O-methyl transferase (eg, BIA-3202) and the monoamine re-uptake mechanism (eg, brasofensine). In addition, a range of full and partial dopamine agonists (eg, sumanirole, piribedil and BP-897) and their new formulations, for example, patch delivery systems (eg, rotigotine) are being developed. We also highlight non-dopaminergic treatments that will have wide ranging applications in the treatment of PD and L-dopa-induced dyskinesia. These include alpha2 adrenergic receptor antagonists (eg, fipamezole), adenosine A2A receptor antagonists (eg, istradefylline), AMPA receptor antagonists (eg, talampanel), neuronal synchronization modulators (eg, levetiracetam) and agents that interact with serotonergic systems such as 5-hydroxytryptamine (5-HT)1A agonists (eg, sarizotan) and 5-HT2A antagonists (eg, quetiapine). Lastly, we examine a growing number of neuroprotective agents that seek to halt or even reverse disease progression. These include anti-apoptotic kinase inhibitors (eg, CEP-1347), modulators of mitochondrial function (eg, creatine), growth factors (eg, leteprinim), neuroimmunophilins (eg, V-10367), estrogens (eg, MITO-4509), c-synuclein oligomerization inhibitors (eg, PAN-408) and sonic hedgehog ligands.

The effect of inhalant anesthetic and body temperature on peri-anesthetic serum concentrations of transdermally administered fentanyl in dogs.

PubMed

Pettifer, Glenn R; Hosgood, Giselle

2004-04-01

To determine whether moderate hypothermia during anesthesia significantly affects the serum concentration of transdermally delivered fentanyl and whether halothane or isoflurane affect these concentrations. Randomized cross-over experimental trial. Six mature, healthy Beagles (three males, three females) weighing 10.6 +/- 0.43 kg. A 50-microg hour(-1) fentanyl patch was applied 36 hours prior to anesthesia. Anesthesia was induced at time 0 (t = 0). Each dog received four treatments: isoflurane + normothermia (ISO-NORM), isoflurane + hypothermia (ISO-HYPO), halothane + normothermia (HAL-NORM), and halothane + hypothermia (HAL-HYPO). Dogs were intubated and maintained at 1.5 times MAC. Animals in the hypothermia treatments were cooled to 35 degrees C during anesthesia. Serum fentanyl analysis was performed at -36, -24, -12, 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 18, and 26 hours. Direct arterial blood pressures and arterial blood gases were monitored. The mean body temperatures (+/-SEM) during the anesthetic period for the four treatments were: ISO-NORM = 37.7 +/- 0.07 degrees C, ISO-HYPO = 35.8 +/- 0.1 degrees C, HAL-NORM = 37.7 +/- 0.06 degrees C, and HAL-HYPO = 35.8 +/- 0.13 degrees C. The mean (+/-SEM) serum fentanyl concentrations (SFC) for both hypothermia treatments were significantly lower than baseline concentrations at t = 1 hour and persisted for the duration of anesthesia for the ISO-HYPO treatment but only from t = 1 to 2 hours for the HAL-HYPO treatment. Serum fentanyl concentrations returned to baseline within one hour of the end of anesthesia, regardless of body temperature. There were no significant differences between treatments for systolic or diastolic blood pressure but mean blood pressures were higher during normothermia versus hypothermia during the last hour of anesthesia. Hypothermia during inhalation anesthesia produced a significant reduction in SFC using transdermal administration and was more protracted with isoflurane than halothane anesthesia. While significant reductions in SFC occurred, the SFC were still within the range believed to confer analgesia.

Ultrasound-mediated transdermal drug delivery of fluorescent nanoparticles and hyaluronic acid into porcine skin in vitro

NASA Astrophysics Data System (ADS)

Wang, Huan-Lei; Fan, Peng-Fei; Guo, Xia-Sheng; Tu, Juan; Ma, Yong; Zhang, Dong

2016-12-01

Transdermal drug delivery (TDD) can effectively bypass the first-pass effect. In this paper, ultrasound-facilitated TDD on fresh porcine skin was studied under various acoustic parameters, including frequency, amplitude, and exposure time. The delivery of yellow-green fluorescent nanoparticles and high molecular weight hyaluronic acid (HA) in the skin samples was observed by laser confocal microscopy and ultraviolet spectrometry, respectively. The results showed that, with the application of ultrasound exposures, the permeability of the skin to these markers (e.g., their penetration depth and concentration) could be raised above its passive diffusion permeability. Moreover, ultrasound-facilitated TDD was also tested with/without the presence of ultrasound contrast agents (UCAs). When the ultrasound was applied without UCAs, low ultrasound frequency will give a better drug delivery effect than high frequency, but the penetration depth was less likely to exceed 200 μm. However, with the help of the ultrasound-induced microbubble cavitation effect, both the penetration depth and concentration in the skin were significantly enhanced even more. The best ultrasound-facilitated TDD could be achieved with a drug penetration depth of over 600 μm, and the penetration concentrations of fluorescent nanoparticles and HA increased up to about 4-5 folds. In order to get better understanding of ultrasound-facilitated TDD, scanning electron microscopy was used to examine the surface morphology of skin samples, which showed that the skin structure changed greatly under the treatment of ultrasound and UCA. The present work suggests that, for TDD applications (e.g., nanoparticle drug carriers, transdermal patches and cosmetics), protocols and methods presented in this paper are potentially useful. Project partially supported by the National Natural Science Foundation of China (Grant Nos. 81127901, 81227004, 81473692, 81673995, 11374155, 11574156, 11274170, 11274176, 11474001, 11474161, 11474166, and 11674173), the Natural Science Foundation of Jiangsu Province, China (Grant No. BK2011812), the Fundamental Research Funds for the Central Universities, and the National High-Tech Research and Development Program of China (Grant No. 2012AA022702).

Advanced Analgesic Drug Delivery and Nanobiotechnology.

PubMed

Stoicea, Nicoleta; Fiorda-Diaz, Juan; Joseph, Nicholas; Shabsigh, Muhammad; Arias-Morales, Carlos; Gonzalez-Zacarias, Alicia A; Mavarez-Martinez, Ana; Marjoribanks, Stephen; Bergese, Sergio D

2017-07-01

Transdermal administration of analgesic medications offers several benefits over alternative routes of administration, including a decreased systemic drug load with fewer side effects, and avoidance of drug degradation by the gastrointestinal tract. Transdermal administration also offers a convenient mode of drug administration over an extended period of time, particularly desirable in pain medicine. A transdermal administration route may also offer increased safety for drugs with a narrow therapeutic window. The primary barrier to transdermal drug absorption is the skin itself. Transdermal nanotechnology offers a novel method of achieving enhanced dermal penetration with an extended delivery profile for analgesic drugs, due to their small size and relatively large surface area. Several materials have been used to enhance drug duration and transdermal penetration. The application of nanotechnology in transdermal delivery of analgesics has raised new questions regarding safety and ethical issues. The small molecular size of nanoparticles enables drug delivery to previously inaccessible body sites. To ensure safety, the interaction of nanoparticles with the human body requires further investigation on an individual drug basis, since different formulations have unique properties and side effects.

Fifteen minute consultation: Practical pain management in paediatric palliative care.

PubMed

Harrop, Emily Jane; Brombley, Karen; Boyce, Katherine

2017-10-01

Pain and distress in the paediatric palliative care population can be very difficult to manage. Clinical scenarios range from the acute management of cancer-related pain at the end of life to the ongoing long-term support of children with complex multimodal pain related to progressive neurological conditions. Understanding the child's underlying condition, possible causes of pain and their preferred mode of communication are important to the delivery of holistic care. Modification of environmental factors, basic care consideration and non-pharmacological measures have a large role to play, alongside conventional analgesics. Medication may also need to be delivered by novel routes such as transdermal patches, continuous subcutaneous infusion of multiple drugs or transmucosal breakthrough analgesic doses. Two cases are used to illustrate approaches to these clinical problems. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Transdermal scopolamine in the prevention of motion sickness - Evaluation of the time course of efficacy

NASA Technical Reports Server (NTRS)

Homick, J. L.; Reschke, M. F.; Degioanni, J.; Cintron-Trevino, N. M.; Kohl, R. L.

1983-01-01

This study evaluated the time course of efficacy of transdermal scopolamine in the prevention of motion sickness induced by exposure to coriolis stimulation in a rotating chair. We measured levels of efficacy, quantified side effects and symptoms, and determined inter- and intra-subject variability following use of transdermal scopolamine. The response to transdermal scopolamine was highly variable, although overall we recorded a 40 percent improvement in test scores 16-72 h after application of the transdermal system. This variability could not be explained solely by the levels of scopolamine present in the blood. The improvement was not due to the artifactual repression by scopolamine of selected symptoms of motion sickness. An unexpectedly high incidence of side effects was reported. It was concluded that the therapeutic use of transdermal scopolamine be evaluated individually and that individuals be cautioned that subsequent usage may not always be effective.

Transdermal delivery of biomacromolecules using lipid-like nanoparticles

NASA Astrophysics Data System (ADS)

Bello, Evelyn A.

The transdermal delivery of biomacromolecules, including proteins and nucleic acids, is challenging, owing to their large size and the penetration-resistant nature of the stratum corneum. Thus, an urgent need exists for the development of transdermal delivery methodologies. This research focuses on the use of cationic lipid-like nanoparticles (lipidoids) for the transdermal delivery of proteins, and establishes an in vitro model for the study. The lipidoids used were first combinatorially designed and synthesized; afterwards, they were employed for protein encapsulation in a vesicular system. A skin penetration study demonstrated that lipidoids enhance penetration depth in a pig skin model, overcoming the barrier that the stratum corneum presents. This research has successfully identified active lipidoids capable of efficiently penetrating the skin; therefore, loading proteins into lipidoid nanoparticles will facilitate the transdermal delivery of proteins. Membrane diffusion experiments were used to confirm the results. This research has confirmed that lipidoids are a suitable material for transdermal protein delivery enhancement.

Transdermal granisetron: a guide to its use in preventing nausea and vomiting induced by chemotherapy.

PubMed

Keating, Gillian M; Duggan, Sean T; Curran, Monique P

2012-09-01

Transdermal granisetron (Sancuso®) is effective in the prevention of nausea and vomiting in patients with cancer who are receiving moderately or highly emetogenic chemotherapy for 3-5 days. Transdermal granisetron is noninferior to oral granisetron in this indication, and is generally well tolerated in this indication. Thus, transdermal granisetron provides a convenient option for the prevention of chemotherapy-induced nausea and vomiting, with the potential to improve patient compliance.

Granisetron transdermal system improves refractory nausea and vomiting in gastroparesis.

PubMed

Simmons, Kellie; Parkman, Henry P

2014-06-01

Symptoms of gastroparesis include nausea and vomiting, which can markedly diminish quality of life. Nausea and vomiting can also make treatment with oral antiemetics problematic. Our aim was to determine whether treatment-resistant nausea and vomiting in patients with gastroparesis improve after granisetron transdermal patch (GTP) therapy. In an open-label pilot study, patients with gastroparesis and symptoms of nausea and vomiting refractory to conventional treatment were treated with GTP. After 2 weeks, patients were asked to assess their therapeutic response using the Clinical Patient Grading Assessment Scale (CPGAS; +7 = completely better; 0 = no change; -7 = very considerably worse). Responders were defined as CPGAS score >0, non-responders as ≤0. Patients (n = 36) were treated with GTP. Of these 36 patients, one patient discontinued treatment due to the GTP not adhering to the skin. Of the remaining 35 patients, 18 improved, 15 remained the same, and two worsened. The average CPGAS score was +1.8 ± 0.4 (SEM) (P < 0.05 vs 0). Of the 18 patients with improvement, the average CPGAS score was +3.7 ± 0.3 (SEM), corresponding to "somewhat" to "moderately better" improvement in nausea/vomiting. Side effects occurred in nine patients: four developed constipation, three patients had skin rash, and two reported headaches. GTP was moderately effective in reducing refractory symptoms of nausea and/or vomiting from gastroparesis in 50% of patients. Mild side effects were reported by 25% of patients. GTP may be an effective treatment for nausea and vomiting in gastroparesis, and further study is warranted.

Transdermal Rivastigmine Delivery for Alzheimer Disease: Amenability of Exposure Predictions of Rivastigmine and Metabolite, NAP226-90, by Linear Regression Model Using Limited Samples.

PubMed

Srinivas, Nuggehally R

2016-01-01

Although an optimized delivery of rivastigmine for management of Alzhiemer disease (AD) is provided by the transdermal patch, it is critical to establish a limited sampling strategy for the measurement of exposure of rivastigmine/NAP226-90. The relationship Cmax versus AUC0-24h for rivastigmine/NAP226-90 was established by regression models. The derived regression equations enabled the prediction AUC0-24h for rivastigmine and NAP226-90. Models were evaluated using statistical criteria. Mixed model was used to predict AUC0-24h for rivastigmine/NAP226-90 from time points such as 8 (C8h), 12 (C12h), and 18 (C18h) hours. Excellent correlation was established for between Cmax and AUC0-24h for rivastigmine and NAP226-90. AUC0-24h predictions of either rivastigmine or NAP226-90 were within 0.8- to 1.25-fold difference. The RMSE in the AUC0-24h predictions ranged from 17.6% to 21.9%, and the R for prediction were greater than 0.96 for both rivastigmine and NAP226-90. Use of mixed model for C8h, C12h, and C18h resulted in AUC0-24h within 1.5-fold difference for rivastigmine or NAP226-90. Cmax of rivastigmine and NAP226-90 was highly correlated with the corresponding AUC0-24h values confirming the role of a time point closer to Cmax for an effective AUC measurement of rivastigmine or the metabolite.

Transdermal and oral dl-methylphenidate-ethanol interactions in C57BL/6J mice: transesterification to ethylphenidate and elevation of d-methylphenidate concentrations.

PubMed

Bell, Guinevere H; Novak, Andrew J; Griffin, William C; Patrick, Kennerly S

2011-07-01

We tested the hypothesis that C57BL/6J mice will model human metabolic interactions between dl-methylphenidate (MPH) and ethanol, placing an emphasis on the MPH transdermal system (MTS). Specifically, we asked: (1) will ethanol increase d-MPH biological concentrations, (2) will MTS facilitate the systemic bioavailability of l-MPH, and (3) will l-MPH enantioselectively interact with ethanol to yield l-ethylphenidate (l-EPH)? Mice were dosed with MTS (¼ of a 12.5 cm(2) patch on shaved skin) or a comparable oral dl-MPH dose (7.5 mg/kg), with or without ethanol (3.0 g/kg), and then placed in metabolic cages for 3 h. MPH and EPH isomer concentrations in blood, brain, and urine were analyzed by gas chromatographic-mass spectrometry monitoring of N-(S)-prolylpiperidyl fragments. As in humans, MTS greatly facilitated the absorption of l-MPH in this mouse strain. Similarly, ethanol led to the enantioselective formation of l-EPH and to an elevation in d-MPH concentrations with both MTS and oral MPH. Although only guarded comparisons between MTS and oral MPH can be made due to route-dependent drug absorption rate differences, MTS was associated with significant MPH-ethanol interactions. Ethanol-mediated increases in circulating concentrations of d-MPH carry toxicological and abuse liability implications should this animal model hold for ethanol-consuming attention-deficit hyperactivity disorder patients or coabusers. Copyright © 2011 Wiley-Liss, Inc. and the American Pharmacists Association

Transdermal drug delivery: feasibility for treatment of superficial bone stress fractures.

PubMed

Aghazadeh-Habashi, Ali; Yang, Yang; Tang, Kathy; Lőbenberg, Raimar; Doschak, Michael R

2015-12-01

Transdermal drug delivery offers the promise of effective drug therapy at selective sites of pathology whilst reducing systemic exposure to the pharmaceutical agents in off-target organs and tissues. However, that strategy is often limited to cells comprising superficial tissues of the body (rarely to deeper bony structures) and mostly indicated with small hydrophobic pharmacological agents, such as steroid hormones and anti-inflammatory gels to skin, muscle, and joints. Nonetheless, advances in transdermal liposomal formulation have rendered the ability to readily incorporate pharmacologically active hydrophilic drug molecules and small peptide biologics into transdermal dosage forms to impart the effective delivery of those bioactive agents across the skin barrier to underlying superficial tissue structures including bone, often enhanced by some form of electrical, chemical, and mechanical facilitation. In the following review, we evaluate transdermal drug delivery systems, with a particular focus on delivering therapeutic agents to treat superficial bone pain, notably stress fractures. We further introduce and discuss several small peptide hormones active in bone (such as calcitonins and parathyroid hormone) that have shown potential for transdermal delivery, often under the added augmentation of transdermal drug delivery systems that employ lipo/hydrophilicity, electric charge, and/or microprojection facilitation across the skin barrier.

Oleic acid-enhanced transdermal delivery pathways of fluorescent nanoparticles

NASA Astrophysics Data System (ADS)

Lo, Wen; Ghazaryan, Ara; Tso, Chien-Hsin; Hu, Po-Sheng; Chen, Wei-Liang; Kuo, Tsung-Rong; Lin, Sung-Jan; Chen, Shean-Jen; Chen, Chia-Chun; Dong, Chen-Yuan

2012-05-01

Transdermal delivery of nanocarriers provides an alternative pathway to transport therapeutic agents, alleviating pain, improving compliance of patients, and increasing overall effectiveness of delivery. In this work, enhancement of transdermal delivery of fluorescent nanoparticles and sulforhodamine B with assistance of oleic acid was visualized utilizing multiphoton microscopy (MPM) and analyzed quantitatively using multi-photon excitation-induced fluorescent signals. Results of MPM imaging and MPM intensity-based spatial depth-dependent analysis showed that oleic acid is effective in facilitating transdermal delivery of nanoparticles.

Delivery of salmon calcitonin using a microneedle patch

PubMed Central

Tas, Cetin; Mansoor, Saffar; Kalluri, Haripriya; Zarnitsyn, Vladimir G.; Choi, Seong-O; Banga, Ajay K.; Prausnitz, Mark R.

2011-01-01

Peptides and polypeptides have important pharmacological properties but only a limited number have been exploited as therapeutics because of problems related to their delivery. Most of these drugs require a parenteral delivery system which introduces the problems of pain, possible infection, and expertise required to carry out an injection. The aim of this study was to develop a transdermal patch containing microneedles (MNs) coated with a peptide drug, salmon calcitonin (sCT), as an alternative to traditional subcutaneous and nasal delivery routes. Quantitative analysis of sCT after coating and drying onto microneedles was performed with a validated HPLC method. In vivo studies were carried out on hairless rats and serum levels of sCT were determined by ELISA. The AUC value of MNs coated with a trehalose-containing formulation (250 ± 83 ng/mL.min) was not significantly different as compared to subcutaneous injections (403 ± 253 ng/mL.min), but approximately 13 times higher than nasal administration (18.4 ± 14.5 ng/mL.min). Tmax (7.5 ± 5 min) values for MN mediated administration were 50% shorter than subcutaneous injections (15 min), possibly due to rapid sCT dissolution and absorption by dermal capillaries. These results suggest that with further optimization of coating formulations, microneedles may enable administration of sCT and other peptides without the need for hypodermic injections. PMID:22172290

Ethosomal nanocarriers: the impact of constituents and formulation techniques on ethosomal properties, in vivo studies, and clinical trials.

PubMed

Abdulbaqi, Ibrahim M; Darwis, Yusrida; Khan, Nurzalina Abdul Karim; Assi, Reem Abou; Khan, Arshad A

2016-01-01

Ethosomal systems are novel lipid vesicular carriers containing a relatively high percentage of ethanol. These nanocarriers are especially designed for the efficient delivery of therapeutic agents with different physicochemical properties into deep skin layers and across the skin. Ethosomes have undergone extensive research since they were invented in 1996; new compounds were added to their initial formula, which led to the production of new types of ethosomal systems. Different preparation techniques are used in the preparation of these novel carriers. For ease of application and stability, ethosomal dispersions are incorporated into gels, patches, and creams. Highly diverse in vivo models are used to evaluate their efficacy in dermal/transdermal delivery, in addition to clinical trials. This article provides a detailed review of the ethosomal systems and categorizes them on the basis of their constituents to classical ethosomes, binary ethosomes, and transethosomes. The differences among these systems are discussed from several perspectives, including the formulation, size, ζ-potential (zeta potential), entrapment efficiency, skin-permeation properties, and stability. This paper gives a detailed review on the effects of ethosomal system constituents, preparation methods, and their significant roles in determining the final properties of these nanocarriers. Furthermore, the novel pharmaceutical dosage forms of ethosomal gels, patches, and creams are highlighted. The article also provides detailed information regarding the in vivo studies and clinical trials conducted for the evaluation of these vesicular systems.

Myth or Reality-Transdermal Magnesium?

PubMed

Gröber, Uwe; Werner, Tanja; Vormann, Jürgen; Kisters, Klaus

2017-07-28

In the following review, we evaluated the current literature and evidence-based data on transdermal magnesium application and show that the propagation of transdermal magnesium is scientifically unsupported. The importance of magnesium and the positive effects of magnesium supplementation are extensively documented in magnesium deficiency, e.g., cardiovascular disease and diabetes mellitus. The effectiveness of oral magnesium supplementation for the treatment of magnesium deficiency has been studied in detail. However, the proven and well-documented oral magnesium supplementation has become questioned in the recent years through intensive marketing for its transdermal application (e.g., magnesium-containing sprays, magnesium flakes, and magnesium salt baths). In both, specialist and lay press as well as on the internet, there are increasing numbers of articles claiming the effectiveness and superiority of transdermal magnesium over an oral application. It is claimed that the transdermal absorption of magnesium in comparison to oral application is more effective due to better absorption and fewer side effects as it bypasses the gastrointestinal tract.

Peptide-chaperone-directed transdermal protein delivery requires energy.

PubMed

Ruan, Renquan; Jin, Peipei; Zhang, Li; Wang, Changli; Chen, Chuanjun; Ding, Weiping; Wen, Longping

2014-11-03

The biologically inspired transdermal enhanced peptide TD1 has been discovered to specifically facilitate transdermal delivery of biological macromolecules. However, the biological behavior of TD1 has not been fully defined. In this study, we find that energy is required for the TD1-mediated transdermal protein delivery through rat and human skins. Our results show that the permeation activity of TD1-hEGF, a fusion protein composed of human epidermal growth factor (hEGF) and the TD1 sequence connected with a glycine-serine linker (GGGGS), can be inhibited by the energy inhibitor, rotenone or oligomycin. In addition, adenosine triphosphate (ATP), the essential energetic molecule in organic systems, can effectively facilitate the TD1 directed permeation of the protein-based drug into the skin in a dose-dependent fashion. Our results here demonstrate a novel energy-dependent permeation process during the TD1-mediated transdermal protein delivery that could be valuable for the future development of promising new transdermal drugs.

Promotion of the transdermal delivery of protein drugs by N-trimethyl chitosan nanoparticles combined with polypropylene electret.

PubMed

Tu, Ye; Wang, Xinxia; Lu, Ying; Zhang, He; Yu, Yuan; Chen, Yan; Liu, Junjie; Sun, Zhiguo; Cui, Lili; Gao, Jing; Zhong, Yanqiang

We recently reported that electret, which was prepared by a corona charging system with polypropylene film, could enhance the transdermal delivery of several drugs of low molecular weight. The aim of this study was to investigate whether electret could enhance the transdermal delivery of protein drugs by N -trimethyl chitosan nanoparticles (TMC NPs) prepared by an ionic gelation method. A series of experiments were performed, including in vitro skin permeation assays and anti-inflammatory effects, to evaluate the transdermal delivery of protein drugs by TMC NPs in the presence of electret. The results showed that in the presence of electret, the transdermal delivery of protein drugs in TMC NPs was significantly enhanced, as demonstrated by in vitro permeation studies and confocal laser scanning microscopy. Notably, superoxide dismutase-loaded TMC NPs combined with electret exhibited the best inhibitory effect on the edema of the mouse ear. TMC NPs combined with electret represent a novel platform for the transdermal delivery of protein drugs.

Poly(lactic-co-glycolic) acid drug delivery systems through transdermal pathway: an overview.

PubMed

Naves, Lucas; Dhand, Chetna; Almeida, Luis; Rajamani, Lakshminarayanan; Ramakrishna, Seeram; Soares, Graça

2017-05-01

In past few decades, scientists have made tremendous advancement in the field of drug delivery systems (DDS), through transdermal pathway, as the skin represents a ready and large surface area for delivering drugs. Efforts are in progress to design efficient transdermal DDS that support sustained drug release at the targeted area for longer duration in the recommended therapeutic window without producing side-effects. Poly(lactic-co-glycolic acid) (PLGA) is one of the most promising Food and Drug Administration approved synthetic polymers in designing versatile drug delivery carriers for different drug administration routes, including transdermal drug delivery. The present review provides a brief introduction over the transdermal drug delivery and PLGA as a material in context to its role in designing drug delivery vehicles. Attempts are made to compile literatures over PLGA-based drug delivery vehicles, including microneedles, nanoparticles, and nanofibers and their role in transdermal drug delivery of different therapeutic agents. Different nanostructure evaluation techniques with their working principles are briefly explained.

Permeation enhancer strategies in transdermal drug delivery.

PubMed

Marwah, Harneet; Garg, Tarun; Goyal, Amit K; Rath, Goutam

2016-01-01

Today, ∼74% of drugs are taken orally and are not found to be as effective as desired. To improve such characteristics, transdermal drug delivery was brought to existence. This delivery system is capable of transporting the drug or macromolecules painlessly through skin into the blood circulation at fixed rate. Topical administration of therapeutic agents offers many advantages over conventional oral and invasive techniques of drug delivery. Several important advantages of transdermal drug delivery are prevention from hepatic first pass metabolism, enhancement of therapeutic efficiency and maintenance of steady plasma level of the drug. Human skin surface, as a site of drug application for both local and systemic effects, is the most eligible candidate available. New controlled transdermal drug delivery systems (TDDS) technologies (electrically-based, structure-based and velocity-based) have been developed and commercialized for the transdermal delivery of troublesome drugs. This review article covers most of the new active transport technologies involved in enhancing the transdermal permeation via effective drug delivery system.

Promotion of the transdermal delivery of protein drugs by N-trimethyl chitosan nanoparticles combined with polypropylene electret

PubMed Central

Tu, Ye; Wang, Xinxia; Lu, Ying; Zhang, He; Yu, Yuan; Chen, Yan; Liu, Junjie; Sun, Zhiguo; Cui, Lili; Gao, Jing; Zhong, Yanqiang

2016-01-01

We recently reported that electret, which was prepared by a corona charging system with polypropylene film, could enhance the transdermal delivery of several drugs of low molecular weight. The aim of this study was to investigate whether electret could enhance the transdermal delivery of protein drugs by N-trimethyl chitosan nanoparticles (TMC NPs) prepared by an ionic gelation method. A series of experiments were performed, including in vitro skin permeation assays and anti-inflammatory effects, to evaluate the transdermal delivery of protein drugs by TMC NPs in the presence of electret. The results showed that in the presence of electret, the transdermal delivery of protein drugs in TMC NPs was significantly enhanced, as demonstrated by in vitro permeation studies and confocal laser scanning microscopy. Notably, superoxide dismutase-loaded TMC NPs combined with electret exhibited the best inhibitory effect on the edema of the mouse ear. TMC NPs combined with electret represent a novel platform for the transdermal delivery of protein drugs. PMID:27822034

Myth or Reality—Transdermal Magnesium?

PubMed Central

Gröber, Uwe; Werner, Tanja; Vormann, Jürgen

2017-01-01

In the following review, we evaluated the current literature and evidence-based data on transdermal magnesium application and show that the propagation of transdermal magnesium is scientifically unsupported. The importance of magnesium and the positive effects of magnesium supplementation are extensively documented in magnesium deficiency, e.g., cardiovascular disease and diabetes mellitus. The effectiveness of oral magnesium supplementation for the treatment of magnesium deficiency has been studied in detail. However, the proven and well-documented oral magnesium supplementation has become questioned in the recent years through intensive marketing for its transdermal application (e.g., magnesium-containing sprays, magnesium flakes, and magnesium salt baths). In both, specialist and lay press as well as on the internet, there are increasing numbers of articles claiming the effectiveness and superiority of transdermal magnesium over an oral application. It is claimed that the transdermal absorption of magnesium in comparison to oral application is more effective due to better absorption and fewer side effects as it bypasses the gastrointestinal tract. PMID:28788060

High-dose transdermal nicotine replacement for tobacco cessation.

PubMed

Brokowski, Laurie; Chen, Jiahui; Tanner, Sara

2014-04-15

The safety and efficacy of high-dose transdermal nicotine-replacement therapy (NRT) for the treatment of tobacco-use cessation were reviewed. Transdermal nicotine doses of 7, 14, and 21 mg daily are approved by the Food and Drug Administration for use in tobacco cessation. However, studies have suggested that these doses are more adequate for people who smoke fewer than 20 cigarettes per day. A literature search was conducted to identify English-language studies that evaluated the use of transdermal nicotine doses of ≥42 mg daily. A total of 11 articles were identified, representing 10 separate trials. In terms of safety, the majority of the trials had no reports of serious adverse events related to transdermal NRT at doses of ≥42 mg daily. A dose-response relationship with adverse events occurred in most trials. In terms of efficacy, a numerically higher abstinence rate was achieved with high-dose transdermal NRT in all trials but 1. However, none of the studies showed significant differences in final abstinence rates at follow-up. Some reasons why statistical significance was not achieved in these trials may be related to the limitations of these trials, such as their small samples and the lack of a power calculation. A more robust trial is needed to support higher nicotine transdermal doses in tobacco cessation and to help elucidate which patient population would be most suitable for their use. The safety and efficacy of high-dose transdermal NRT for tobacco cessation have not been established in the medical literature.

Recent trends in the transdermal delivery of therapeutic agents used for the management of neurodegenerative diseases.

PubMed

Ita, Kevin

2017-06-01

With the increasing proportion of the global geriatric population, it becomes obvious that neurodegenerative diseases will become more widespread. From an epidemiological standpoint, it is necessary to develop new therapeutic agents for the management of Alzheimer's disease, Parkinson's disease, multiple sclerosis and other neurodegenerative disorders. An important approach in this regard involves the use of the transdermal route. With transdermal drug delivery systems (TDDS), it is possible to modulate the pharmacokinetic profiles of these medications and improve patient compliance. Transdermal drug delivery has also been shown to be useful for drugs with short half-life and low or unpredictable bioavailability. In this review, several transdermal drug delivery enhancement technologies are being discussed in relation to the delivery of medications used for the management of neurodegenerative disorders.

Transdermal flunixin meglumine minimally alters neutrophil functionality in beef heifers administered a respiratory disease challenge

USDA-ARS?s Scientific Manuscript database

The objectives were to determine the effects of altering time of transdermal flunixin meglumine (BTD; Banamine Transdermal, Merck Animal Health) administration relative to a viral-bacterial challenge in beef heifers. Thirty-two heifers (170 ± 21.1 kg BW) were assigned to one of four treatments: 1) C...

Acute metabolic responses to a combined viral-bacterial respiratory disease challenge in heifers administered transdermal flunixin meglumine

USDA-ARS?s Scientific Manuscript database

A trial was conducted to determine effects of altering time of transdermal flunixin meglumine (BTD; Banamine Transdermal, Merck Animal Health, Summit, NJ) administration relative to a viral-bacterial respiratory disease challenge in beef heifers. Thirty-two healthy heifers (170±21.1 kg BW) were assi...

Turning theory into practice: the development of modern transdermal drug delivery systems and future trends.

PubMed

Perumal, O; Murthy, S N; Kalia, Y N

2013-01-01

Despite its remarkable barrier function, the skin remains an attractive site for systemic drug delivery given its easy accessibility, large surface area and the possibility to bypass the gastrointestinal tract and the liver and so modify drug absorption kinetics. The pioneering work of Scheuplein, Higuchi and others in the 1960s helped to explain the processes involved in passive percutaneous absorption and led to the development of mathematical models to describe transdermal drug delivery. The intervening years have seen these theories turned to practice and a significant number of transdermal systems are now available including some that employ active drug delivery. This review briefly discusses the evolution of transdermal therapeutic systems over the years and the potential of newer transdermal technologies to deliver hydrophilic drugs and macromolecules through the skin. © 2013 S. Karger AG, Basel.

Self-reported and verified compliance in a phase 3 clinical trial of a novel low-dose contraceptive patch and pill.

PubMed

Kaunitz, Andrew M; Portman, David; Westhoff, Carolyn L; Archer, David F; Mishell, Daniel R; Foegh, Marie

2015-03-01

Pregnancy rates in US contraceptive clinical trials are increasing due to decreased treatment compliance. This study compared compliance with a new low-dose levonorgestrel (LNG) and ethinyl estradiol (EE) contraceptive patch (CP, Twirla™) with that of a low-dose combination oral contraceptive (COC) in a demographically diverse population. This analysis was part of an open-label, parallel-group, multicenter phase 3 study that randomized healthy sexually active women (17-40years) to 13cycles of LNG/EE CP or 6cycles of COC, then 7cycles of LNG/EE CP. We defined self-reported compliance as cycles that, according to diaries, show 21days of patch wear without missed days or any patch worn >7days or 21days of pill-taking without missed pill days. We verified compliance by detectable plasma presence of LNG and EE at cycles 2, 6, and 13. Of the intention-to-treat population with diary information (N=1328, mean age 26.4years, 46% minorities, 33% obese), 10.0% of the CP (n=998) versus 21.2% of the COC group (n=330) self-reported noncompliance after 6cycles (p<.001). Laboratory assessments verified 10-14% of participants in both groups as noncompliant. Self-reported perfect use did not vary between obese [body mass index (BMI) ≥30kg/m(2)] versus nonobese (BMI <30kg/m(2)) participants in both groups or when stratified by age, education, or race/ethnicity in the CP group. Self-reported compliance was significantly greater in the CP than COC group and did not vary by obesity status. Discrepancies between self-reported and verified compliance question reliability of patient diaries. This paper, based on an analysis of a phase 3 trial, shows that compliance was significantly greater with a new weekly transdermal CP than with a once-daily COC in obese as well as nonobese participants. Discrepancies between self-reported compliance and laboratory-verified compliance raise questions regarding the reliability of patient diaries. Copyright © 2015 Elsevier Inc. All rights reserved.

Acute immunological responses to a combined viral-bacterial respiratory disease challenge in heifers administered transdermal flunixin meglumine

USDA-ARS?s Scientific Manuscript database

Time of flunixin meglumine transdermal (FTD; Finadyne Transdermal, Merck Animal Health, Summit, NJ) administration relative to a viral-bacterial challenge was evaluated in beef heifers. Thirty-two beef heifers (170 ± 21.1 kg BW) were randomly assigned to one of four treatments: 1) Control (CON), rec...

Transdermal nitroglycerin for the treatment of preterm labor: a systematic review and metaanalysis.

PubMed

Conde-Agudelo, Agustín; Romero, Roberto

2013-12-01

The purpose of this study was to evaluate the efficacy and safety of transdermal nitroglycerin as a tocolytic agent in women with preterm labor. We conducted a systematic review and metaanalysis of randomized controlled trials. Thirteen studies were included (1302 women) comparing transdermal nitroglycerin vs placebo (2 studies; n = 186); β2-adrenergic receptor agonists (9 studies; n = 1024); nifedipine (1 study; n = 50); and magnesium sulfate (1 study; n = 42). There were no significant differences between transdermal nitroglycerin and placebo for delivery within 48 hours of the initiation of treatment or at <28, <34, or <37 weeks of gestation, adverse neonatal outcomes, and neurodevelopmental status at 24 months of life. Nevertheless, 1 study found a marginally significant reduction in the risk of a composite outcome of major neonatal morbidity and perinatal death (3/74 [4.1%] vs 11/79 [13.9%]; relative risk, 0.29; 95% confidence interval, 0.08-1.00). When compared with β2-adrenergic receptor agonists, transdermal nitroglycerin was associated with a significant reduction in the risk of preterm birth at <34 and <37 weeks of gestation, admission to the neonatal intensive care unit, use of mechanical ventilation, and maternal side effects. There were no significant differences between transdermal nitroglycerin and nifedipine and magnesium sulfate in delivery within 48 hours of treatment and pregnancy prolongation, respectively. Overall, women who received transdermal nitroglycerin had a higher risk of headache. Although transdermal nitroglycerin appears to be more effective than β2-adrenergic receptor agonists, the current evidence does not support its routine use as a tocolytic agent for the treatment of preterm labor. Further double-blind placebo-controlled trials are needed. Copyright © 2013 Mosby, Inc. All rights reserved.

Pharmacokinetic characteristics of formulated alendronate transdermal delivery systems in rats and humans.

PubMed

Choi, Ahyoung; Gang, Hyesil; Whang, Jiae; Gwak, Hyesun

2010-05-01

The objective of this study was to examine the absorption of alendronate from formulated transdermal delivery systems in rats and humans. When alendronate was applied to rats by transdermal delivery systems (7.2 mg) and oral administration (30 mg/kg), a statistically significant difference was found in the amount remaining to be excreted at time t (Ae(t)) and the amount remaining to be excreted at time 0 (Ae(infinity)) (p < 0.01). The highest Ae(infinity) (1267.7+/-65.2 ng) was found in the formulation containing 6% caprylic acid in propylene glycol (PG), which was 5.4- and 2.0-times higher than the PG only formulation and oral administration, respectively. Compared to oral administration, significantly delayed half-life values were obtained from all the formulated transdermal delivery systems. There was a linear relationship (r(2) = 0.9854) between the drug loading dose and Ae(infinity). The Ae(infinity) values from the transdermal delivery system containing 6% caprylic acid (53.8 mg as alendronate) and an oral product (Fosamax), 70 mg as alendronate) in humans were 127.0 +/- 34.2 microg and 237.2 +/- 56.3 microg, respectively. The dose-adjusted relative Ae(infinity) ratio of the transdermal delivery system to oral product was calculated to be 69.7%. The long half-life of alendronate in the transdermal delivery system (50.6 +/- 6.4 h), compared to that of the oral product (3.5 +/- 1.1 h) could allow less-frequent dosing. In conclusion, this study showed that a transdermal delivery system containing 6% caprylic acid in PG could be a favorable alternative for alendronate administration.

3D printing applications for transdermal drug delivery.

PubMed

Economidou, Sophia N; Lamprou, Dimitrios A; Douroumis, Dennis

2018-06-15

The role of two and three-dimensional printing as a fabrication technology for sophisticated transdermal drug delivery systems is explored in literature. 3D printing encompasses a family of distinct technologies that employ a virtual model to produce a physical object through numerically controlled apparatuses. The applicability of several printing technologies has been researched for the direct or indirect printing of microneedle arrays or for the modification of their surface through drug-containing coatings. The findings of the respective studies are presented. The range of printable materials that are currently used or potentially can be employed for 3D printing of transdermal drug delivery (TDD) systems is also reviewed. Moreover, the expected impact and challenges of the adoption of 3D printing as a manufacturing technique for transdermal drug delivery systems, are assessed. Finally, this paper outlines the current regulatory framework associated with 3D printed transdermal drug delivery systems. Copyright © 2018 Elsevier B.V. All rights reserved.