Cai, Bing; Engqvist, Håkan; Bredenberg, Susanne
With the increasing number of misuse and abuse of opioids, the resistance to tampering becomes an important attribute for transdermal opioid patches. In this study, drug-containing geopolymer granules were integrated into an adhesive matrix to improve the resistance of fast drug release against some common abuse techniques. Bench testing showed that fentanyl loaded geopolymer granules had better resistance to tampering compared to a commercial fentanyl patch. Moreover, in a pilot in vivo study on a few rats, the granules showed potential to give similar drug plasma concentrations as the commercial fentanyl patch. After integrating geopolymer granules into an adhesive matrix, the new patch showed a better resistance against the investigated tampering tests compared with the commercially available patch. In this study, we showed that incorporating drug loaded geopolymer granules into a patch adhesive has potential to improve the resistance of the fentanyl patch against tampering without compromising the drug release.
Romualdi, Patrizia; Santi, Patrizia; Candeletti, Sanzio
The efficacy of transdermal fentanyl for cancer pain and chronic non-cancer pain (chronic lower back pain, rheumatoid arthritis, osteoarthritis, neuropathic pain) is well established. Several formulations of fentanyl transdermal systems have been developed to improve the drug delivery and prevent misuse of the active principle. The addition of a rate controlling membrane to the matrix system represented an important advance. The design and functional features of Alghedon patch are compared with other approved generic fentanyl transdermal systems, emphasizing the distinctiveness of Alghedon patch. Alghedon patch has no liquid component in the finished product, therefore no leakage of active ingredient from the system can occur. A rate-controlling membrane provides controlled release of the active substance from the matrix reservoir, ensuring that fentanyl delivery and entry into the microcirculation is not solely controlled by the skin's permeability to this active substance. Alghedon patch contains part of the drug (approximately 15%) in the skin-contact adhesive: this innovative solution allows to overcome a typical drawback of transdermal patches, i.e. the long lag-time before the drug appears in plasma after the first administration, and provides rapid analgesia during the first hours of administration. Alghedon Fentanyl Transdermal System employs materials commonly used in other transdermal applications and having established safety profiles. For each strength level, the fentanyl content - and, thus, the resulting residual fentanyl remaining in the patch after use - is at the lowest end of the range used in commercially available fentanyl patches, minimizing the potential for abuse and misuse.
Vasovic, Miroslav; Andric, Miroslav; Todorovic, Ljubomir; Kokovic, Vladimir
Background Surgical removal of impacted lower third molars is a common oral surgical procedure, generally followed by moderate to severe postoperative pain. Transdermal drug delivery as a concept offers interesting possibilities for postoperative pain control. The aim of this study was to evaluate the efficacy of transdermal system with fentanyl in relieving pain following impacted lower third molar surgery. Material and Methods Seventeen patients with bilateral impacted lower third molars were included in this preliminary study. For postoperative pain control, patients randomly received a fentanyl patch plus placebo tablet after the first operation and regular (placebo) patch and an analgesic, after the second operation. Analgesia was evaluated during first 24 hours postoperatively according to patients’ reports about time of first pain appearance and additional analgesic consumption. Pain severity was rated using a 10 cm long visual analogue scale (VAS). Results Intensity of postoperative pain and postoperative analgesic consumption were significantly lower after the Fentanyl Transdermal System (FTS) was applied (p<0.05). Duration of postoperative analgesia was significantly higher with FTS when compared to control treatment (p<0.05). Conclusions Based on the results of this preliminary study, transdermal system with fentanyl significantly reduced postoperative pain after third molar surgery. Key words:Analgesia, fentanyl, transdermal administration, third molar surgery, acute pain, postoperative care. PMID:27475691
Bista, Sudeep R; Haywood, Alison; Hardy, Janet; Norris, Ross; Hennig, Stefanie
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.
Pawasauskas, Jayne; Perdrizet, George
Hyperbaric oxygen therapy (HBOT) is a treatment for a variety of conditions, particularly nonhealing wounds. The treatment requires the inhalation of pure oxygen in a sealed chamber that is pressurized to 1.5 to 3 times that of normal atmospheric pressure. HBOT safety protocols require all transdermal products to be removed prior to entrance into the hyperbaric chamber, and many institutional policies state that removed patches are not to be reapplied. Limited data are available regarding the use of transdermal fentanyl patches in patients undergoing HBOT. For such patients, the patch would need to be changed on a daily basis. Although the recommended dosing interval is 72 hours, many references discuss the use of 48-hour intervals in select patients, and no published reference recommends dosing intervals shorter than 48 hours. The authors evaluated the clinical safety and efficacy parameters for two patients receiving daily application of transdermal fentanyl while receiving HBOT. Patient 1 was a 47-year-old female with diabetes mellitus, sepsis, and left foot wound with toe necrosis. Complicating her management was the presence of chronic pain syndrome secondary to fibromyalgia. Patient 2 was a 70-year-old female with paralysis secondary to spinal fracture who presented with a stage IV sacral pressure ulcer, who was later diagnosed with osteomyelitis. Both patients were successfully managed with daily application of fentanyl transdermal patch.
Bakovic, Marija; Nestic, Marina; Mayer, Davor
We present a case of fatal intoxication by the application of a transdermal fentanyl patch upon a superficial bleeding abrasion of a 2-year-old girl. The grandmother discovered the body of the child in bed at approximately 7 a.m. External examination revealed a properly developed, nourished, and hydrated child, with some vomit in the nostrils and inside the mouth. There was no evidence of trauma besides small contusions and abrasions on the knees, with a patch placed over the largest abrasion. Closer inspection revealed that this was transdermal fentanyl patch. Internal examination and microscopic analysis revealed regurgitation of stomach content, cerebral and pulmonary edema, and liver congestion. Toxicology analysis revealed trace levels of fentanyl in the blood just above the limit of detection (2 ng/mL), while concentrations in the urine, liver, and kidney were approximately 102, 28, and 10 ng/mL, respectively. Investigation discovered that the child injured her knee while playing the evening before. The grandmother applied the patch to cover the injury, unaware that she had used a fentanyl transdermal patch instead of simple band-aid. Although fatal intoxications are uncommon among young children in high-income countries, it is of major interest to raise awareness of such events especially since a great majority of these are preventable. The presented case points at the need for more thorough education of users and more strict rules in prescribing and handling of this potent medicine. As well, we find this case to be a useful contribution to the evaluation of postmortem fentanyl concentrations in fatal intoxication in a small child.
Koike, Kazuhiko; Terui, Takeshi; Nagasako, Tomokazu; Horiuchi, Iori; Machino, Takayuki; Kusakabe, Toshiro; Hirayama, Yasuo; Mihara, Hiroyoshi; Yamakage, Michiaki; Kato, Junji; Nishisato, Takuji; Ishitani, Kunihiko
The recommended dosing interval for transdermal fentanyl is every 72 h. However, some patients will have "end-of-dose failure," which may be seen as an increase of episodes of severe pain flares at the third day after application of the patch. A new once-a-day fentanyl patch was developed in Japan since 2010. This study aimed to assess the efficacy of the once-a-day fentanyl citrate patch for patients with cancer-related pain receiving the 72-h transdermal fentanyl not lasting 72 h. We performed a cross-sectional retrospective analysis of 445 inpatients with the 72-h transdermal fentanyl at Higashi Sapporo Hospital. We could switch to the once-a-day fentanyl citrate patch if patients reported inadequate pain relief beyond 48 h after application of the 72-h transdermal fentanyl. Patients recorded baseline scores for background pain intensity (PI) and the frequency of use of daily rescue medication for breakthrough cancer pain (BTcP). Of all patients, 10.1% showed the increase in PI of 30% or more baseline PI on the third day after application of the 72-h transdermal fentanyl. Of patients, 84.4% were converted from equivalent dose of the 72-h transdermal fentanyl to the once-a-day fentanyl citrate patch. On the third day after switching, 60.5% of patients showed a reduction of more than 30% from baseline PI. Switching to the once-a-day fentanyl citrate patch significantly reduced the mean frequency of daily rescue dose for BTcP. A once-a-day fentanyl citrate patch provided stable pain control. Its use may be considered as the dominant strategy for patients receiving a 72-h transdermal fentanyl not lasting 72 h.
Pekcan, Zeynep; Koc, Bahattin
To investigate the analgesic and side effects of epidural morphine or a fentanyl patch after ovariohysterectomy in dogs. Prospective, randomized clinical study. Twenty female mongrel dogs undergoing ovariohysterectomy. The dogs were allocated to one of two groups: epidural morphine or transdermal fentanyl patch. Anaesthesia was induced with propofol and maintained with isoflurane. Morphine (0.1 mg kg(-1)) was administered epidurally in the epidural morphine group and a transdermal fentanyl patch was applied 24 hours before the operation in the fentanyl patch group. The heart rate, respiratory rate, body temperature, plasma cortisol concentration, and sedation and analgesia scores were recorded during the 24 hour post-operative period. Adverse effects such as vomiting, anorexia, skin reactions, urinary retention, and time to start licking the surgical site were also recorded. p<0.05 was considered significant. Statistical analyses utilized anova for repeated measures, Friedman tests, Mann-Whitney U-tests and independent sample t-tests as relevant. Pain scores were lower in the epidural group than in the fentanyl group at all post-operative times. The dogs in the epidural morphine group were calm and relaxed, whereas discomfort and vocalization were recorded in the fentanyl patch group. The sedation scores were higher in the fentanyl patch group throughout the 12 hour period. Salivation and anorexia lasted longer in the fentanyl patch group than in the epidural morphine group. Plasma cortisol concentrations were high in the early post-operative period in both groups. The fentanyl patch group had higher cortisol concentrations than the epidural morphine group. Slight erythema was recorded in two dogs when the patches were removed. Epidurally administered morphine provided better analgesia and caused fewer adverse effects than the fentanyl patch after ovariohysterectomy in dogs. © 2010 The Authors. Veterinary Anaesthesia and Analgesia © 2010 Association of Veterinary
Sindali, Katia; Sherry, Katie; Sen, Sankhya; Dheansa, Baljit
Fentanyl transdermal patches have been widely used in the treatment of chronic pain and in palliative care settings since 1991 in cases where prolonged opioid use is often necessary. Transdermal drug delivery is deemed safe and effective with the advantages of delivering a steady dose of the drug and improving patient compliance due to its ease of use. However, intentional and unintentional misuse and overdose using transdermal opioid patches has been widely reported in the literature. We describe the case of a 77-year-old Caucasian woman who developed severe opioid toxicity while sun tanning, likely due to altered fentanyl transdermal patch function in a heated environment. As a result of prolonged sun exposure due to an opioid-induced coma she then sustained hyperthermia and severe burns to her abdomen and lower limbs. This inadvertent fentanyl overdose necessitated initial treatment in intensive care and follow on care in a specialist burn unit. Patients who are using fentanyl patches and their relatives should be educated about how to use the patch safely. Healthcare practitioners should warn patients about the possibility of overdosing on transdermally delivered drugs if used incorrectly. They should avoid strenuous activities and external heat sources such as warming blankets, hot water bottles, saunas, hot tubs or sunbathing and should seek medical attention if they develop a fever. Additionally, any burns sustained in the context of altered consciousness levels such as in this case with opioid overdose should raise suspicion about a potential deeper burn injury than is usually observed.
Van Nimmen, Nadine F J; Veulemans, Hendrik A F
The method development and validation characteristics are described of a simple gas chromatographic-mass spectrometric (GC-MS) analytical procedure to determine residual fentanyl in used Durogesic reservoir patches and Durogesic D-Trans matrix technology based systems to estimate the actual rate of transdermal fentanyl delivered in individual patients. The sample preparation protocol constituting a saline based extraction of sets of new patches of each nominal dose available, resulted in fentanyl extraction recoveries to increase steadily as a function of increasing extraction time. For the reservoir type transdermal therapeutic system (TTS), fentanyl extraction efficiencies at equilibrium (16 h) ranged from approximately 60% (100-microg/h TTS) to 95% (25-microg/h TTS), whereas for the matrix type system considerable lower recoveries were demonstrated for the highest nominal dose rates (35%-52%), while reaching 90% for the 25-microg/h system. For the latter type of fentanyl TTS, an optimized methanol based extraction protocol yielded virtually quantitative fentanyl recoveries for each matrix patch nominal dose level at substantially shorter extraction periods (15 min). The GC-MS analytical method using selected ion monitoring (SIM) and deuterated fentanyl as internal standard was shown to be adequately selective with regard to the presence of other compounds in the Durogesic patches. It was further demonstrated that the developed analytical protocols provided highly reproducible and accurate estimates of the initial fentanyl content of each patch type at all available nominal doses, with coefficients of variation and relative errors generally below 10%. These advantageous assay validation characteristics can be further transposed to the application of residual fentanyl level estimates in used patches, provided that with each batch of samples also a set of new TTSs with equal dose is assayed to perfectly mimic extraction phenomena. Finally, the presented GC
Cummings, Oneka T; Enders, Jeffrey R; McIntire, Gregory L; Backer, R; Poklis, A
Poklis and Backer published a survey of the concentrations of fentanyl and norfentanyl that could be expected in urine from patients using Duragesic(®), a transdermal fentanyl patch. That study employed a relatively small number of patient data points and analysis by Gas Chromatography/Mass Spectrometry. This work examines a larger population of patient positives for fentanyl and norfentanyl to determine whether more than a decade later the original report remains accurate in predicting the range and median levels of fentanyl and norfentanyl concentrations physicians can expect to see from their patients. Additionally, these data were transformed to develop a model that results in a near Gaussian distribution of urine drug test results. This retrospective approach was developed to transform and normalize urine drug testing results to provide a historical picture of expected patient values for this important analgesic. The resulting near Gaussian distribution is dose independent and as such should be of value to physicians in quickly assessing whether their patient is consistent with this historical population in the broad terms of this model. While this comparison alone is not definitive for adherence with a treatment regimen, together with patient interviews, prescription history and other clinical criteria, it can add an idea of expected patient values from urine drug testing. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: firstname.lastname@example.org.
Fentanyl is considered to be an effective, transdermal treatment of chronic, cancer, and noncancer pain. This noninterventional, clinical practice-based study, on 426 patients attending 42 practices, assessed a proprietary, Aloe vera-containing, transdermal fentanyl matrix patch (Fentavera), for its analgesic effects, patients' quality of life (QoL) effects, tolerability, and adhesiveness. Study outcomes were mean changes from baseline of patient (11-point scales) and physician (5-point scales) ratings. After 1 and 2 months treatment, there were significant (P < 0.0001) decreases in patients' ratings of pain intensity, and impairment of walking, general activity, sleep quality, and QoL. For each parameter, the patient response rate was >30% at 2 months (response = 2-point decrease on 11-point rating scale). In a large majority of patients, the physicians rated the matrix patch as good or very good for analgesic effect, systemic and local tolerance, and adhesiveness. There were 30 adverse events in 4.2% of patients and analgesic comedications were reduced during treatment compared to before treatment. It is concluded, from this population-based data, that the proprietary, transdermal fentanyl matrix patch is effective and safe for chronic pain management in clinical practice, with significant positive analgesic and QoL effects, while being well tolerated and exhibiting good or very good adhesiveness. PMID:25861472
Mücke, M; Conrad, R; Marinova, M; Cuhls, H; Elsner, F; Rolke, R; Radbruch, L
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.
Calis, K A; Kohler, D R; Corso, D M
The physicochemical properties, pharmacology, pharmacokinetics, serum concentrations and clinical effects, adverse effects and contraindications, and dosage of transdermally administered fentanyl are described, and clinical studies evaluating the use of a transdermal fentanyl system in the treatment of postoperative pain and chronic cancer-associated pain are reviewed. After application of a transdermal system, fentanyl is absorbed into the skin beneath the patch, where a depot forms in the upper skin layers. Plasma fentanyl concentrations are barely detectable for about two hours after patch placement. Eight to 12 hours after patch placement, concentrations approximate those achieved with equivalent i.v. doses of fentanyl. Some studies comparing transdermally administered fentanyl with placebo in postoperative patients showed that the patients who received fentanyl required fewer supplementary analgesics and reported less pain than the patients who received placebo. However, the overall efficacy and safety of the transdermal fentanyl system for the treatment of postoperative pain have not been adequately evaluated. Studies of cancer patients showed that transdermally administered fentanyl appears to be effective in the management of chronic, cancer-related pain. Dermatological reactions to the fentanyl patch are generally transient and mild. Other adverse effects are those that are commonly associated with narcotic analgesics. The 25-micrograms/hr patch should be used for initial treatment in patients not previously treated with narcotics. The dosage may be gradually increased until effective analgesia is obtained. Although experience with the product is limited, transdermally administered fentanyl appears to be effective for the long-term management of cancer-related pain.
Heiskanen, Tarja; Mätzke, Sorjo; Haakana, Soile; Gergov, Merja; Vuori, Erkki; Kalso, Eija
Fentanyl is an opioid with high lipid solubility, suitable for intravenous, spinal, transmucosal and transdermal administration. The transdermal fentanyl patch has become widely used in the treatment of both malignant and non-malignant chronic pain. The absorption of fentanyl from the patch is governed by the surface area of the patch, by skin permeability and by local blood flow. The aim of this study is to find out whether absorption of fentanyl in cachectic patients with cancer-related pain is different from that of normal weight cancer patients. We recruited ten normal weight (mean body mass index (BMI) 23 kg/m(2)) and ten cachectic (mean BMI 16 kg/m(2)) cancer pain patients. A transdermal fentanyl patch with a dose approximately equianalgesic to the patients' previous opioid dose was administered to the upper arm of the patient for 3 days. Prior to patch application, the height, weight and BMI of the patient, as well as upper arm skin temperature, local sweating, thickness of skin fold and local blood flow were measured. Plasma fentanyl concentrations were analyzed from blood samples taken at baseline, 4, 24, 48 and 72 h. Plasma fentanyl concentrations adjusted to dose were significantly lower at 48 and 72 h in cachectic patients than normal weight patients. The cachectic patients had a significantly thinner upper arm skin fold, but no differences were found in local blood flow, sweating, or skin temperature. Absorption of transdermal fentanyl is impaired in cachectic patients compared with that of normal weight cancer pain patients.
Arnet, Isabelle; Schacher, Sabrina; Balmer, Eva; Koeberle, Dieter; Hersberger, Kurt E
Renewal of fentanyl transdermal patch (transdermal therapeutic system [TTS]) should occur every 3 days (72 hours) according to manufacturer's guidelines. Some studies mentioned patients reporting end-of-dose failure, and thus, some authors recommend shortening the interval of application to 2 days (48 hours). However, reasons for early replacement are mostly unknown. The objectives of this study were to assess the prevalence of early replacement of fentanyl TTS in a cancer center in Basel, Switzerland, and to assess the reasons for early replacement in stationary patients. We retrieved all fentanyl TTS administered in a cancer center in Basel, Switzerland, between November 11, 2011, and January 31, 2015, from the electronic medical database. A total of 739 patients (mean age 71.4±11.5 years, 55% women) were administered 2,250 fentanyl TTS (dosage 6-500 µg/hour). Most replacements occurred after 72 hours (61.6%) and a few after 48 hours (7.4%). Patients with early replacement after 48 hours were significantly younger (63.8 years versus 71.5 years, p<0.001) and obtained higher mean dosages of fentanyl TTS (89 µg/hour versus 44.1 µg/hour, p<0.001) and rescue medication (calculated as oral morphine equivalent in milligrams: 185.1 mg versus 39.6 mg during the first 24 hours after replacement, p<0.001). No pharmacological rationale for early replacement was observed. According to 57 physicians, nurses, and pharmacists, the most often reasons for early TTS replacement were end-of-dosage pain (41.4%) and poor adhesion (31.4%). In the absence of any physiological, pharmacological, or environmental reasons recorded in the database to explain an early replacement of fentanyl TTS, skin adhesion problems may point practical reasons and mimic end-of-dosage failure.
Arnet, Isabelle; Schacher, Sabrina; Balmer, Eva; Koeberle, Dieter; Hersberger, Kurt E
Context Renewal of fentanyl transdermal patch (transdermal therapeutic system [TTS]) should occur every 3 days (72 hours) according to manufacturer’s guidelines. Some studies mentioned patients reporting end-of-dose failure, and thus, some authors recommend shortening the interval of application to 2 days (48 hours). However, reasons for early replacement are mostly unknown. Objectives The objectives of this study were to assess the prevalence of early replacement of fentanyl TTS in a cancer center in Basel, Switzerland, and to assess the reasons for early replacement in stationary patients. Methods We retrieved all fentanyl TTS administered in a cancer center in Basel, Switzerland, between November 11, 2011, and January 31, 2015, from the electronic medical database. Results A total of 739 patients (mean age 71.4±11.5 years, 55% women) were administered 2,250 fentanyl TTS (dosage 6–500 µg/hour). Most replacements occurred after 72 hours (61.6%) and a few after 48 hours (7.4%). Patients with early replacement after 48 hours were significantly younger (63.8 years versus 71.5 years, p<0.001) and obtained higher mean dosages of fentanyl TTS (89 µg/hour versus 44.1 µg/hour, p<0.001) and rescue medication (calculated as oral morphine equivalent in milligrams: 185.1 mg versus 39.6 mg during the first 24 hours after replacement, p<0.001). No pharmacological rationale for early replacement was observed. According to 57 physicians, nurses, and pharmacists, the most often reasons for early TTS replacement were end-of-dosage pain (41.4%) and poor adhesion (31.4%). Conclusion In the absence of any physiological, pharmacological, or environmental reasons recorded in the database to explain an early replacement of fentanyl TTS, skin adhesion problems may point practical reasons and mimic end-of-dosage failure. PMID:27877065
Lilleng, Peer K; Mehlum, Lars Ivar; Bachs, Liliana; Morild, Inge
Fentanyl is a potent synthetic opioid used as a general anesthetic and analgetic. Fatal outcome from intravenous misuse of transdermal fentanyl is rare, and there are few such reports in literature. Here we report two cases of fatal intravenous injection of the content from fentanyl patches. Both were male drug addicts, found dead within a one week interval in the same apartment. Post-mortem femoral blood was screened for amphetamines, cannabinoids, cocaine, and opioids with immunological methods (EMIT II) and further with headspace gas chromatography for alcohol and with liquid chromatography mass spectrometry (LC-MS) for different drugs, including fentanyl. Confirmatory analysis of fentanyl and morphine was performed by gas chromatography-mass spectrometry (GC-MS). In the first case, the toxicological analysis revealed fentanyl (2.7 ng/mL), morphine (31.4 ng/mL), and ethanol (1.1 g/L) in postmortem blood and amphetamine, cannabinoids, morphine, and ethanol (1.4 g/L) in postmortem urine. In the second case, the analysis revealed fentanyl (13.8 ng/mL), 7-aminoclonazepam (57.1 ng/mL), and sertralin (91.9 ng/mL) in postmortem blood and a small amount of ethanol (0.1 g/L) in postmortem urine. Police investigation revealed that both the deceased had bought the patches from the same source. The present cases demonstrate the possibility of intravenous misuse of transdermal patches and the risk of fatal outcome.
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 ...
Takahashi, Hiroaki; Chiba, Takeshi; Tairabune, Tomohiko; Kimura, Yusuke; Wakabayashi, Go; Takahashi, Katsuo; Kudo, Kenzo
It is unknown whether nutritional status influences pain intensity in cancer patients receiving a transdermal fentanyl patch (FP). This study aimed to determine whether nutritional status is associated with pain intensity and to evaluate the influence of changes in nutritional status on pain intensity in cancer patients receiving transdermal FP treatment. We included 92 patients receiving transdermal FP treatment for the first time with switching from oxycodone. The patients were classified into low- and normal-nutrition groups based on their nutritional status, which was assessed according to the Nutrition Risk Screening 2002 (NRS 2002) parameters. The pain intensity of each patient was evaluated by a numeric rating scale (11-point scale from 0 to 10). NRS 2002 score and pain intensity were obtained on day 3 after the FP was applied to the skin. Pain intensities were significantly higher among patients in the low-nutrition group than among patients in the normal-nutrition group. NRS 2002 scores showed a significant positive correlation with the pain intensities. In 52 of 92 patients, who were evaluated using the NRS 2002 score and pain intensity on day 30 after FP application, the changes in NRS 2002 scores were significantly related to changes in pain intensities (odds ratio, 30.0; 95% confidence interval, 4.48-200.97; p=0.0005). These results suggest that an increase in the NRS 2002 score is a risk factor for an increase in pain intensity in cancer patients receiving FP treatment. Malnutrition may lead to poor pain management in cancer patients receiving FP treatment.
... that causes difficulties with movement, muscle control, and balance) including shaking of parts of the body, stiffness, slowed movements, and problems with balance. Rotigotine transdermal patches are also used to treat ...
... dextromethorphan (found in many cough medications; in Nuedexta); lithium (Lithobid); medications for migraine headaches such as almotriptan ( ... pressure; or thyroid, heart, liver, pancreas, gallbladder, or kidney disease.tell your doctor if you are breastfeeding.you ...
Carlson, Amy M; Kelly, Richard; Fetterer, David P; Rico, Pedro J; Bailey, Emily J
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
Delaski, Kristina M; Gehring, Ronette; Heffron, Brendan T; Negrusz, Adam; Gamble, Kathryn C
Providing appropriate analgesia is an important concern in any species. Fentanyl, a μ-receptor specific opioid, use is common in mammalian species but has been incompletely evaluated for this purpose in avian species. Transdermal fentanyl patches were applied to domestic chickens (n = 10) of varying breeds for 72 hours. Repeated blood samples were collected from the birds to assess time-concentration of fentanyl and norfentanyl in plasma, as assayed by liquid chromatography-mass spectrometry, throughout patch application and for 48 hours after patch removal. Compartmental modeling was used to characterize the elimination profiles. Evaluation as a large bolus, followed by slower elimination rates over the remaining time, best fit the data as a one-compartment open model. Although maximum plasma fentanyl concentrations varied substantially by individual birds, chickens trended into 2 general groups of maximum plasma concentration, clearance, and volume of distribution, which was attributed to absorption variability. For all birds, harmonic mean of elimination half-life was 7.2 ± 3.7 hours and showed less individual variation than the other pharmacokinetic parameters. Because the application of transdermal fentanyl patches in the chickens achieved plasma fentanyl concentrations considered therapeutic in people, this approach could provide an additional analgesic option for avian patients.
Friesen, Kevin J; Woelk, Cornelius; Bugden, Shawn
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. 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. 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). 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. © 2016 Canadian Medical Association or its licensors.
Friesen, Kevin J.; Woelk, Cornelius; Bugden, Shawn
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
Christou, Chris; Oliver, Rema A; Rawlinson, John; Walsh, William R
Fentanyl delivered via a transdermal patch has the potential to decrease the need for post-operative handling of sheep undergoing surgical procedures. Two studies were performed to test: (1) the ideal timing for the application of pre-emptive analgesic patches and (2) the efficacy of a 2 µg/kg/h dose, as extrapolated from other species. The first study had sheep divided into two groups. Group 1 had a fentanyl patch applied for 24 h prior to a patch change and group 2 had a fentanyl patch applied 72 h prior to a change. The second study applied the results obtained in the first and tested the efficacy of 2 µg/kg/h as an effective dose in an orthopaedic surgical environment. Results indicated that the ideal time for pre-emptive fentanyl patch administration is 24-36 h prior to surgery and that 2 µg/kg/h is an effective minimum therapeutic dose rate for the use of fentanyl as an analgesic in an orthopaedic surgical environment.
Juebner, Martin; Fietzke, Mathias; Beike, Justus; Rothschild, Markus A; Bender, Katja
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.
[Validity of recommended minimum dose of prior morphine to initiate transdermal fentanyl patch in prescribing information - multicenter survey of on prescriptions by palliative care specialists in Japan].
Hashizume, Takahiro; Tomiyasu, Shiro; Yomiya, Kinomi; Yoshimoto, Tetsusuke; Harada, Akiko; Matoba, Motohiro
For initiating the minimum-size (0.25 microg/hour) transdermal fentanyl patch (TDF), 45 mg a day of oral morphine is the recommended minimum dose (RMD) in Japan according to the prescribing information. However, little is known about the validity of the RMD, and we can presume there are many cases where clinicians are inclined to initiate the minimum-size TDF at the early stage contrary to the RMD due to the high morbidity rate of digestive system cancer in Japan. In order to verify the validity of the RMD, we collected 71 retrospective cases where the minimum-size TDF was initiated against the restriction of RMD. The prior morphine (or equivalent doses of other opioids) was prescribed by palliative care specialists at 5 facilities which belong to Symptom Control Research Group (SCORE-G). Then, the side effects and pain control from the 1st to the 4th day were analyzed. The mean age of subjects was 68, and the main reason for initiating TDF therapy was gastrointestinal symptoms (63.4%). The frequency of side effects such as somnolence, nausea, vomiting and constipation did not show a significant correlation with the prior opioid dose.However,severe dyspnea and respiration depression were documented in two patients, and the above rate was three times higher than the nationwide result of the same side effects (0.9 8%). According to the Numeric Rating Scale (from 0: no pain to 10: the worst pain), the pain intensity decreased from 6.6 on the 1st day to 2.8 on the 2nd day, 3.3 on the 3rd day, and 2.9 (p < 0.001) on the 4th day. We conclude that, although introducing the minimum-size TDF against the RMD served to decrease the pain intensity,it raised the side effects on the respiratory system even when prescribed by palliative care specialists. Therefore,the RMD regulation is valid for general practitioners from a medical safety standpoint.
... 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 ...
... still remove the patch at your regular patch removal time. Do not apply extra patches to make ... room temperature and away from excess heat and moisture (not in the bathroom). Do not refrigerate or ...
Alberts, David S; Smith, Christina Cognata; Parikh, Neha; Rauck, Richard L
To investigate the relationship between effective fentanyl sublingual spray (FSS) doses for breakthrough cancer pain (BTCP) and around-the-clock (ATC) transdermal fentanyl patch (TFP). Adults tolerating ATC opioids received open-label FSS for 26 days, followed by a 26-day double-blind phase for patients achieving an effective dose (100-1600 µg). Out of 50 patients on ATC TFP at baseline, 32 (64%) achieved an effective dose. FSS effective dose moderately correlated with mean TFP dose (r = 0.4; p = 0.03). Patient satisfaction increased during the study. Common adverse event included nausea (9%) and peripheral edema (9%). FSS can be safely titrated to an effective dose for BTCP in patients receiving ATC TFP as chronic cancer pain medication. ClinicalTrials.gov identifier: NCT00538850.
Hayashi, Norihito; Kanai, Akifumi; Suzuki, Asaha; Nagahara, Yuki; Okamoto, Hirotsugu
Prediction of the response to transdermal fentanyl (FENtd) before its use for chronic pain is desirable. We tested the hypothesis that the response to intravenous fentanyl infusion (FENiv) can predict the response to FENtd, including the analgesic and adverse effects. The study subjects were 70 consecutive patients with chronic pain. The response to fentanyl at 0.1 mg diluted in 50 ml of physiological saline and infused over 30 min was tested. This was followed by treatment with FENtd (Durotep MT patch 2.1 mg) at a dose of 12.5 µg/h for 2 weeks. Pain intensity before and after FENiv and 2 weeks after FENtd, and the response to treatment, were assessed by the numerical rating scale (NRS), clinical global impression-improvement scale (CGI-I), satisfaction scale (SS), and adverse effects. The NRS score decreased significantly from 7 (4-9) [median (range)] at baseline to 3 (0-8) after FENiv (p < 0.001), and to 4 (1-8) after FENtd (p < 0.001). The effects of FENiv, as evaluated by ΔNRS, CGI-I, and SS, were significantly greater than those of FENtd (p < 0.001, each), but not by the frequency and the severity of adverse effects, with the exception of dizziness. ΔNRS, and severity of adverse effects (drowsiness, dizziness, nausea, dry mouth, and pruritus) of FENiv correlated significantly with those of FENtd (rs > 0.04, each). The analgesic and side effects after intravenous fentanyl infusion can be used to predict the response to short-term transdermal treatment with fentanyl.
Thomasy, S M; Slovis, N; Maxwell, L K; Kollias-Baker, C
This study investigated the pharmcokinetics, efficacy, and safety of the fentanyl transdermal therapeutic system (TTS) in horses in which there was an inadequate analgesic response to nonsteroidal anti-inflammatory drugs (NSAIDs) alone. Nine horses with pain that was refractory to therapeutic doses of phenylbutazone (n = 3) or flunixin meglumine (n = 6) subsequently also received between 39 and 110 microg/kg of transdermal fentanyl. Blood samples were collected at 0, 1, 2, 3, 4, 5, 6, 12, 24, 36, 48, 60, and 72 hours after patch application, and a radioimmunoassay was used to determine serum fentanyl concentrations. Pharmacokinetic values were determined by noncompartmental analysis. Physical examination findings were recorded in all horses, and pain and lameness grading systems were used to assign scores to 8 and 6 horses, respectively. All horses tolerated the administration of fentanyl TTS, in that no clinically significant adverse effects attributable to fentanyl were observed. Use of the TTS resulted in variable serum concentrations of fentanyl, with a peak serum concentration of 2.2+/-1.1 ng/mL (mean+/-SD) and a time to peak serum concentration of 26+/-13 hours. After transdermal fentanyl administration, mean time to reach serum fentanyl concentrations consistent with analgesia in other species (1 ng/mL) was 14 hours. In addition, serum fentanyl concentrations of 1 ng/mL or greater were maintained in all but one horse for at least 18 hours. Pain scores were significantly decreased after fentanyl TTS and NSAID administration (P < .05), but lameness scores were not significantly different (P > .05). Overall, administration of fentanyl TTS had a favorable pharmacokinetic profile in horses with clinical pain, and the fentanyl TTS in combination with NSAIDs appeared to provide safe and effective analgesia in most of the horses with pain that was refractory to NSAID therapy alone.
Lidocaine patches are used to relieve the pain of post-herpetic neuralgia (PHN; the burning, stabbing pains, ... for months or years after a shingles infection). Lidocaine is in a class of medications called local ...
... you can use baby oil or a medical adhesive removal pad to remove residue that will not come off with soap and water. Do not use alcohol, nail polish remover, or other solvents. Apply a new patch to a different area immediately by following steps 1 to 6.
... you can use baby oil or a medical adhesive removal pad to remove residue that will not come off with soap and water. Do not use alcohol, nail polish remover, or other solvents. Apply a new patch to a different area immediately by following steps 1–5.
... press down on its center to lift the edges away from the skin. Hold the edge gently and slowly peel the patch away from ... your medications or monitor you carefully for side effects.tell your doctor if you think you may ...
Riviere, J E; Papich, M G
A new frontier in the administration of therapeutic drugs to veterinary species is transdermal drug delivery. The primary challenge in developing these systems is rooted in the wide differences in skin structure and function seen in species ranging from cats to cows. The efficacy of a transdermal system is primarily dependent upon the barrier properties of the targeted species skin, as well as the ratio of the area of the transdermal patch to the species total body mass needed to achieve effective systemic drug concentrations. A drug must have sufficient lipid solubility to traverse the epidermal barrier to be considered for delivery for this route. A number of insecticides have been developed in liquid "pour-on" formulations that illustrate the efficacy of this route of administration for veterinary species. The human transdermal fentanyl patch has been successfully used in cats and dogs for post-operative analgesia. The future development of transdermal drug delivery systems for veterinary species will be drug and species specific. With efficient experimental designs and available transdermal patch technology, there are no obvious hurdles to the development of effective systems in many veterinary species.
Allan, Laurie; Hays, Helen; Jensen, Niels-Henrik; de Waroux, Bernard Le Polain; Bolt, Michiel; Donald, Royden; Kalso, Eija
Objectives To compare patients' preference for transdermal fentanyl or sustained release oral morphine, their level of pain control, and their quality of life after treatment. Design Randomised, multicentre, international, open label, crossover trial. Setting 35 centres in Belgium, Canada, Denmark, Finland, the United Kingdom, the Netherlands, and South Africa. Participants 256 patients (aged 26-82 years) with chronic non-cancer pain who had been treated with opioids. Main outcome measures Patients' preference for transdermal fentanyl or sustained release oral morphine, pain control, quality of life, and safety assessments. Results Of 212 patients, 138 (65%) preferred transdermal fentanyl, whereas 59 (28%) preferred sustained release oral morphine and 15 (7%) expressed no preference. Better pain relief was the main reason for preference for fentanyl given by 35% of patients. More patients considered pain control as being “good” or “very good” with fentanyl than with morphine (35% v 23%, P=0.002). These results were reflected in both patients' and investigators' opinions on the global efficacy of transdermal fentanyl. Patients receiving fentanyl had on average higher quality of life scores than those receiving morphine. The incidence of adverse events was similar in both treatment groups; however, more patients experienced constipation with morphine than with fentanyl (48% v 29%, P<0.001). Overall, 41% of patients experienced mild or moderate cutaneous problems associated with wearing the transdermal fentanyl patch, and more patients withdrew because of adverse events during treatment with fentanyl than with morphine (10% v 5%). However, within the subgroup of patients naive to both fentanyl and morphine, similar numbers of patients withdrew owing to adverse effects (11% v 10%, respectively). Conclusion Transdermal fentanyl was preferred to sustained release oral morphine by patients with chronic non-cancer pain previously treated with opioids. The main
Scott, Lesley J
Fentanyl iontophoretic transdermal system (ITS) [Ionsys(®)] is indicated for the management of acute postoperative pain in adults requiring opioid analgesia in the hospital setting. This article reviews the clinical use of fentanyl ITS for postoperative pain management, and summarizes the pharmacology of fentanyl and the characteristics of the two-component fentanyl ITS (Ionsys(®)) device. In well-designed, multicentre clinical trials, fentanyl ITS was an effective and generally well tolerated method for managing acute postoperative pain in inpatients who had undergone major abdominal, thoracic or orthopaedic surgery. Overall, fentanyl ITS provided equivalent analgesic efficacy to that with morphine patient-controlled intravenous analgesia (PCIA), but was perceived to be more convenient/easier to use than morphine PCIA by patients, nurses and physical therapists. Patients receiving fentanyl ITS also had a greater ability to mobilize after surgery than patients receiving morphine PCIA. In addition, relative to morphine PCIA, fentanyl ITS offers advantages in terms of the noninvasive administrative route (i.e. transdermal needle-free administration), pre-programmed delivery (no risk of programming errors/incorrect dosing) and improved tolerability with regard to the overall incidence of opioid-related adverse events (ORAEs) and some individual ORAEs. Hence, fentanyl ITS is a useful option for the management of acute postoperative pain in adults requiring opioid analgesia in the hospital setting.
Heikkinen, Emma M; Kokki, Hannu; Heikkinen, Aki; Ranta, Veli-Pekka; Räsänen, Juha; Voipio, Hanna-Marja; Kokki, Merja
Opioids given to pregnant and parturient women are relatively freely transferred across the placenta. Spinal, epidural and intravenous fentanyl has been studied in pregnant women and neonates, but foetal safety of fentanyl dosing with transdermal patch during pregnancy and labour is not sufficiently studied. Foetal pH is physiologically lower than maternal pH, and thus, opioids, which are weak bases, are ionized and may cumulate to foetus. Foetal asphyxia may further worsen acidosis, and ion trapping induced by low pH is assumed to increase the foetal exposure to opioids. Here, we show that no correlation between foetal acidosis and ion trapping of fentanyl could be found. In three experiments, 29 pregnant sheep were administered fentanyl with 2 μg/kg/h patch supplemented with IV boluses/infusion. Foetal exposure to fentanyl was extensive, median 0.34 ng/ml (quartiles 0.21, 0.42), yet drug accumulation to foetus was not observed, and median of foetal/maternal concentration (F/M) ratio was 0.63 (0.43, 0.75) during the first hours after the fentanyl administration. Low foetal pH and pH difference between ewe and the foetus did not correlate with fentanyl concentration in the foetus or F/M ratio. At steady-state during the second patch worn, foetal plasma fentanyl was low, 0.13 ng/ml, and the median of F/M ratio was 0.69. Our results demonstrate that drug accumulation to foetus caused by ion trapping seen with some weak base opioids may not be that significant with fentanyl. These results have a clinical relevance when fentanyl is dosed to pregnant woman and the foetus is acidemic.
Wirz, Stefan; Wittmann, Maria; Schenk, Michael; Schroeck, Andreas; Schaefer, Nico; Mueller, Marcus; Standop, Jens; Kloecker, Norbert; Nadstawek, Joachim
The purpose of this trial was to evaluate the effect of long-term treatment with oral sustained-release hydromorphone, transdermal fentanyl, and transdermal buprenorphine on nausea, emesis and constipation. Randomly selected outpatients with cancer pain receiving one of the study medications were enrolled in a prospective, open-labeled, controlled trial (n=174). Mobility, pain, and gastrointestinal symptoms were assessed directly and per selected item on the ECOG (Eastern Cancer Oncology Group), EORTC (European Organisation for Research and Treatment of Cancer) questionnaires, NRS (Numerical Rating Scales), and analyzed statistically. Demographic and medical data were comparable in all groups. Only 15% of patients suffered from constipation. 59% took the prescribed laxatives. The incidence of stool free periods >72 h was significantly higher with transdermal opioids (transdermal fentanyl: 22%; transdermal buprenorphine: 21%; oral hydromorphone: 2%; p=0.003). 21% of patients revealed nausea and emesis. The mean NRS for nausea (transdermal fentanyl:1.3; transdermal buprenorphine: 1.2; oral hydromorphone: 1.5; p=0.6), the consumption of antiemetics (transdermal fentanyl: 42%; transdermal buprenorphine: 33%; oral hydromorphone: 36%; p=0.6) and laxatives (transdermal fentanyl:53%; transdermal buprenorphine:66%; oral hydromorphone: 61%; p=0.2) did not differ significantly, in contrast to the score for emesis (transdermal fentanyl: 16%; transdermal buprenorphine:13%; oral hydromorphone: 33%; p=0.02). Morphine equivalent opioid doses differed (mg/d transdermal fentanyl: 183; transdermal buprenorphine: 89; oral hydromorphone: 143; p=0.001), because of obvious tolerance varying after long-term treatment. Gastrointestinal symptoms of cancer pain patients undergoing an opioid therapy are related to multifactorial causes. Transdermal opioids showed no benefit over oral controlled-release hydromorphone with regard to gastrointestinal symptoms. The conversion ratios for
Pastore, Michael N; Kalia, Yogeshvar N; Horstmann, Michael; Roberts, Michael S
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
Pastore, Michael N; Kalia, Yogeshvar N; Horstmann, Michael; Roberts, Michael S
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.
Jen, Kimberly Y; Dyson, Melissa C; Lester, Patrick A; Nemzek, Jean A
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.
Lenz, Thomas L; Gillespie, Nicole
Transdermal drug delivery systems, such as the transdermal patch, continue to be a popular and convenient way to administer medications. There are currently several medications that use a transdermal patch drug delivery system. This article describes the potential untoward side effects of increased drug absorption through the use of a transdermal patch in individuals who exercise or participate in sporting events. Four studies have been reported that demonstrate a significant increase in the plasma concentration of nitroglycerin when individuals exercise compared with rest. Likewise, several case reports and two studies have been conducted that demonstrate nicotine toxicity and increased plasma nicotine while wearing a nicotine patch in individuals who exercise or participate in sporting events compared with rest. Healthcare providers, trainers and coaches should be aware of proper transdermal patch use, especially while exercising, in order to provide needed information to their respective patients and athletes to avoid potential untoward side effects. Particular caution should be given to individuals who participate in an extreme sporting event of long duration. Further research that includes more medications is needed in this area.
Mystakidou, Kyriaki; Katsouda, Emmanuela; Tsilika, Eleni; Parpa, Efi; Vlahos, Lambros
Fentanyl, a surgical analgesic and general anaesthetic, is a lipophilic short-acting synthetic opioid, having a selective potent effect on mu receptors. The transdermal therapeutic fentanyl-system (TTS-F) allows for a continued and sustained titratable amount of fentanyl to be delivered without the inconvenience of the typical 24-h administration of other analgesics. Although incidences of respiratory depression led to TTS-F being contraindicated for postoperative analgesia, it is currently undergoing Phase III trials for nociceptive, neuropathic and chronic moderate to severe pain in a variety of settings. It demonstrates a slow pharmacokinetic profile and incidences of breakthrough pain may still require rapid analgesia, for which intravenous and bolus administration of rapid acting opioids remain 'gold standard' However, TTS-F is finding uses for chronic pain of cancer origin where it offers a solution for step 3-pain (WHO) management on the WHO analgesic ladder. More recent data indicates that TTS-F is not only effective for neuropathic but also nociceptive non-cancer and cancer pain alike. This review presents an overview of the synthesis, delivery, pharmacokinetics, toxicity and clinical pharmacology of the transdermal delivery of fentanyl.
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
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.
Ackerman, Stacey J; Mordin, Margaret; Reblando, Joseph; Xu, Xiao; Schein, Jeff; Vallow, Sue; Brennan, Michael
Although use of long-acting opioid analgesics has increased for chronic nonmalignant pain management, little is known about patient-reported utilization patterns. To assess patient-reported utilization patterns of fentanyl transdermal system and oxycodone hydrochloride (HCl) controlled-release among patients with chronic nonmalignant pain and to compare these patterns to standard dose administration guidelines recommended in the manufacturers. prescribing information (PI). Cross-sectional, observational, multicenter study of English-speaking patients who were seeking chronic nonmalignant pain management from 6 outpatient pain clinics. The inclusion criteria for the study were (1) diagnosis of chronic nonmalignant pain, (2) prescription for and current use of either transdermal fentanyl or oxycodone HCl controlled-release, and (3) duration of use for either transdermal fentanyl or oxycodone HCl controlled-release of at least 6 weeks. Patients completed either an oxycodone HCl controlled-release or transdermal fentanyl utilization questionnaire. A conversion table was used to standardize opioid analgesic doses from transdermal fentanyl or oxycodone HCl controlled-release to daily oral morphine equivalents. The principal outcome measures were the average interval between oxycodone HCl controlled-release administrations, the number of days the current transdermal fentanyl patch would be worn, and the percentage of oxycodone HCl controlled-release and transdermal fentanyl patients whose administration frequency exceeded the standard recommendation in the manufacturer.s PI (every 12 hours for oxycodone HCl controlled-release or every 72 hours for transdermal fentanyl). Other outcome measures included the number of oxycodone HCl controlled-release tablets per administration, the daily dose of long-acting opioid, the duration of adequate pain relief, and the difference in daily oral morphine equivalents between transdermal fentanyl and oxycodone HCl controlled
Vizserálek, Gábor; Berkó, Szilvia; Tóth, Gergő; Balogh, Réka; Budai-Szűcs, Mária; Csányi, Erzsébet; Sinkó, Bálint; Takács-Novák, Krisztina
Using the skin as absorption site presents unique advantages that have facilitated the progression of transdermal drug delivery in the past decades. Efforts in drug research have been devoted to find a quick and reproducible model for predicting the skin permeation of molecules. The Parallel Artificial Membrane Permeability Assay (PAMPA) has been extended for prediction of transdermal permeation by developing a model with completely artificial membrane, which can mimic the permeation through the stratum corneum. The present study aims to extend the Skin PAMPA method for testing transdermal and local therapeutic patches. The original method was modified and seven commercially available transdermal and local therapeutic patches with four different active pharmaceutical ingredients (nicotine, fentanyl, rivastigmine and ketoprofen) were studied. Data were compared to the declared delivery rates that are indicated by the manufacturers. Ex vivo permeation study was also performed in order to compare the permeated amount of the released drugs obtained by the two methods. The flux across the artificial membrane as well as the human skin (ex vivo) has been calculated and compared to the in vivo flux deduced from the labelled delivery rate and the active area of the patches. The results suggest that Skin PAMPA system can serve as a useful tool for evaluation and classification of the transdermal patches. Copyright © 2015 Elsevier B.V. All rights reserved.
Caram, Anthony M; Patel, Nirav; Sandler, Hayden M
Postoperative management of pain has traditionally utilized intravenous (IV) morphine for pain control. An alternative approach to the invasive patient-controlled analgesia (PCA) system is the administration of transdermal analgesics, such as fentanyl. In 2006 the Food and Drug Administration (FDA) approved the fentanyl hydrochloride (fentanyl HCl) iontophoretic transdermal system (ITS), which utilizes iontophoretic technology to produce a controlled electrical current that propels ionized fentanyl molecules into the systemic vasculature. Transdermal fentanyl has been shown to be equivalent or superior to IV morphine PCA in a variety of postoperative settings with patients experiencing decreased pain scores and a favorable side effect profile. PMID:27688989
Burke, Megan J; Soma, Lawrence R; Boston, Raymond C; Rudy, Jeffery A; Schaer, Thomas P
Evaluate the analgesic properties and pharmacokinetics of transdermal fentanyl patches (TFPs) in goats. Prospective, randomized study. Preclinical Testing Facility at a University Teaching Hospital. Thirty-four adult female Boer-cross goats. Goats underwent surgery as part of a concurrent orthopedic research study. Twelve hours prior to surgery, each goat received a TFP (target dosage of 2.5 μg/kg/h), or a placebo patch with analgesia provided by buprenorphine (0.01 mg/kg, IM, q 6 h). Patches were removed after 72 hours. Blood was sampled at specified intervals, up to 84 hours following TFP placement. Plasma concentrations of fentanyl (FEN) were determined using liquid chromatography-mass spectrometry. Postoperative pain assessments were performed by two independent blinded observers. TFPs were applied at a mean (± standard deviation, SD) dose of 2.54 ± 0.36 μg/kg/h. No adverse events occurred. Pain scores between TFP and BUP groups were not significantly different at any time point. Mean plasma FEN concentration (± SD) 2 hours following patch application was 1.06 ± 0.85 ng/mL, and remained above 0.5 ng/mL for 40 hours. Maximum mean plasma FEN concentration (Cmax ) was 1.84 (ranging from 0.81 to 3.35) ng/mL with average time to maximum concentration (Tmax ) of 12 hours after patch application. TFP resulted in consistent FEN absorption and plasma concentrations within the human and ovine therapeutic ranges. Pain scores for goats administered TFP were not different than those administered buprenorphine. Ease of administration, duration of analgesia, and decreased dosing frequency make TFPs an attractive option for pain management in goats. © Veterinary Emergency and Critical Care Society 2017.
Turan, Alparslan; White, Paul F; Koyuncu, Onur; Karamanliodlu, Beyhan; Kaya, Gaye; Apfel, Christian C
A single 3 mg intranasal dose of nicotine has been reported to have analgesic properties. We designed placebo-controlled study to test the hypothesis that transdermal nicotine (TDN) administered over a 3-day period would decrease postoperative pain and opioid analgesic usage and improve the recovery process after lower abdominal surgery. Ninety-seven patients undergoing abdominal hysterectomy procedures were randomly assigned to one of two treatment groups: (1) control group received inert (sham) patches 1 h before and for 2 days after surgery, or the (2) nicotine group received TDN 30 (21 mg nicotine) patches 1 h before induction of anesthesia and for two additional days after surgery. The anesthetic technique was identical in both groups, and the postoperative assessments included verbal rating scales for pain and sedation, IV patient-controlled analgesia morphine usage, quality of recovery assessment, recovery of bowel function, resumption of normal activities, and patient satisfaction with their pain management. Follow-up evaluations were performed at 1 and 3 mo after the operation to assess late recovery events. Postoperative patient-controlled analgesia morphine usage and pain scores while supine or sitting up, intraoperative fentanyl use, oral analgesic consumption, return of bowel sounds, and passage of flatus did not differ between the two groups. Although ambulation and hospitalization times, as well as quality of recovery scores, did not differ, resumption of oral intake was delayed in the nicotine group. Discharge eligibility scores were higher in the nicotine group at 48 and 72 h compared with the control group, but the time to return to work was 19 days in both treatment groups. Perioperative administration of a high-dose TDN patch did not improve postoperative pain control or decrease the analgesic requirement after pelvic gynecological surgery. Despite delayed resumption of oral intake, more patients in the nicotine group were ready for discharge at
Perez-Lloret, Santiago; Rey, María Verónica; Ratti, Pietro Lucca; Rascol, Olivier
Rotigotine, a non-ergot dopamine agonist, has been developed as a novel transdermal formulation. The rotigotine transdermal patch has received EMEA marketing authorization for the treatment of adult patients with early or advanced Parkinson's disease (PD) or with moderate to severe restless legs syndrome (RLS). FDA originally granted a marketing authorization for early PD, which was later suspended, and is now studying the authorization for RLS. The aim of this review is to review the pharmacokinetics, pharmacodynamics as well as the clinical efficacy and tolerability of the rotigotine transdermal patch in PD. Source material was identified using a PubMed search for the term 'rotigotine' and PD. Articles published up to January 2011 or abstract submitted to most relevant international neurology congresses were reviewed. The rotigotine transdermal patch is efficacious for the treatment of PD. Tolerability profile appears to be well within the range of that observed with other non-ergot dopamine agonists in PD. Application-site reactions were the most frequent adverse event, and they were considered mild to moderate in the majority of cases. The rotigotine transdermal patch offers a safe and efficacious alternative for the treatment of PD. Further studies should focus on the possibility that continuous dopamine stimulation by means of the transdermal patch has any influence on levodopa-related motor complications.
Mazzitelli, Stefania; Pagano, Cinzia; Giusepponi, Danilo; Nastruzzi, Claudio; Perioli, Luana
The effect of different preparation parameters were analyzed with respect to the rheological and pharmaceutical characteristics of hydrogel blend patches, as transdermal delivery formulation. Mixtures of pectin and gelatin were employed for the production of patches, with adjustable properties, following a two-step gelation procedure. The first gelation, a thermal one, is trigged by the presence of gelatin, whereas, the second gelation, an ionic one, is due to the formation of the typical egg box structure of pectin. In particular, the patch structural properties were assessed by oscillation stress sweep measurements which provided information concerning their viscolelastic properties. In addition, different modalities for drug loading were analyzed with respect to drug homogeneous distribution; testosterone was employed as model drug for transdermal administration. Finally, the performances of the produced transdermal patches were studied, in term of reproducibility and reliability, by determination of in vitro drug release profiles. Copyright © 2013 Elsevier B.V. All rights reserved.
Koltzenburg, Martin; Pokorny, Rolf; Gasser, Urs E; Richarz, Ute
This is the first randomized controlled trial that tests the analgesic efficacy of transdermally delivered opioids in healthy volunteers and that assesses the sensitivity of different experimental pain tests to detect analgesia in this setting. Transdermal application of the full agonist fentanyl (TDF: 12.5 or 25 microg/h) and the partial agonist buprenorphine (TDB: 35 microg/h) was compared in three experimental models of acute pain (heat pain, painful electrical stimulation, cold pressor) in a double-blind, randomized, placebo-controlled, 4-arm crossover study with 20 healthy subjects (15 men, 5 women). Patches were administered for 72 h and pain levels measured at baseline and 24 and 72 h, with an 11-day wash-out. The cold pressor test was most sensitive to analgesic effects, with significant reductions in area under the pain intensity curve for all active compounds at 24 h (average reductions: 14% TDF 12.5 microg/h, 35% TDF 25 microg/h, 43% TDB 35 microg/h). There were significant increases in heat pain threshold for TDF 25 microg/h and TDB 35 microg/h. Painful electrical stimulation failed to demonstrate an analgesic effect. The magnitude of analgesia in the cold pressor model showed some correlation with TDF dosage and comparable effects for the full agonist fentanyl and the partial agonist buprenorphine. We conclude that the cold pressor test was most sensitive to analgesic effects in healthy subjects and that a transdermal dose of 12.5 microg/h fentanyl achieved significant pain reduction compared with placebo. Subjects experienced opioid-typical AEs including dizziness, nausea and vomiting. No serious AEs occurred.
Davaran, Soodabeh; Rashidi, Mohammad R; Khandaghi, Reza; Hashemi, Mahdi
A transdermal patch for delivering nicotine for periods of 12-48h was designed. An inclusion complex formed between the nicotine and beta-cyclodextrine (beta-CD) was used in drug depot. The usefulness of a specially cross-linked polyvinyl alcohol (cross-PVA) membrane was investigated as a rate controlling membrane. The influence of carbopol polymers, type C-934P and C-940 and propylene glycol on transdermal permeation of nicotine through the rat skin was investigated. The results indicated a maximum flux of 42 microgcm(-2)h(-1) after 48 h from the patches made from C-934P when the propylene glycol concentration was 15% and the nicotine-beta-CD mole ratio in the inclusion complex was 3:1. These nicotine transdermal patches can be fabricated to obtain a controlled release, zero order systems.
Song, Jae-Hwang; Kang, Chan; Hwang, Deuk-Soo; Hwang, Jung-Mo; Shin, Byung-Kon
The analgesic effects of preoperative ultrasound-guided nerve blocks wear off after about 12 hours, leaving some patients in substantial pain. Transdermal fentanyl concentrations peak at 12 to 24 hours after application and maintain this concentration for approximately 72 hours. We sought to determine whether combining the use of a transdermal fentanyl patch with either a sciatic or femoral-sciatic nerve block would improve pain control in patients undergoing foot and/or ankle surgery. Consecutive patients in the no-patch control group (n = 104) were enrolled from July 2011 to October 2011, and those in the treatment group (n = 232) were enrolled from November 2011 to May 2012 and received a transdermal patch (4.125 mg/7.5 cm(2) releasing 25 μg of fentanyl per hour) applied to their chest postoperatively. Pain was assessed using a visual analog scale at 6, 12, 24, and 48 hours after surgery. The primary outcome measure was the number of requests for additional postoperative pain medication. Additional postoperative analgesia was requested by 49 of the 104 control patients (47.1%) and 63 of the 232 treated patients (27.1%; p = .002). The mean pain scores were also lower in the treatment group, with a statistically significant difference (p < .05) at 12, 24, and 48 hours. Thus, patients receiving a fentanyl patch combined with an ultrasound-guided nerve block required less supplemental analgesia to maintain adequate pain control than did those receiving a nerve block alone. In conclusion, a fentanyl patch is a useful adjunct to an ultrasound-guided nerve block in foot and ankle surgery. Copyright © 2016 American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.
Fanelli, Andrea; Sorella, Maria Cristina; Chelly, Jacques E
Intravenous (I.V.) morphine administered through a patient-controlled system currently represents the gold standard treatment for moderate to severe acute postoperative pain. To fix the limitations showed by the available I.V. patient-controlled analgesia (PCA) systems that may restrict its use in the clinical practice a needle-free, iontophoretic, fentanyl patient-controlled transdermal system has been developed and recently approved by the United States Food and Drug Administration (FDA) and by the European Medicines Agency (EMA). This review aims at describing the technology, pharmacology and clinical efficacy of fentanyl iontophoretic transdermal system (ITS) in the treatment of acute pain. A literature search was conducted in the PUBMED database using the term 'fentanyl iontophoretic transdermal system' through September 2015 and results from the main clinical trials are discussed. In 2015, the appropriate treatment of acute pain after surgery is still a challenge and it represents a primary goal in the care of the surgical patient. When regional analgesia techniques are not applicable and systemic analgesia is required, patient controlled systems represent the standard of care for opioid administration. The fentanyl ITS presents several potential advantages compared to the currently used PCA devices. In particular, it does not require intravenous lines and eliminates the potential for drug administration errors, observed with manually programmed standard PCA devices. Nevertheless, further studies are needed to address eventual inter-individual variability especially for opioid tolerant patients.
Sivakumar, Walavan; Karsy, Michael; Brock, Andrea; Schmidt, Richard H
Postoperative pain is a significant concern for patients who undergo surgery via a midline posterior approach to the occipitocervical junction and spinal axis. The development of the disposable, ambulatory pain pump presents a novel alternative for treatment of postoperative pain. The authors describe a multimodal treatment algorithm for postoperative pain after posterior occipitocervical junction surgery that uses the On-Q pain catheter system (I-Flow Corp., Lake Forest, CA) and a fentanyl patch. The On-Q PainBuster catheter system is a disposable, ambulatory device that allows for continuous anesthetic delivery directly into or adjacent to the wound. On-Q catheters are placed in the nuchal musculature for continuous infusion of 0.5% bupivacaine. The On-Q catheter infusion is continued for three days, and the catheters are then withdrawn. Patients are also provided with a transdermal fentanyl patch at the start of surgery. In regards to complications at our facility, there have been no cases of respiratory depression or arrest postoperatively and no wound infections, but one case of inadvertent subdural placement. The technique described for the use of the fentanyl patch and a continuous anesthetic delivery device in surgery of the occipitocervical junction presents a novel alternative to the current standard of care in pain control after suboccipital decompression.
Sivakumar, Walavan; Karsy, Michael; Brock, Andrea
Postoperative pain is a significant concern for patients who undergo surgery via a midline posterior approach to the occipitocervical junction and spinal axis. The development of the disposable, ambulatory pain pump presents a novel alternative for treatment of postoperative pain. The authors describe a multimodal treatment algorithm for postoperative pain after posterior occipitocervical junction surgery that uses the On-Q pain catheter system (I-Flow Corp., Lake Forest, CA) and a fentanyl patch. The On-Q PainBuster catheter system is a disposable, ambulatory device that allows for continuous anesthetic delivery directly into or adjacent to the wound. On-Q catheters are placed in the nuchal musculature for continuous infusion of 0.5% bupivacaine. The On-Q catheter infusion is continued for three days, and the catheters are then withdrawn. Patients are also provided with a transdermal fentanyl patch at the start of surgery. In regards to complications at our facility, there have been no cases of respiratory depression or arrest postoperatively and no wound infections, but one case of inadvertent subdural placement. The technique described for the use of the fentanyl patch and a continuous anesthetic delivery device in surgery of the occipitocervical junction presents a novel alternative to the current standard of care in pain control after suboccipital decompression. PMID:27433423
Sarkar, Gunjan; Saha, Nayan Ranjan; Roy, Indranil; Bhattacharyya, Amartya; Bose, Madhura; Mishra, Roshnara; Rana, Dipak; Bhattacharjee, Debashis; Chattopadhyay, Dipankar
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.
Malavasi, L M; Nyman, G; Augustsson, H; Jacobson, M; Jensen-Waern, M
The objective of this work was to evaluate the physiological and behavioural effects of opioid analgesic treatment in pigs subjected to abdominal surgery. Ten Swedish Landrace x Yorkshire pigs (20 +/- 4 kg b.w.) were submitted for intestinal cannulation. The pigs were allocated into two groups during one preoperative, one surgical and two postoperative days. All pigs were anaesthetized with medetomidine, tiletamine and zolazepam. One group was treated with epidural morphine (0.1 mg/kg) preoperatively, and transdermal fentanyl patches (50 microg/kg/h) were applied behind the ear immediately after surgery. The other group received epidural saline (equivalent volume) and placebo patches. All pigs were regularly weighed and clinically examined and repeated blood samples were analysed for serum concentrations of cortisol, beta-endorphin and fentanyl. Pre- and postoperative behaviours were evaluated by a swine specialist blinded to the treatment, three times a day, and were also videotape recorded for a total of 84 h per pig. No differences in behaviour were noted by the observer. During the first postoperative 12 h, treated pigs did not differ in activity compared with preoperative recordings, while untreated pigs were found to be less active. The treated group started to show interest in eating immediately after anaesthesia recovery, whereas the placebo group did not. During the 12-60 h postoperative period, the treated group had lower activity levels compared with the preoperative levels, which were similar to those in the placebo group. Treated pigs gained 0.5 +/- 0.2 kg during the subsequent two postoperative days, whereas the untreated pigs lost weight throughout the experiment. Cortisol concentration differed immediately after the surgery: Group P had 325 +/- 120 nmol/L and Group M 159 +/- 49 nmol/L. beta-endorphin concentration did not differ between groups. The highest serum fentanyl concentration (0.37 +/- 0.3 ng/mL) was measured 24 h postoperatively
... contraceptive patch is a very effective method of birth control, but it does not prevent the spread of ... period, you must use a backup method of birth control (such as a condom and/or a spermicide) ...
Kumar, Santosh; Singh, Prithvi Kumar; Verma, Reetu; Chandra, Girish; Bhatia, Vinod Kumar; Singh, Dinesh; Bogra, Jaishri
Introduction Buprenorphine is a semi-synthetic derivative of thebaine; its low concentration is sufficient to provide effective pain relief. Aim To evaluate the efficacy of transdermal buprenorphine patch in postoperative pain management. Materials and Methods After ethical approval and taking informed consent from the patients, they were randomized into three groups (n=30 in each group) using a computer generated random number table. Group A: placebo patch; Group B: buprenorphine (10mg) patch and Group C: buprenorphine (20mg) patch. Haemodynamic and analgesic effects were compared by using analysis of variance (ANOVA) followed by Turkey’s post hoc test. The proportion of side effects was compared using the Chi-square test. Results Haemodynamic changes were not statistically different in all the three groups A, B and C, whereas at the end of surgery VAS score of Group A subjects was significantly higher (4.93±0.98) as compared to Group B (1.73±0.64) and Group C (1.40±0.50). On 2nd postoperative day, no pain was reported by the Group C patients and on 4th day after surgery, no pain was reported by Group B patients. Conclusion The transdermal buprenorphine patch (20mg) was effective in attenuating postoperative pain, maintaining haemodynamic stability requiring no rescue analgesia, with fewer postoperative rescue analgesic requirements in low dose of buprenorphine patch (10mg) group. PMID:27504383
Prabhu, Prabhakar; Shah, Samip; Gundad, Shankar
Aim and Background: Domperidone is a dopamine antagonist with antiemetic properties having a plasma half life of 7-9 h with 15% oral bioavailability. In the present work transdermal patches of domperidone were prepared with the objective to improve its therapeutic efficacy, patient compliance and to reduce the frequency of dosing and side effects, as well as to avoid its extensive first pass metabolism of the drug. Materials and Methods: The patches were prepared using ethyl cellulose (EC): Poly vinyl pyrrolidone (PVP), poly vinyl alcohol (PVA): Poly vinyl pyrrolidone (PVP) and hydroxypropylmethylcellulose (HPMC): Sodium (carboxy methyl cellulose) CMC as polymers in combination. The physicochemical parameters like thickness, drug content, weight variation, moisture absorption and drug permeation studies were evaluated for the prepared patches. No significant difference in thickness, average weight and in the drug content among the patches. Results: It was observed that from hydrophilic polymers the drug release was found to be faster compared to (F5 and F6 & F3 and F4) combination of hydrophilic and lipophilic polymers used in the study. Patches containing HPMC and Sodium CMC (F5 and F6) showed faster release as the patches showed maximum percentage amount moisture absorption. The in vitro release data was treated with kinetic equations and it followed Higuchi's diffusion mechanism. The in vivo bioavailability study was performed in rats and observed that, drug reached to the peak in approximately 60 min (16%) after oral route of administration. However, approximately same amount of drug was found in the serum from transdermal formulation in 6 h and further increase in the amount of drug in the serum, indicated that the drug 5 bioavailability could be better and hence the hepatic metabolism can be avoided, as it is evident from the data. Further, the decrease in the amount of drug present in the serum 45 min after oral administration also indicated that major
Page, F; Coleman, G; Conduit, R
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.
Harrison, Adrian P; Hansen, Steen H; Bartels, Else M
Pain treatment in ancient Greece, and through the middle ages in Europe, was to a great extent based on the expertise of the Greek physician Galen (c. 129-200 A.D.). Galen makes particular reference to "Olympic Victor's Dark Ointment" (OVDO), which is listed with a number of collyria. Galen states that OVDO can be useful for treating extreme pain and swellings, forming one of the best eye salves. Olympic Victor's Dark Ointment, an opium-based treatment, forms a "patch" when applied externally as an ointment, because it quickly dries to cover a localized region but still retains its elastic properties. This study has recreated OVDO and applied the ointment to abdominal mouse skin, in vitro. To assess the efficacy of OVDO, the transdermal transfer of morphine was measured when given as OVDO and compared to morphine administered in the form of a solution of Opium + PBS (ringer). Olympic Victor's Dark Ointment showed a transdermal transfer of morphine over time comparable to 25% of the most efficient modern transdermal opioid patches, while hardly any morphine was able to penetrate the skin when applied mixed in PBS. We conclude that OVDO is very efficient in its composition and may carry some forgotten abilities in terms of drug delivery, which could be transferred to modern medicine. Indeed, this may lead to a better choice of morphine use and controlled management in individual patient cases, taking both pain relief and anti-inflammatory aspects into account.
This study was designed to evaluate the utility of transdermal fentanyl (transdermal fentanyl, TDF) for the treatment of pain due to osteoarthritis (osteoarthritis, OA) of the knee and hip, which was not adequately controlled by nonopioid analgesics or weak opioids. WOMAC is a reliable, valid, and responsive multidimensional, self-administrated outcome measure designed specifically to evaluate patients with OA of the knee or hip. TDF significantly increased pain control and improved functioning and quality of life. Metoclopramide appeared to be of limited value in preventing nausea and vomiting.
Mutalik, S; Udupa, N
In the present study, matrix type transdermal patches containing glibenclamide were prepared using different ratios of ethyl cellulose (EC)/polyvinylpyrrolidone (PVP) and Eudragit RL-100 (ERL)/Eudragit RS-100 (ERS) by solvent evaporation technique. The possible drug and polymer interaction was studied by infrared spectroscopy, differential scanning calorimetry, and HPTLC analysis. All the prepared formulations were subjected to physicochemical studies (thickness, weight variation, drug content, moisture content and uptake, and flatness), in vitro release and in vitro permeation studies through mouse skin. The results suggested that there was no interaction between drug and polymers. Variations in drug release/permeation profiles among the formulations studied were observed. The microphotographs obtained by scanning electron microscopy showed the formation of pores on the surface of the patches after in vitro skin permeation studies. Based on physicochemical and in vitro skin permeation studies, the formulations with EC:PVP (3:2) and ERL:ERS (4:1) were selected for in vivo experiments. The hypoglycemic activity of the patches in comparison with oral glibenclamide administration was studied for acute (24 h) and long-term (6 weeks) effect in both normal and streptozotocin-induced diabetic mice. Various biochemical parameters (serum levels of high-density lipoprotein-cholesterol, triglycerides, total cholesterol, alanine transaminase, aspertate transaminase, urea, and creatinine and liver protein and glycogen content) and histopathological (liver, pancreas and stomach) studies were carried out in diabetic mice after treating for 6 weeks. The patches were subjected to skin irritation test (by both visual observation and histopathological evaluation), oral glucose tolerance test and pharmacokinetic evaluation in mice. The results revealed that the patches successfully prevented the severe hypoglycemia in the initial hours, which is the major side effect associated with
Perepa, Anisha; Sinha, Brig Ramen; Uppada, Uday Kiran; Kumar, Avss Subramanya
To evaluate the analgesic efficacy of a diclofenac transdermal patch with diclofenac intra muscular injection in the immediate postoperative period in patients undergoing major oral surgical procedures. Subjects who underwent bijaw surgeries for surgical correction of various dentofacial deformities were included. Sixty such patients who belonged to the above entity were randomly categorized into two groups from Jan 2012-Aug 2015. Group A (study group) received a single dose of 100 mg transdermal diclofenac patch, Group B (control group) received 75 mg intramuscular diclofenac and tramadol HCl 2 mg/kg body wt was used as rescue analgesic in the immediate post operative phase. The analgesic efficacy of the drugs are evaluated on periodic patient's perception of pain in the immediate postoperative phase of 2nd, 6th, 12th, 24th and 48 hours. The mean VAS score in Group A was 2, mean duration of analgesia was 16 h 9 min, and in Group B the mean VAS score was 4, duration of analgesia was 8 h and 4 min. Tramadol HCl was given as rescue analgesia in 22 % (6) of patients belonging to Group A. None of the patients from both the groups reported local complications. A noninvasive application of a single dose of 100 mg transdermal diclofenac patch is more effective than intramuscular diclofenac (75 mg) in the immediate post operative phase, without any significant side-effects is a novel ingress into the field of oral and maxillofacial surgery for post operative pain management.
Joshi, Nitin; Lemke, John; Danesi, Hassan
Fentanyl iontophoretic transdermal system (ITS) is a patient-controlled analgesia system used for the management of acute postoperative pain. The first-generation fentanyl ITS was an integrated one-piece system; however, corrosion that could limit reliability was detected in a small number of systems. A second-generation fentanyl ITS was designed to separate the hydrogels in the Drug Unit from the electronic circuit of the Controller during manufacture and storage, removing the primary cause of corrosion and thereby improving reliability. No evidence of corrosion has been observed in over 10,000 systems tested in real-time aging studies for the second generation fentanyl ITS. The second generation fentanyl ITS design features combine to ensure safe operation of the system with high reliability.
Chen, Mei-Chin; Ling, Ming-Hung; Lai, Kuan-Ying; Pramudityo, Esar
This paper introduces a chitosan microneedle patch for efficient and sustained transdermal delivery of hydrophilic macromolecules. Chitosan microneedles have sufficient mechanical strength to be inserted in vitro into porcine skin at approximately 250 μm in depth and in vivo into rat skin at approximately 200 μm in depth. Bovine serum albumin (BSA, MW=66.5 kDa) was used as a model protein to explore the potential use of chitosan microneedles as a transdermal delivery device for protein drugs. In vitro drug release showed that chitosan microneedles can provide a sustained release of BSA for at least 8 days (approximately 95% of drugs released in 8 days). When the Alexa Fluor 488-labeled BSA (Alexa 488-BSA)-loaded microneedles were applied to the rat skin in vivo, confocal microscopic images showed that BSA can gradually diffuse from the puncture sites to the dermal layer and the fluorescence of Alexa 488-BSA can be observed at the depth of 300 μm. In addition, encapsulation of BSA within the microneedle matrix did not alter the secondary structure of BSA, indicating that the gentle nature of the fabrication process allowed for encapsulation of fragile biomolecules. These results suggested that the developed chitosan microneedles may serve as a promising device for transdermal delivery of macromolecules in a sustained manner.
Waugh, Lynnette; Knych, Heather; Cole, Gretchen; D'Agostino, Jennifer
The objective of this study was to investigate the pharmacokinetics of a long-acting fentanyl solution in helmeted guineafowl ( Numida meleagris ) after transdermal administration. Twenty-one guineafowl received a single administration of 5 mg/kg of fentanyl transdermal solution. No adverse effects on behavior were appreciated. Plasma fentanyl concentrations were determined by liquid chromatography-mass spectrometry analysis of protein-precipitated samples. Mean maximum plasma concentration was 228.8 ng/ml at 4 hr. The mean plasma terminal half-life was 33.2 hr. At 168 hr the mean plasma concentration was 1.3 ng/ml. A single topical dose of 5 mg/kg appears to be safe for use in this species and maintained plasma concentrations above those reported to be analgesic in dogs for at least 7 days.
Minkowitz, Harold S; Danesi, Hassan; Ding, Li; Jones, James B
The fentanyl iontophoretic transdermal system (ITS) is a needle-free, patient-activated drug delivery system used for patient-controlled analgesia in adult hospitalized patients with postoperative pain. The system design has been updated to a separated system consisting of a Controller and a Drug Unit, and has had regulatory submissions in USA and Europe in 2014. Fentanyl ITS has been shown to be therapeutically equivalent to morphine intravenous (iv.) patient-controlled analgesia. One of the advantages of fentanyl ITS is that patients have better mobility as there is no need for an iv. pump, iv. lines and pole. The introduction of the updated fentanyl ITS will add a versatile tool to the postoperative pain management armamentarium.
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
Moore, Kenneth T; Sathyan, Gayatri; Richarz, Ute; Natarajan, Jaya; Vandenbossche, Joris
This randomized, open-label, 5-treatment, 5-sequence crossover study was designed to evaluate the effects of a heating pad on serum fentanyl concentrations with reservoir and matrix transdermal fentanyl systems. Subjects were randomized to 1 of 5 treatment sequences, receiving 5 fentanyl treatments (1 per period) for 36 hours: 25 µg/h reservoir without heat, 25 µg/h reservoir with heat, 25 µg/h matrix without heat, 25 µg/h matrix with heat, and a 50 µg/h reservoir without heat. The 25 µg/h systems with heat had a heating pad applied from 0 to 10 and 26 to 36 hours post application. Washout periods between treatments were 5 to 14 days. Naltrexone was given to block the opioid effects of fentanyl. Study results indicate that external heat had a similar effect on both matrix and reservoir systems, with heat applied during the first 10 hours of treatment increasing fentanyl exposure by approximately 61% to 81% at 10 hours (observed serum concentration at 10 hours) and overall exposure (area under the curve from 0 to 10 hours) by approximately 120% to 184%, but had minimal effect from 26 to 36 hours. The increased exposure observed with heat in both 25 µg/h systems, between 0 and 10 hours, was higher than that obtained with the 50 µg/h reservoir system applied without heat.
... Trends and Alerts Alcohol Club Drugs Cocaine Hallucinogens Heroin Inhalants Marijuana MDMA (Ecstasy/Molly) Methamphetamine Opioids Prescription ... Street names for fentanyl or for fentanyl-laced heroin include Apache, China Girl, China White, Dance Fever, ...
Bista, Sudeep Raj; Hardy, Janet; Tapuni, Angela; Fu, Jinlin; Gibbons, Kirsten; Good, Phillip; Norris, Ross; Haywood, Alison
The therapeutic efficacy of a transdermal system (TDS) is directly related to the adhesion of TDS, with partial adhesion resulting in lower plasma concentration. Currently there is no TDS adhesion scoring tool available for use in the clinical setting. To validate a U.S. Food and Drug Administration (FDA) scoring system for the adhesion of the fentanyl TDS in cancer patients. A library of images was created from photographs of fentanyl/placebo TDS placed on patients/volunteers. Thirty photographs, reflecting varying degrees of adhesion, were selected for each of series A and B, with 10 photographs common to both series. Each series was shown to 30 health professionals asked to score the photographs using the FDA scoring system. Validity was assessed using Spearman's rank correlation and reliability by Cohen's kappa (k). Photo editing software was used to assign control scores to each photograph. Validity was high for both series (≥ 0.954). Inter-reliability (k) ranged from 0.327 to 0.858 (average, 0.547) and 0.433-0.910 (average, 0.620) in series A and B, respectively. The combined agreement across both series was 0.585. Intra-rater agreement (k) of the 10 common images was 0.605. No significant difference was observed between the scoring patterns for those with more than 10 years of working experience. Overall, the TDS adhesion score determined by the participants visually in this study corresponded well to those generated by photo editing software, thus rendering the scoring system highly valid. The FDA scoring system is an adequate tool for assessing fentanyl TDS adhesion in clinical practice. Copyright © 2015 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.
Nguyen, Thao M; Lee, Sebin; Lee, Sang Bok
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.
Doris, Mhairi K; Sandilands, Euan A
A 19-year-old man with a history of eczema was admitted to the emergency department following collapsing at home. The paramedics found him unresponsive with poor respiratory effort and a widespread erythematous rash. Anaphylaxis, thought to be secondary to flucloxacillin he had recently been prescribed, was diagnosed. Epinephrine, steroids and antihistamines were administered without clinical improvement. On arrival to hospital, constricted pupils were noted prompting the emergency physicians to consider opiate toxicity. Intravenous naloxone brought about an immediate recovery. His father subsequently disclosed that he had given his son one of his own fentanyl patches to alleviate the distressing symptoms of eczema. Although the patient had removed the patch prior to collapsing, he had suffered life-threatening opioid toxicity likely due to enhanced opiate absorption through eczematous skin. This case highlights the risks associated with fentanyl patches in patients with chronic skin conditions.
Reddy, Akhila; Yennurajalingam, Sriram; Reddy, Suresh; Wu, Jimin; Liu, Diane; Dev, Rony; Bruera, Eduardo
One-third of cancer patients require opioid rotation (OR) to treat uncontrolled pain or opioid-induced neurotoxicity. Although fentanyl is the most frequently rotated opioid in cancer patients, the accurate opioid rotation ratio (ORR) from transdermal fentanyl (TDF) to other so-called "strong" opioids is unknown. We aimed to determine the ORR of TDF to strong opioids, as measured by morphine equivalent daily dose (MEDD). We reviewed 2471 consecutive patient visits (938 patients) to our supportive care center for an OR from TDF to strong opioids. Information regarding demographics, symptoms, and MEDD was collected in patients who followed up within six weeks. Linear regression analysis was used to estimate the ORR between TDF dose and net MEDD (MEDD after OR minus MEDD of the breakthrough opioid used along with TDF before OR). Among 47 eligible patients, the median age was 54 years, 53% were male, and 77% had advanced cancer. The median time to follow-up was 14 days. Uncontrolled pain (83%) was the most common reason for OR. In patients with OR and no worsening of pain at follow-up (n = 41), the median ORR (range) from TDF mg/day to net MEDD mg/day was 100 (12.5-217) and from TDF mcg/hour to net MEDD was 2.4 (0.3-5.2); the correlation of TDF dose to net MEDD was 0.60 (P < 0.0001). The median ORR from TDF mg/day to MEDD is 100 and from TDF mcg/hour to MEDD is 2.4, suggesting that TDF 100 mcg/hour is equivalent to an MEDD of 240 mg. Copyright © 2016 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.
Freise, K J; Newbound, G C; Tudan, C; Clark, T P
Application of transdermal drugs to different anatomical sites can result in different absorption characteristics. The pharmacokinetics (PKs) and bioequivalence of a single 2.6 mg/kg (50 μL/kg) dose of a novel, long-acting transdermal fentanyl solution were determined when applied topically to the ventral abdominal or dorsal interscapular skin of 40 healthy laboratory Beagles. The PKs were differentiated by a more rapid initial absorption of fentanyl from the dorsal application site. Mean plasma fentanyl concentrations remained above 0.6 ng/mL from 4 to 96 h in the dorsal application group and from 8 to 144 h in the ventral application group. Bioequivalence analysis demonstrated that the sites were not equivalent; the 90% confidence intervals of the ratio of the geometric means for both the maximum concentration (C(max)) and the area under the curve (AUC) were not contained within the 80-125% interval. The C(max) was 2.34 ± 1.29 (mean ± standard deviation) and 2.02 ± 0.84 ng/mL for the ventral and dorsal application groups, respectively. The terminal elimination half-lives (t(1/2)) for both groups were similar with values of 137 ± 58.9 and 117 ± 59.6 h for the ventral and dorsal application site groups, respectively. A mean absorption rate of ≥ 2 μg · kg/h was maintained from 2 to 144 h following dorsal application and from 2 to 264 h following ventral application. These results suggest that transdermal fentanyl solution could be applied as a single dose to the dorsal scapular area 2-4 h prior to surgery with analgesia lasting a minimum of 4 days. © 2012 Blackwell Publishing Ltd.
Rajabi, Mina; Roxhed, Niclas; Shafagh, Reza Zandi; Haraldson, Tommy; Fischer, Andreas Christin; Wijngaart, Wouter van der; Stemme, Göran; Niklaus, Frank
This paper demonstrates flexible and stretchable microneedle patches that combine soft and flexible base substrates with hard and sharp stainless steel microneedles. An elastomeric polymer base enables conformal contact between the microneedle patch and the complex topography and texture of the underlying skin, while robust and sharp stainless steel microneedles reliably pierce the outer layers of the skin. The flexible microneedle patches have been realized by magnetically assembling short stainless steel microneedles into a flexible polymer supporting base. In our experimental investigation, the microneedle patches were applied to human skin and an excellent adaptation of the patch to the wrinkles and deformations of the skin was verified, while at the same time the microneedles reliably penetrate the surface of the skin. The unobtrusive flexible and stretchable microneedle patches have great potential for transdermal biointerfacing in a variety of emerging applications such as transdermal drug delivery, bioelectric treatments and wearable bio-electronics for health and fitness monitoring.
Rajabi, Mina; Roxhed, Niclas; Shafagh, Reza Zandi; Haraldson, Tommy; Fischer, Andreas Christin; van der Wijngaart, Wouter; Stemme, Göran; Niklaus, Frank
This paper demonstrates flexible and stretchable microneedle patches that combine soft and flexible base substrates with hard and sharp stainless steel microneedles. An elastomeric polymer base enables conformal contact between the microneedle patch and the complex topography and texture of the underlying skin, while robust and sharp stainless steel microneedles reliably pierce the outer layers of the skin. The flexible microneedle patches have been realized by magnetically assembling short stainless steel microneedles into a flexible polymer supporting base. In our experimental investigation, the microneedle patches were applied to human skin and an excellent adaptation of the patch to the wrinkles and deformations of the skin was verified, while at the same time the microneedles reliably penetrate the surface of the skin. The unobtrusive flexible and stretchable microneedle patches have great potential for transdermal biointerfacing in a variety of emerging applications such as transdermal drug delivery, bioelectric treatments and wearable bio-electronics for health and fitness monitoring. PMID:27935976
... who are taking regularly scheduled doses of another narcotic (opiate) pain medication, and who are tolerant (used to the effects of the medication) to narcotic pain medications. Fentanyl is in a class of ...
Barratt, Daniel T.; Klepstad, Pål; Dale, Ola; Kaasa, Stein; Somogyi, Andrew A.
Common adverse symptoms of cancer and chemotherapy are a major health burden; chief among these is pain, with opioids including transdermal fentanyl the mainstay of treatment. Innate immune activation has been implicated generally in pain, opioid analgesia, cognitive dysfunction, and sickness type symptoms reported by cancer patients. We aimed to determine if genetic polymorphisms in neuroimmune activation pathways alter the serum fentanyl concentration-response relationships for pain control, cognitive dysfunction, and other adverse symptoms, in cancer pain patients. Cancer pain patients (468) receiving transdermal fentanyl were genotyped for 31 single nucleotide polymorphisms in 19 genes: CASP1, BDNF, CRP, LY96, IL6, IL1B, TGFB1, TNF, IL10, IL2, TLR2, TLR4, MYD88, IL6R, OPRM1, ARRB2, COMT, STAT6 and ABCB1. Lasso and backward stepwise generalised linear regression were used to identify non-genetic and genetic predictors, respectively, of pain control (average Brief Pain Inventory < 4), cognitive dysfunction (Mini-Mental State Examination ≤ 23), sickness response and opioid adverse event complaint. Serum fentanyl concentrations did not predict between-patient variability in these outcomes, nor did genetic factors predict pain control, sickness response or opioid adverse event complaint. Carriers of the MYD88 rs6853 variant were half as likely to have cognitive dysfunction (11/111) than wild-type patients (69/325), with a relative risk of 0.45 (95% CI: 0.27 to 0.76) when accounting for major non-genetic predictors (age, Karnofsky functional score). This supports the involvement of innate immune signalling in cognitive dysfunction, and identifies MyD88 signalling pathways as a potential focus for predicting and reducing the burden of cognitive dysfunction in cancer pain patients. PMID:26332828
Small, Gary; Dubois, Bruno
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.
Reddy, Akhila; Tayjasanant, Supakarn; Haider, Ali; Heung, Yvonne; Wu, Jimin; Liu, Diane; Yennurajalingam, Sriram; Reddy, Suresh; de la Cruz, Maxine; Rodriguez, Eden Mae; Waletich, Jessica; Vidal, Marieberta; Arthur, Joseph; Holmes, Carolyn; Tallie, Kimmie; Wong, Angelique; Dev, Rony; Williams, Janet; Bruera, Eduardo
Transdermal fentanyl (TDF) is 1 of the most common opioids prescribed to patients with cancer. However, the accurate opioid rotation ratio (ORR) from other opioids to TDF is unknown, and various currently used methods result in wide variation of the ORR. The objective of this study was to determine the ORR of the oral morphine equivalent daily dose (MEDD) to the TDF dose when correcting for the MEDD of breakthrough opioids (the net MEDD) in cancer outpatients. The records of 6790 consecutive patients were reviewed at the authors' supportive care center from 2010 to 2013 to identify those who underwent rotation from other opioids to TDF. Data regarding Edmonton Symptom Assessment Scale scores and MEDDs were collected for patients who returned for a follow-up visit within 5 weeks. Linear regression analysis was used to estimate the ORR between the TDF dose and the net MEDD (the MEDD before opioid rotation [OR] minus the MEDD of the breakthrough opioid used along with TDF after OR). In total, 129 patients underwent OR from other opioids to TDF. The mean patient age was 56 years, 59% were men, and 88% had advanced cancer. Uncontrolled pain (80%) was the most frequent reason for OR. In 101 patients who underwent OR and had no worsening of pain at follow-up, the median ORR from net MEDD to TDF (in mg per day) was 0.01 (range, -0.02 to 0.04), and the correlation coefficient of the TDF dose to the net MEDD was 0.77 (P < .0001). The ORR was not significantly impacted by body mass index or serum albumin. The ORR of 0.01 suggests that an MEDD of 100 mg is equivalent to 1 mg TDF daily or approximately 40 micrograms per hour of TDF (1000 micrograms/24 hours). The median ORR from MEDD to TDF in mg per day was 0.01. These results warrant further studies. © 2015 American Cancer Society.
Fong Yen, Woo; Basri, Mahiran; Ahmad, Mansor; Ismail, Maznah
Galantamine hydrobromide is formulated in tablets and capsules prescribed through oral delivery for the treatment of Alzheimer's disease. However, oral delivery of drugs can cause severe side effects such as nausea, vomiting, and gastrointestinal disturbance. Transdermal delivery of galantamine hydrobromide could avoid these unwanted side effects. In this work, galantamine hydrobromide was formulated in gel drug reservoir which was then fabricated in the transdermal patch. The in vitro drug release studies revealed that the drug release from the donor chamber to receptor chamber of Franz diffusion cell was affected by the amount of polymer, amount of neutralizer, amount of drug, types of permeation enhancer, and amount of permeation enhancer. Visual observations of the gels showed that all formulated gels are translucent, homogeneous, smooth, and stable. These gels have pH in the suitable range for skin. The gel also showed high drug content uniformity. Hence, this formulation can be further used in the preparation of transdermal patch drug delivery system. PMID:25853145
Glenn, Irene M.; Dallery, Jesse
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…
Wang, Hao; Pastorin, Giorgia; Lee, Chengkuo
A wearable adhesive skin patch for transdermal drug delivery is developed with bendable microneedles, dry adhesive and triboelectric energy harvester (TEH). The bendable microneedle array can overcome the needle breakage issue. The dry adhesive can realize a conformal attachment. The TEH can generate power when attached on flat skin or joint to power active components to be integrated in the future.
Sørensen, Lars T; Jorgensen, Lars N; Zillmer, Rikke; Vange, Jakob; Hemmingsen, Ulla; Gottrup, Finn
Cigarette smokers deposit less collagen, expressed as hydroxyproline, in granulation tissue than nonsmokers. We studied the effect of abstinence from smoking and transdermal nicotine patches on deposition of hydroxyproline, proline, type I procollagen, and total proteins. Fifty-four healthy smokers were studied during 10 days of smoking and again from days 10 to 20 following smoking cessation. After the first 10 days of abstinence they were randomized to double-blind treatment with transdermal nicotine patches of 25 mg/day or placebo for a period of 10 days. During this period and during smoking, an expanded polytetrafluoroethylene tube was implanted into the subcutis. Following removal of the implant, total amino acids and peptides were extracted. Hydroxyproline and proline were analyzed by high-pressure liquid chromatography, type I procollagen was analyzed by enzyme-linked immunoassay, and total proteins were determined colorimetrically. In the 39 subjects who complied with the study protocol, abstinence from smoking did not affect the deposition of hydroxyproline, proline, type I procollagen, or total protein in the implants. During abstinence, the type I procollagen level increased by 18% in the transdermal nicotine patches group and decreased by 10% in the placebo group (p<0.05). We conclude that 20 days of abstinence from smoking does not affect collagen deposition in granulation tissue. However, in abstinent smokers, transdermal nicotine patches appears to increase type I collagen synthesis.
Glenn, Irene M; Dallery, Jesse
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 women) completed the four 5-day phases of the study: baseline, patch treatment, voucher treatment, and return to baseline. The order of the two treatment phases was counterbalanced across participants. In the patch treatment condition, participants wore a 14-mg transdermal nicotine patch every day. In the voucher treatment condition, participants received vouchers contingent on abstinence from smoking, defined as producing carbon monoxide (CO) readings of < or =4 parts per million. Participants e-mailed two video clips per day showing them breathing into a CO monitor and the resulting CO reading to clinic staff. In the voucher treatment, 24% of samples were negative, and 5% of samples were negative in the patch treatment. Results suggest that contingent vouchers were more effective than transdermal nicotine patches in promoting abstinence.
Shin, Soo Hyeon; Ghosh, Priyanka; Newman, Bryan; Hammell, Dana C; Raney, Sam G; Hassan, Hazem E; Stinchcomb, Audra L
At elevated temperatures, the rate of drug release and skin permeation from transdermal delivery systems (TDS) may be higher than at a normal skin temperature. The aim of this study was to compare the effect of heat on the transdermal delivery of two model drugs, nicotine and fentanyl, from matrix-type TDSs with different formulations, using in vitro permeation tests (IVPT). IVPT experiments using pig skin were performed on two nicotine and three fentanyl TDSs. Both continuous and transient heat exposures were investigated by applying heat either for the maximum recommended TDS wear duration or for short duration. Continuous heat exposure for the two nicotine TDSs resulted in different effects, showing a prolonged heat effect for one product but not the other. The Jmax enhancement ratio due to the continuous heat effect was comparable between the two nicotine TDS, but significantly different (p < 0.05) among the three fentanyl TDSs. The Jmax enhancement ratios due to transient heat exposure were significantly different for the two nicotine TDSs, but not for the three fentanyl TDSs. Furthermore, the transient heat exposure affected the clearance of drug from the skin depot after TDS removal differently for two drugs, with fentanyl exhibiting a longer heat effect. This exploratory work suggests that an IVPT study may be able to discriminate differences in transdermal drug delivery when different TDS are exposed to elevated temperatures. However, the clinical significance of IVPT heat effects studies should be further explored by conducting in vivo clinical studies with similar study designs.
Ahad, Hindustan Abdul; Ishaq, Beludari Mohammed; Shaik, Muneer; Bandagisa, Faheem
The purpose of this investigation was to prepare matrix type transdermal patches of Tramadol HCl using various ratios of Ficus carica fruit mucilage and Povidone. The matrix type transdermal patches were prepared using Tramadol HCl with Ficus carica fruit mucilage and Povidone. The interactions between Tramadol HCl with F. carica fruit mucilage and Povidone were performed by Differential Scanning Calorimetry (DSC) and Fourier Transform Infrared spectroscopy (FTIR). The prepared patches were examined for physicochemical characterization and in vitro drug permeation studies (using a Keshary-Chien diffusion cell across hairless Albino rat skin), skin irritation studies and accelerated stability studies. The drug was found to be free from negligible interactions with the polymers used. The formulated patches possessed satisfactory physicochemical properties, in vitro drug permeation and devoid of serious skin irritation. The selected formulation (F-5) was retains the characteristics even after the accelerated environmental conditions. The study concludes that F. carica fruit mucilage with Povidone is a good combination for preparing transdermal patches.
The Transdermal Drug Delivery System (TDDS) is one of the novel routes for systemic delivery of drugs through intact skin. A transdermal patch (TP) is a medicated patch that is placed on skin for delivery of medication through skin into the blood stream. The aim of present study was to formulate and evaluate a Unani transdermal patch that could be used for antiemetic therapy. The incorporation of Unani ingredients, namely, Khardal (Brassica nigra), Zanjabeel (Zingiber officinale), Podina (Mentha arvensis), and Sirka (Vinegar) were envisaged. The TP was prepared by solvent evaporation technique and was evaluated for organoleptic characteristics and other physicochemical properties, such as thickness, weight uniformity, folding endurance, moisture content, drug content, and tolerability and acceptability of patch. The in vitro permeation study of the patch was carried out through Franz diffusion cell using egg shell membrane as barrier membrane. Phosphate buffer pH 7.4 was used as dissolution medium and the temperature was maintained at 37 ± 1°C. The in vitro permeation study of the prepared TP indicated a time dependent increase in drug release throughout the study. The percentage of cumulative drug release was found to be 77.38% in 24 hours. The study shows a new approach to work in Unani pharmaceutics. PMID:27403377
Mato Montero, Abigail; Limeres Posse, Jacobo; Tomás Carmona, Inmaculada; Fernández Feijoo, Javier; Diz Dios, Pedro
Transdermal scopolamine has been shown to be very useful in the management of drooling, particularly in patients with neurological or neuropsychiatric disturbances or severe developmental disorders. In this paper, we present the case of a 24-year-old patient with a diagnosis of cerebral palsy and a severe problem of drooling, exacerbated by marked mandibular prognathism. After exclusion of other therapeutic alternatives, it was decided to use sustained-release transdermal scopolamine patches (Scopoderm TTS). This technique consists of the application every three days of a patch with 1.5 mg of scopolamine in the area of the mastoid apophysis; the patch releases a dose of 0.5 mg of the active substance over each 24 hour period. The patient underwent periodic clinical and laboratory follow-up over a period of three years, achieving satisfactory results with no significant undesirable effects.
Warburton, D M; Mancuso, G
The purpose of this study was to determine whether a transdermal nicotine patch will produce the same effects on performance and mood as cigarette smoking. The nicotine patch improved attentional processing and produced some improvements in memory. It produced the calming effects of smoking and induced feelings of happiness which were increased with smoking. These effects were obtained 6 h after application of the patch, showing that acute tolerance for these behavioural effects had not developed completely, if at all, after exposure to nicotine, although it is still possible that tolerance might occur with longer exposure.
Richmond, R L; Kehoe, L; de Almeida Neto, A C
A total of 305 subjects from Sydney were randomly allocated to receive either an active (24 hour transdermal nicotine patch over a 10 week course) or placebo nicotine patch. All subjects participated in a multicomponent cognitive-behavioural smoking cessation programme over five weeks in two-hour group sessions. The continuous abstinence rates at three years (validated by expired carbon monoxide) were 13.8% for the active group and 5.2% for placebo group (p = 0.011). The active nicotine patch with behavioural therapy achieved more than double the abstinence rates early in treatment compared with placebo and this difference was maintained throughout the three year follow up.
Arnold, L Eugene; Lindsay, Ronald L; López, Frank A; Jacob, Sharon E; Biederman, Joseph; Findling, Robert L; Ramadan, Yaser
Stimulant medications (amphetamine and methylphenidate) are the best-documented treatments for attention-deficit/hyperactivity disorder, but their short pharmacokinetic and behavioral half-lives have historically produced irksome time-course effects. New drug-delivery systems designed to eliminate the need for frequent dosing include the methylphenidate transdermal system, in which the matrix acts as both the drug reservoir and the skin adhesive. The methylphenidate transdermal system patch, in contrast to long-acting oral preparations, requires a paradigmatic shift in clinical thinking, as well as refinement of clinical management skills. For dosing with the methylphenidate transdermal system patch, clinicians must think in terms of a retrievable form of drug delivery (in milligrams per hour) rather than a fixed nonretrievable dose (in milligrams per dose or milligrams per day). Clinicians and patients can determine the optimal clinical dose by controlling 2 variables: (1) patch size (controlling milligrams per hour) and (2) duration of patch wear. The new paradigm is worth learning, because the patch offers several advantages over oral preparations for some patients, chiefly individualized control over effect duration (determined by when the patch is applied in the morning and removed in the afternoon/evening). Taking full advantage of this treatment option requires educating the patient and parents regarding practical elements of daily use. These elements include patch-site selection, application techniques, management of wear time to optimize the daily time course of clinical benefits, and skin hygiene. This article summarizes clinical principles that physicians may find useful in managing this new addition to the attention-deficit/hyperactivity disorder treatment armamentarium.
Zuppa, Athena F.; Tejani, Shamim M.; Cullen, Edward J.; Nadkarni, Vinay M.
Clonidine is used for hypertension and narcotic withdrawal prophylaxis in adults and children. This study described plasma absorption of clonidine from whole and cut transdermal clonidine patches. This was a retrospective descriptive study in an 18 bed multidisciplinary pediatric intensive care unit, evaluating 15 critically ill children with a median age of 1.1 years (range 0.3–11 years) treated with transdermal clonidine for narcotic withdrawal prophylaxis, and who had plasma clonidine concentrations measured. An assessment of the relationship between clonidine dose and patch integrity (whole vs. cut) with plasma concentrations was performed, with further analysis by Spearman Correlation Coefficient. Clonidine doses averaged 7.5±4.2 μg/kg/day (range 2.3–20 μg/kg/day) for 9.8±4.3 days (range 4–20 days). There were 9 cut patches and 6 whole patches. The average prescribed dose delivered by cut patches was 6.4±3 μg/kg/day, resulting in a mean plasma concentration of 1±1.1 ng/ mL (range <0.05–3.3 ng/mL). The average prescribed dose delivered by whole patches was 7±1.7 μg/kg/day, resulting in a mean plasma concentration of 0.55±0.3 ng/mL (range 0.13–1.5 ng/mL). The Spearman Correlation Coefficient was calculated to evaluate the correlation between dose and concentration. For whole and cut patches the correlation coefficient was 0.94 (P=0.005) and 0.72 (P=0.002), respectively. Doses ranging from 1.7 to 20 μg/kg/day using whole patches resulted in no plasma concentrations >2 ng/mL. However, a plasma concentration >2 ng/mL was achieved with a dose of 8.8 μg/kg/day delivered by a cut patch. In addition, the 2 samples that resulted in undetectable concentrations were taken from patients who were treated with cut patches. The results from this pilot study suggest that critically ill children absorb clonidine from transdermal patches, but the rate and extent of absorption appears to be more predictable with the use of whole patches compared to patches
Tønnesen, P; Nørregaard, J; Simonsen, K; Säwe, U
The use of nicotine chewing gum combined with psychological support improves the success rate in quitting smoking. We studied the safety and efficacy of a transdermal nicotine patch in smoking cessation. We conducted a double-blind randomized study comparing the effects of a 16-hour nicotine patch (15 +/- 3.5 mg of nicotine in 16 hours) with those of a placebo patch. Of the 289 smokers (207 women and 82 men) enrolled in the study, 145 were treated with nicotine patches and 144 with placebo patches for 16 weeks. Rates of sustained abstinence were significantly better with active treatment than with placebo: 53, 41, 24, and 17 percent of those in the nicotine-patch group were abstinent after 6, 12, 26, and 52 weeks, respectively, as compared with 17, 10, 5, and 4 percent of those in the placebo-patch group (P less than 0.0001). Only two subjects with the nicotine patch and one with the placebo patch had to withdraw from the study because of side effects. The nicotine skin patch proved to be safe and effective, as demonstrated by a higher rate of abstinence than with placebo. However, the absolute rate of abstinence after one year was only 17 percent, which is lower than the rate in studies that have combined the use of nicotine chewing gum with behavioral therapy.
Dengiz, Alan; Meng, Xiangyi; Olin, Jason T.
Objective: To evaluate the long-term safety, tolerability, and efficacy of 2 strategies for switching from donepezil to rivastigmine transdermal patches in patients with mild to moderate Alzheimer's disease. Method: This was a prospective, 25-week, randomized, open-label, parallel-group study to evaluate an immediate or delayed switch (7-day withdrawal) from donepezil (5 to 10 mg/d) to rivastigmine transdermal patches (4.6 mg/24 h). Participants included male and female patients, aged ≥ 50 years, with a DSM-IV-TR diagnosis of mild to moderate dementia of the Alzheimer's type, defined as a Mini-Mental State Examination score of 10–24, inclusive. Patients were enrolled between February 2007 and February 2008. The study was split into a 5-week core phase and a 20-week extension phase. Safety and efficacy results from the extension phase are presented. Results: Both switching strategies were well tolerated. Rates of discontinuation for any reason were similar between the groups. Discontinuations due to adverse events were also similar, and the incidence of gastrointestinal adverse events was low. Apart from Alzheimer's Disease Cooperative Study–Activities of Daily Living Scale scores, at the end of the study, there was no statistically significant change from baseline in cognitive, behavioral, or global outcomes. Over half of the patients preferred rivastigmine transdermal patches to a tablet. Conclusions: This study suggests that the majority of patients receiving donepezil tablets can be safely switched to rivastigmine transdermal patches without significant deterioration in cognition, behavior, and global functioning. Trial Registration: clinicaltrials.gov Identifier: NCT00305903 PMID:21274364
Lee, Jeong Woo; Choi, Seong-O; Felner, Eric I.
Clinical impact of biotechnology has been constrained by the limitations of traditional hypodermic injection of biopharmaceuticals. Microneedle patches have been proposed as a minimally invasive alternative. In this study, we assess the translation of a dissolving microneedle patch designed for simple, painless self-administration of biopharmacetucials that generates no sharp biohazardous waste. To study pharmacokinetics and safety of this approach, human growth hormone (hGH) was encapsulated in 600 μm long dissolving microneedles composed of carboxymethylcellulose and trehalose using an aqueous, moderate-temperature process that maintained complete hGH activity after encapsulation and retained most activity after storage for up to 15 months at room temperature and humidity. After manual insertion into the skin of hairless rats, hGH pharmacokinetics were similar to conventional subcutaneous injection. After patch removal, the microneedles had almost completely dissolved, leaving behind only blunt stubs. The dissolving microneedle patch was well tolerated, causing only slight, transient erythema. This study suggests that a dissolving microneedle patch can deliver hGH and other biopharmaceuticals in a manner suitable for self-administration without sharp biohazardous waste. PMID:21360810
Kim, Yo Han; Choi, Hee Youn; Lim, Hyeong-Seok; Lee, Shi Hyang; Jeon, Hae Sun; Hong, Donghyun; Kim, Seong Su; Choi, Young Kweon; Bae, Kyun-Seop
Background Donepezil is an acetylcholinesterase inhibitor indicated for Alzheimer’s disease. The aim of this randomized, single-blind, placebo-controlled, single-dose, dose-escalation study was to investigate the safety, tolerability, and pharmacokinetics of the donepezil patch in healthy male subjects. Methods Each healthy male subject received a single transdermal donepezil patch (72 hours patch-on periods) of 43.75 mg/12.5 cm2, 87.5 mg/25 cm2, or 175 mg/50 cm2. Serial blood samples were collected up to 312 hours after patch application. The plasma concentrations of donepezil were determined by using a validated liquid chromatography–tandem mass spectrometry method. Pharmacokinetic parameters were obtained by noncompartmental analysis. Tolerability of the patches and performance of the patches (adhesion, skin irritation, residual donepezil content in the patch) were assessed throughout the study. Results The study was completed by 36 healthy subjects. After patch application, the maximal plasma donepezil concentration (Cmax) and the area under the curve (AUC) increased in a dose-proportional manner. Median time to Cmax was ~74–76 hours (~2–4 hours after patch removal), and mean t1/2β was ~63.77–93.07 hours. The average donepezil residue in the patch after 72 hours was ~73.9%–86.7% of the loading dose. There were neither serious adverse events nor adverse events that lead to discontinuation. Skin adhesion of the patch was good in 97.2% of the subjects. All skin irritations after patch removal were mild and were resolved during the study period. Conclusion The donepezil patch appeared to be generally well tolerated and adhesive. Pharmacokinetic analysis of the donepezil patch demonstrated linear kinetics. PMID:25792802
Sadeghi, Mohsen; Ganji, Fariba; Taghizadeh, Seyyed Mojtaba; Daraei, Bahram
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. PMID:28479923
Gao, Yanli; Liang, Jinying; Liu, Jianping; Xiao, Yan
The combination therapy of gestodene (GEST) and ethinylestradiol (EE) has shown advanced contraception effect and lower side effect. The present study was designed to develop a weekly sustained release matrix type transdermal patch containing GEST and EE using blends of different polymeric combinations. The multiple-layer technique was adopted in order to maintain a steady permeation flux for 7 days. The effects of polymer types, polymer ratios, permeation enhancers, drug loadings and drug ratios in different layers on the skin permeations of the drugs were evaluated using excised mice skin. Polariscope examination was carried out to observe the drug distribution behavior. The formulation with the mixture of polyvinyl alcohol (PVA) and polyvinyl pyrrolidone (PVP) (7:1) was found to provide the regular release and propylene glycol (PG) could enhance the permeation fluxes of drugs. Double-layer transdermal drug delivery system (TDDS) could sustain the steady permeation flux of drugs for 7 days when the ratio of drug in drug release layer and drug reservoir layer was 1:4 with the identical total drug amount. The in vitro transdermal permeation fluxes were 0.377 microg/cm(2)/h and 0.092 microg/cm(2)/h, for GEST and EE respectively. The uniformity of dosage units test showed that the distribution of drugs in the matrix was homogeneous, which was further demonstrated by the polariscope result. The developed transdermal delivery system containing GEST and EE could be a promising non-oral contraceptive method.
Gupta, Varsha; Singh, Swati; Srivarstava, Madhumita; Ahmad, Hafsa; Pachauri, Shakti Deep; Khandelwal, Kiran; Dwivedi, Pankaj; Dwivedi, Anil Kumar
This research aims at the development of controlled release contraceptive transdermal patches of centchroman using ethylcellulose (EC) as film-forming polymer, polydimethylsiloxane (PDMS) as pressure sensitive adhesive with propylene glycol and Di-n-butyl-phthalate for their penetration enhancer and plasticizing properties, respectively. The physicochemical compatibility of the drug and the polymers was performed by differential scanning calorimetry and Fourier transform infrared (FTIR) spectroscopic technique. Effects of EC and PDMS ratios on moisture uptake, moisture content, tensile strength (TS), Young's modulus, adhesive strength, water vapor transmission rate (WVTR) and in vitro permeation of centchroman through Sprague-Dawley rats abdominal skin using Franz's diffusion cell were evaluated. A 3(2) full factorial design was employed to observe the effect of independent variables; concentration of ethyl cellulose and PDMS on drug permeated after 32 h, which was selected as dependent variable. Compatibility studies suggested that there were no significant interaction between the drug and polymers used. It was found that incorporation of only EC resulted in too hard patches and addition of PDMS produced patches with lower TS, increased percentage elongation, WVTR and Young's modulus. Statistical analyses suggested that independent variables have a significant effect on the dependent variable. All formulation follows zero-order release kinetics with r(2) > 0.990. In conclusion, drug in adhesive transdermal patches can be successfully fabricated for non-steroidal contraceptive centchroman to obtain a zero-order release systems.
Kajaysri, Jatuporn; Chumchoung, Chaiwat; Wutthiwitthayaphong, Supphathat; Suthikrai, Wanvipa; Sangkamanee, Praphai
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
Seong, Keum-Yong; Seo, Min-Soo; Hwang, Dae Youn; O'Cearbhaill, Eoin D; Sreenan, Seamus; Karp, Jeffrey M; Yang, Seung Yun
Proteins are important biologic therapeutics used for the treatment of various diseases. However, owing to low bioavailability and poor skin permeability, transdermal delivery of protein therapeutics poses a significant challenge. Here, we present a new approach for transdermal protein delivery using bullet-shaped double-layered microneedle (MN) arrays with water-swellable tips. This design enabled the MNs to mechanically interlock with soft tissues by selective distal swelling after skin insertion. Additionally, prolonged release of loaded proteins by passive diffusion through the swollen tips was obtained. The bullet-shaped MNs provided an optimal geometry for mechanical interlocking, thereby achieving significant adhesion strength (~1.6Ncm(-2)) with rat skin. By harnessing the MN's reversible swelling/deswelling property, insulin, a model protein drug, was loaded in the swellable tips using a mild drop/dry procedure. The insulin-loaded MN patch released 60% of insulin when immersed in saline over the course of 12h and approximately 70% of the released insulin appeared to have preserved structural integrity. An in vivo pilot study showed a prolonged release of insulin from swellable MN patches, leading to a gradual decrease in blood glucose levels. This self-adherent transdermal MN platform can be applied to a variety of protein drugs requiring sustained release kinetics. Copyright © 2017 Elsevier B.V. All rights reserved.
Findling, Robert L; Dinh, Steven
Transdermal technology is currently approved in the US for the administration of more than 20 medications. This current review describes the clinical research pertaining to the use of a methylphenidate patch in the treatment of attention-deficit hyperactivity disorder (ADHD) in children and adolescents. PubMed searches were conducted using the search term 'methylphenidate transdermal system', and were limited to clinical trials. No limits were set for dates of publication. A total of 21 citations were identified. Studies evaluating the safety and efficacy of the methylphenidate transdermal system (MTS) in children and adolescents were included in this review. Additional studies were identified from bibliographies and the 'Related Citations' section of PubMed searches. The MTS delivers a range of methylphenidate doses using a drug-in-adhesive matrix patch. According to current labeling, the patch should be applied to the hip once daily for a maximum of 9 h. Serum methylphenidate levels increase over wear time, with mean time to maximum concentration (t max) reached between 8 and 10 h for a 9-h wear time, and the elimination half-life for methylphenidate is 3-4 h after patch removal. In clinical trials, ADHD symptoms were measured using the ADHD Rating Scale, Version IV, and several parent-, teacher-, and patient-rated scales. Treatment effects show statistically significant differences from baseline symptom scores starting at the first evaluation, 2 h after the patch is applied, with significant benefit lasting up to 12 h with a 9-h wear time. Adverse events with the MTS are similar to those seen with other formulations of methylphenidate, with the exception of skin-related reactions at the site of application, which were generally mild to moderate in severity. The incidence of contact allergic dermatitis with MTS is <1%. Statistically significant improvements in health-related quality of life and medication satisfaction were also observed with the MTS compared with
Bai, Jie; Lu, Yang; Li, Peng-yue; Liu, Cong-min; Wu, Hui-chao; Wen, Ran; Du, Shou-ying
Current work aimed to develop and evaluate a transdermal delivery system of hydrogel patch for ferulic acid to treat skin damage induced by UV radiation. VISCOMATE(TM) NP700, dihydroxy aluminium aminoacetate, glycerine, tartaric acid were used in combination in different ratios to design the hydrogel patch. In vitro release rate was selected as an index to optimize the formulation. The formulated hydrogel patch was evaluated by several parameters like tacking strength, cohesive strength, peeling strength, residuals after peeling and drug content determination. The in vitro penetration was determined by Franz diffusion technology with hairless mouse skin as permeability media. Different kinetics models were employed to simulate the release and penetrate patterns of ferulic acid from patches in order to investigate the drug transport mechanism. The residual drugs in the patch and skin were determined after the penetration experiment. The optimized preparation was dihydroxy aluminium aminoacetate: NP700: glycerine: ferulic acid as a ratio of 0.02:0.4:1.5:1.25:0.25. The cumulative percentage of release was 60.4465±1.7679% for 24h, which results from a combination of diffusion effect and polymer erosion effect. For the barrier of stratum corneum, the cumulative penetrate rate was only 1.3156±0.3588% and the release mechanism turn out to be the effect of erosion of polymer surface. The residual drugs in the patch were 97.5949±1.4932%. The in vitro data revealed that it was easy for ferulic acid to release from the paste while difficult to permeate through the skin barrier, which resulted in most of drugs residued in the paste. Hence, further experiments will be necessary for finding the penetration enhancer in ferulic acid transdermal delivery.
The annual risk of venous thrombosis has been estimated at 5 to 10 cases per 100 000 women aged 15 to 44 years who are not using hormonal contraception.The risk increases with age for all women. Combined oral oestrogen-progestin contraceptives increase the risk of venous and arterial thrombosis. The risk of venous thrombosis varies, depending on which oestrogen-progestin combination is used. It is about 20 cases per 100,000 woman-years with contraceptives combining norethisterone or levonorgestrel with ethinylestradiol at doses below 50 microgram.The risk is twice as high with third-generation oral contraceptives. In addition to the oral route, hormonal contraception is available as a a transdermal patch or a vaginal ring. What is the risk of thrombosis associated with these non-oral forms? A cohort study showed that the risk of venous thrombosis was approximately 8-fold higher among women using a transdermal patch and 7-fold higher in those using a vaginal ring compared to women not using contraception. Another study on arterial thrombosis demonstrated a statistically significant increase in the risk of stroke among vaginal ring users, but not in the risk of myocardial infarction. In practice, overall, these data show that the use of contraceptive transdermal patch or the contraceptive vaginal ring increases the risk of venous thrombosis.The excess risk of arterial thrombosis is unknown.When hormonal contraception is requested, it is better to recommend a combination containing levonorgestrel and less than 50 microgram of ethinylestradiol per tablet, which carries a lower risk of venous or arterial thrombosis.
Tang, Jian; Fan, Jin; Yao, Yilun; Cai, Weihua; Yin, Guoyong; Zhou, Wei
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
Poplawski, Steven; Johnson, Matthew; Philips, Philip; Eberhart, Leopold H J; Koch, Tilo; Itri, Loretta M
Fentanyl iontophoretic transdermal system (ITS) [IONSYS(®), The Medicines Company, Parsippany, NJ, USA] is a needle-free, patient-controlled, postoperative opioid pain management treatment. It is indicated for the short-term management of acute postoperative pain in adults requiring opioid analgesia in the hospital. The safety and effectiveness of fentanyl ITS for acute postoperative pain management has been demonstrated in a range of surgery and patient types studied in seven phase 3 trials (three placebo-controlled trials and four active-comparator trials). The majority of the patients in the phase 3 trials had undergone either abdominal/pelvic, orthopedic, or thoracic surgery. Consistent with the prescribing information, physicians in clinical practice may treat patients with this system following any type of surgery including those that may not have been included in the phase 3 trials. The purpose of this case series is to illustrate how fentanyl ITS is being utilized for postoperative pain management in real-world clinical practice following a variety of surgeries and in current pain management protocols that may have evolved since the completion of the phase 3 program. There are seven cases from three clinical centers described within this case series, each using fentanyl ITS according to the prescribing information. The surgery types included are bariatric (N = 3), prostate (N = 2), colorectal (N = 1), and perirectal abscess drainage (N = 1). A systematic review of each patient chart was conducted via a standardized retrospective assessment by the clinicians who managed each patient. Additionally, each healthcare professional was interviewed regarding their overall experience and key learnings using fentanyl ITS. Overall, fentanyl ITS was effective and well tolerated in these case reports in current-day clinical practice settings. These case studies are informative about fentanyl ITS use shortly after product approval and set the stage for
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
Raine, Tina R.; Epstein, Laura B.; Harper, Cynthia C.; Brown, Beth A.; Boyer, Cherrie B.
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
Coplan, Paul M; Sessler, Nelson E; Harikrishnan, Venkatesh; Singh, Richa; Perkel, Charles
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.
Patient-Controlled Fentanyl Iontophoretic Transdermal System Improved Postoperative Mobility Compared to Intravenous Patient-Controlled Analgesia Morphine: A Pooled Analysis of Randomized, Controlled Trials.
Oliashirazi, Ali; Wilson-Byrne, Timothy; Shuler, Franklin D; Parvizi, Javad
Postoperative pain management protocols that use patient-controlled analgesia (PCA) can hinder mobility due to attached machinery and tubing. Immobility in the postoperative setting can increase complications, length of stay (LOS), and costs. Early and enhanced mobilization can reduce the cost of care while improving patient outcomes. A needle-free, compact, patient-activated, and portable fentanyl iontophoretic transdermal system (fentanyl ITS, IONSYS; The Medicines Company, Parsippany NJ) has been shown to provide comparable efficacy and tolerability to intravenous (IV) PCA morphine that promotes improved mobility. This pooled analysis of 1,882 patients across three randomized, controlled trials compared fentanyl ITS to IV PCA morphine for postoperative pain management. Outcomes of patient mobility were assessed by a validated Patient Ease of Care Questionnaire that was given to patients, patients' nurses, and physical therapists involved in patient care. Safety was assessed via spontaneously reported treatment-emergent adverse events (TEAE). Fentanyl ITS significantly improved overall patient mobility, each mobility subscore (P < 0.0001) across all demographics (male/female; elderly/non-elderly; normal BMI/overweight/obese/morbidly obese) and surgery types, and was consistent across nurses and physical therapists mobility assessments. TEAEs were generally similar between the two groups. However, more patients reported an opioid-related TEAE with morphine IV PCA than with fentanyl IV PCA (P = 0.003). Due to improved mobility with fentanyl ITS, complications are expected to be less frequent than with IV PCA and epidural PCA. Incorporation of this strategy into postoperative pain management protocols may reduce LOS and total hospital costs. © 2016 World Institute of Pain.
Merema, Danielle K; Schoenrock, Emily K; Le Boedec, Kevin; McMichael, Maureen A
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).
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
Elshoff, Jan-Peer; Timmermann, Lars; Schmid, Miriam; Arth, Christoph; Komenda, Michael; Brunnert, Marcus; Bauer, Lars
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
Jung, Eunjae; Lee, Eun Young; Choi, Hoo-Kyun; Ban, Sang-Jun; Choi, Seung-Hyuk; Kim, Jung Sun; Yoon, In-Soo; Kim, Dae-DuK
The aim of this study was to develop drug-in adhesive (DIA) patch formulations for the transdermal delivery of fluoxetine (FX). The DIA patch formulations containing FX were prepared and optimized with various pressure sensitive adhesives, drug contents and enhancers. Among the various formulations, DuroTak 87-502B-based patch formulation containing 20% (w/w) FX with no enhancer was selected for in vivo pharmacokinetic study based on in vitro permeation studies using hairless mouse, rat and human cadaver skins. The Cmax of FX after the transdermal administration of the optimized patch formulation in rats was 52.38 ng/ml, and plasma concentration of FX was maintained for 36 h. Moreover, the predicted human Css (55.79 ng/ml) and Cmax (27.35 ng/ml) were in good agreement with the reported plasma levels (15-55 ng/ml) of oral FX in clinical applications. These results suggest that the optimized patch formulation could be further developed for clinical applications, providing the therapeutic plasma level of FX over an extended period. To the best of our knowledge, our results are the first reported in vitro and in vivo data on the preparation and optimization of FX-loaded DIA patch, showing its feasibility as an effective transdermal delivery system for FX.
Myung, Seung Kwon; Yoo, Keun-Young; Oh, Seung Won; Park, Seong Hi; Seo, Hong Gwan; Hwang, Seung Sik; Park, Sue Kyung
The one-year effectiveness of transdermal nicotine patches versus placebo patches for smoking cessation based on continuous or sustained abstinence was studied. A literature search of MEDLINE (PubMed), EMBASE, and the Cochrane Central Register of Controlled Trials up to April 2006 was conducted. Articles containing relevant keywords were reviewed by two evaluators independently. To be considered for inclusion in the meta-analysis, studies had to be randomized clinical trials with a transdermal nicotine patch group and a placebo patch group, had to include at least one year of follow-up, had to have abstinence biochemically verified, and had to include the odds ratio (OR) as an outcome measure. Sixteen trials met the selection criteria. The total number of subjects was 9457 (6084 in the nicotine patch group and 3373 in the placebo patch group). The pooled OR for smoking abstinence at one year for the nicotine patch group versus the placebo patch group was 1.79 (95% confidence interval [CI], 1.55-2.08). The pooled OR for one-year continuous or sustained abstinence for the nicotine patch compared with placebo, excluding four studies reporting only point-prevalence abstinence, was 1.75 (95% CI, 1.49-2.05). A meta-analysis of trials of transdermal nicotine patch therapy versus placebo for smoking cessation yielded ORs for smoking abstinence of about 1.8 at one year after the start of therapy. ORs were similar whether the endpoint was point-prevalence abstinence, continuous or sustained abstinence, or both.
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
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.
Saluja, Sonal; Kasha, Purna C; Paturi, Jyotsna; Anderson, Carter; Morris, Russell; Banga, Ajay K
The nature of Alzheimer's disease limits the effectiveness of available oral treatments. The aim of this study was to assess the feasibility of transdermal iontophoretic delivery of donepezil in a hairless rat model as a potential treatment modality in Alzheimer's and to evaluate the effect of current densities on its pharmacokinetics. Donepezil loaded integrated Wearable Electronic Drug Delivery (WEDD(®)) patches supplied current levels of 0, 0.13, 0.26 and 0.39 mA. Plasma extracted donepezil was analyzed by HPLC. Noncompartmental analysis was used to characterize disposition of the drug. The amount delivered across hairless rat skin and areas under the curve (AUC) were found to rise in proportion to the current levels. Peak plasma levels of 0.094, 0.237 and 0.336 μg/ml were achieved at 0.13, 0.26 and 0.39 mA respectively. Time to peak plasma concentrations was after termination of current and same for all current levels. Transdermal elimination half-life was significantly increased from the true value of 3.2h due to depot formation, prolonging complete absorption of the drug. Donepezil was successfully delivered iontophoretically at levels sufficient to produce pharmacodymanic effect. Pharmacokinetic analysis demonstrated linear kinetics at the current levels used and flip flop kinetics following iontophoretic administration. Copyright © 2013 Elsevier B.V. All rights reserved.
Marinangeli, Franco; Ciccozzi, Alessandra; Aloisio, Luca; Colangeli, Antonello; Paladini, Antonella; Bajocco, Chiara; Coaccioli, Stefano; Varrassi, Giustino
The aim of the study was to facilitate dose escalation of strong opioids. In this randomized open-label study the influence of tramadol on dose adjustment of transdermal fentanyl in advanced cancer pain control was prospectively evaluated. Seventy patients affected by intractable cancer disease with visual analog scale (VAS) score >3 were enrolled. Thirty-five patients were treated conventionally with increasing transdermal fentanyl dosage as required (group F) and 35 patients received oral tramadol added to their transdermal fentanyl before each increment of the transdermal opioid dosage (group T). Pain control was equally satisfactory in the two groups. VAS scores at baseline (T: 4.36 +/- 1.53; F: 4.51 +/- 1.36; n.s.) and at the end of the study (T: 1.8 +/- 1.6; F: 1.6 +/- 1.5; n.s.) did not differ. However, in the tramadol group this level of pain control was achieved with much slower dose escalation of fentanyl. The mean application time of the fentanyl-Transdermal Therapeutic System patch for each dosage (25, 50, 75 microg/hour) was significantly greater in patients receiving tramadol. No patient in group T escalated to the 100 microg/hour patch, while in 12 patients of group F the 100 microg/hour patch was applied after a 75 microg/hour patch mean application period of 18.6 +/- 4.7 days. The number of fentanyl-TTS dosage changes was significantly lower in group T (1.2 +/- 0.4 vs. 2.3 +/- 0.5; P < 0.05). The mean total duration of treatment in group T, was 37.1 +/- 11.6 days. The amount of fentanyl used at study end was 56.6 +/- 11.2 microg/hour plus 141.1 +/- 151.9 mg tramadol per day (median: 200 mg/day) in group T patients compared with 84.1 +/- 12.2 microg/hour in group F patients (P < 0.05). The combination of a strong opioid with a weak opioid to treat severe cancer pain allowed a more gradual increase of analgesic delivery than was possible using fentanyl-TTS alone, minimizing periods of under- and overdosing. In addition, it considerably slowed the
Pu, Tingting; Li, Xiaohui; Sun, Yuming; Ding, Xue; Pan, Yaqing; Wang, Qing
The current study aimed to develop a prolonged-release pramipexole (PPX) transdermal patch for the treatment of Parkinson's disease. Permeation parameters of PPX were investigated using human cadaver skin. Pramipexole patches were prepared using DURO-TAK(®) pressure-sensitive-adhesive (PSA) and evaluated for drug stability, drug loading, in vitro drug release, and in vitro permeation through mouse skin. The results indicated that blends of DURO-TAK(®) 87-2852 and DURO-TAK(®) 87-2510 were suitable for creating a prolonged-release PPX patch due to their advantages in drug release, drug loading, and stability. The final formulation consisted of 87-2852/87-2510 (70:30), 10% PG, and 15% PPX and showed a cumulative permeation amount of 1497.19 ± 102.90 μg/cm(2) with a continuous flux over 6.0 μg/(cm(2)·h) across human cadaver skin for 7 days. In vivo studies in rats indicated that PPX patch produced a significantly longer (p < 0.001) half-life (t 1/2, 75.16 ± 17.37 h) and mean residence time (MRT, 135.89 ± 24.12 h) relative to oral tablets (Sifrol(®)) and had a relative bioavailability of 51.64 ± 21.32%. Therefore, this study demonstrated the feasibility of developing a prolonged-release PPX patch, which proposed the potential to serve as an alternate to conventional oral tablets and may therefore improve patient compliance.
Fentanyl iontophoretic transdermal system versus morphine intravenous patient-controlled analgesia for pain management following gynecological surgery: a meta-analysis of randomized, controlled trials.
Saffer, Craig S; Minkowitz, Harold S; Ding, Li; Danesi, Hassan; Jones, James B
To compare the efficacy and safety of patient-controlled fentanyl iontophoretic transdermal system (ITS) with morphine intravenous (i.v.) patient-controlled analgesia (PCA) for pain management following gynecological surgery. Two-open-label, multicenter, randomized, active-controlled, parallel-group studies (n = 1142) were conducted that compared fentanyl ITS with morphine iv. PCA for postoperative pain. The subgroup of gynecological surgery patients from each trial was utilized for this meta-analysis (n = 604). Of these patients, 295 received fentanyl ITS (40 μg/dose) and 309 received morphine i.v. PCA (1 mg/dose) for up to 72 h. Efficacy measures included the patient global assessment (PGA) and the investigator global assessment (IGA) of the method of pain control. Gynecological surgery patients (n = 604) included in this meta-analysis had a mean age of 45 years, were predominantly Caucasian (65%) and had a mean body mass index of 29 mg/kg2. There were statistically significantly more patients treated with fentanyl ITS and more investigators who rated their pain control method as 'excellent' on the PGA at 24 h (49.3 vs 37.4%, respectively; p = 0.0029) and IGA at the last assessment (59.5 vs. 38.0%, respectively; p < 0.0001), respectively, compared with morphine iv. PCA at the last assessment. Following gynecological surgery, patients and investigators were more satisfied (had a higher percent of an 'excellent' rating on the PGA and IGA, respectively) with fentanyl ITS than morphine iv. PCA as a method of pain control.
Yang, Zhen; Teng, Yang; Wang, Hao; Hou, Huimin
A reservoir-type transdermal delivery system (TDS) of bufalin was designed and evaluated for various formulation variables like different penetration enhancers, formulation matrix, rate controlling membranes as well as biopharmaceutical characteristics. Hairless mouse skin was used in permeation experiments with Franz diffusion cells. In vitro skin permeation study showed that terpenes, especially d-limonene was the most effective enhancer when ethanol and PG were used as the vehicle with a synergistic effect. Among different rate controlling membranes, ethylene vinyl acetate (EVA) membrane containing 19% vinyl acetate demonstrated a more suitable release rate for bufalin than the other membranes. In vivo pharmacokinetic study of the bufalin patch in rat showed steady-state of bufalin from 3h to 12 h. In vivo release rate and cumulative amount analyzed by deconvolution method demonstrated the sustained release of bufalin as long as the patch remained on the animal for at least 12 h. The MRT increased from 1h of IV administration to 9h of transdermal administration. In vitro permeation across mouse skin was found to have biphasic correlation with plasma AUC in the in vivo pharmacokinetic study. Current in vitro-in vivo correlation (IVIVC) enabled the prediction of pharmacokinetic profile of bufalin from in vitro permeation results. In conclusion, current reservoir transdermal patch containing 10% D-limonene as a permeation enhancer, 40% ethanol, 30% PG and 15% carbopol-water gel complex provided an improved sustained release of bufalin through transdermal administration. The bufalin patch was successfully applied to biopharmaceutical study in rats and demonstrated the feasibility of this transdermal formulation for future development and clinical trials. Copyright © 2013 Elsevier B.V. All rights reserved.
Comparison of fentanyl iontophoretic transdermal system and routine care with morphine intravenous patient-controlled analgesia in the management of early postoperative mobilisation: results from a randomised study
Langford, Richard M; Chang, Kuang-Yi; Ding, Li; Abraham, Jeffrey
Introduction: Fentanyl iontophoretic transdermal system (ITS) (IONSYS®, The Medicines Company, Parsippany, NJ, USA) and morphine intravenous (IV) patient-controlled analgesia (PCA) have demonstrated equivalent pain control in several published studies. The primary objective of the current study was to compare fentanyl ITS with morphine IV PCA with regard to the patient’s ability to mobilise with acute postoperative pain. Methods: In this multicentre, open-label, randomised, active-controlled, prospective phase IV study, postoperative patients initially received IV morphine and were titrated to pain score ⩽ 4out of 10 on a Numeric Rating Scale (NRS) and then received fentanyl ITS (up to 240 µg (6 doses)/hour; up to a maximum of 3.2 mg (80 doses)/24 hours) or morphine IV PCA (doses up to 20 mg morphine/2 hours, up to 240 mg/24 hours). The primary efficacy measure was ability to mobilise, assessed using patient responses to three validated questions regarding mobility on a 6-point Likert scale (0 = no difficulty to mobilise to 5 = a very great deal of difficulty to mobilise). The study was originally planned to include ~200 patients. However, following the early suspension and termination of the study, a total of 108 patients were randomised to study treatment. Results: One hundred and eight patients were recruited prior to undergoing surgical procedures (orthopaedic surgical procedures (72%) or underwent major abdominal procedures (28%)). Postoperatively, 58 were randomised to receive fentanyl ITS, and 50 to morphine IV PCA. Fentanyl ITS patients had a greater ability to mobilise at the time of stopping study drug, with an adjusted mean ability to mobilise score (95% confidence interval (CI)) of 0.14 (−0.19, 0.47) for fentanyl ITS patients and 2.37 (1.98, 2.76) for morphine IV PCA patients (p < 0.001). Conclusion: Patients treated with fentanyl ITS reported that they were better able to mobilise than patients treated with morphine IV PCA, at all time
Hu, Ying; Wu, Yao-Yao; Xia, Xiao-Jing; Wu, Zheng; Liang, Wen-Quan; Gao, Jian-Qing
A transdermal drug delivery system has been reported that can increase the bioavailability, reduce the administration duration, and maintain the concentration of drug in blood. In the present study, drug-in-adhesive transdermal patches of α-asarone using Eudragit E100 as pressure-sensitive adhesives and oleic acid plus isopropyl myristate as penetration co-enhancers were developed. In vitro permeation, in vivo pharmacokinetics in rabbits, and efficacy in asthmatic rats were evaluated. The results showed that co-enhancers could induce a synergistic effect on α-asarone permeability. In vivo study suggested that the patch can keep a relatively certain blood level of drug within 10-30 h in rabbits. Furthermore, the patch with the size of 4 cm² containing drug 3 mg/cm² showed a noticeable treating effect on asthmatic rats which is equivalent to the effect of dexamethasone, while avoiding the side-effect induced by the corticorsteroid. This suggests that the drug-in-adhesive transdermal patch is a promising delivery system containing α-asarone to be used for asthma treatment.
Weinberger, Andrea H; Smith, Philip H; Kaufman, Mira; McKee, Sherry A
Transdermal nicotine patch (TNP) is 1 of the most commonly used smoking cessation treatments; however, the efficacy of TNP by sex is not yet clear. The purpose of the current review was to synthesize how sex has been considered in published clinical trials of TNP for smoking cessation. The specific aims of the study were to examine the inclusion of sex in analyses of cessation outcomes, TNP-related variables (compliance, side effects), and quit-related variables (withdrawal, cravings); to review the consideration of sex-related variables (menstrual cycle phase, pregnancy); and to identify needs for future research. Potential articles published through December 31, 2013 were identified through a MEDLINE search of the terms "clinical trial," "nicotine patch," and "smoking cessation." Forty-two studies used all 3 terms and met the inclusion criteria. Approximately half of the studies reported that they considered sex in smoking cessation outcomes, with 15 studies finding no difference by sex and 7 studies finding better outcomes for men versus women. Only 5 studies reported data on outcomes by sex in their publications. No studies reported analysis of TNP compliance or withdrawal by sex. In the 1 study that examined side effects by sex, more women than men reported discontinuing TNP because of skin irritation. No study examined the association of cessation outcomes with menstrual cycle phase. There is a need to include sex in research on TNP, as well as other pharmacological and behavioral smoking treatments, to clarify the picture of treatment efficacy for women compared with men.
Le Loët, Xavier; Pavelka, Karel; Richarz, Ute
Background This study was designed to evaluate the utility of transdermal fentanyl (TDF, Durogesic®) for the treatment of pain due to osteoarthritis (OA) of the knee or hip, which was not adequately controlled by non-opioid analgesics or weak opioids. The second part of the trial, investigating TDF in patients with rheumatoid arthritis (RA) is reported separately. Methods Current analgesia was optimised during a 1-week run-in. Patients then received 28 days treatment with TDF starting at 25 μg/hr, with the option to increase the dose until adequate pain control was achieved. Metoclopramide was taken during the first week and then as needed. Results Of the 159 patients recruited, 75 with OA knee and 44 with OA hip completed the treatment phase, 30 knee and 18 hip patients entered the one-week taper-off phase. The most frequently used maximum dose of TDF was 25 μg/hr. The number of patients with adequate pain control increased during the run-in period from 4% to 27%, and further increased during TDF treatment to 88% on day 28. From baseline to endpoint, there were significant reductions in pain (p < 0.001) and improvements in functioning (p < 0.001) and physical (p < 0.001) and mental (p < 0.05) health. Scores for 'pain right now' decreased significantly within 24 hours of starting TDF treatment. TDF was assessed favourably and 84% of patients would recommend it for OA-related pain. Nausea and vomiting were the most common adverse events (reported by 32% and 26% of patients respectively), despite prophylaxis with metoclopramide, which showed limited efficacy in this setting. Conclusion TDF significantly increased pain control, and improved functioning and quality of life. Metoclopramide appeared to be of limited value in preventing nausea and vomiting; more effective anti-emetic treatment may enable more people to benefit from strong opioids such as TDF. This study suggests that four weeks is a reasonable period to test the benefit of adding TDF to improve pain
Myles, M E; Alack, C; Manino, P M; Reish, E R; Higaki, S; Maruyama, K; Mallakin, A; Azcuy, A; Barker, S; Ragan, F A; Thompson, H; Hill, James M
The identification of factors involved in herpes virus latency and reactivation is critical to a better understanding of the mechanisms essential to viral neuroinvasiveness and neurovirulence. Recurrent episodes of ocular herpes infections cause irreversible corneal scarring and are the primary cause of loss of vision due to an infectious agent in industrialized countries. In this study, we examined the ability of nicotine, a compound known to be involved in stress-associated immunomodulation and recognized as one of the most frequently used addictive agents, to induce ocular shedding in rabbits latently infected with herpes simplex virus type 1 (HSV-1) strain McKrae. New Zealand white rabbits latently infected with HSV-1 at 3-4 weeks post-inoculation were randomly divided into two groups. The corneas of all rabbits were free of lesions as verified by slit lamp biomicroscopy. One group received nicotine by transdermal patch (21 mg/day) for 20 days and the other group served as the control. Reactivation data were obtained by detection of virus in tear film collected by ocular swabbing performed concurrently with the administration of nicotine. Compilation of data from three separate experiments demonstrated that 16.5% (258/1560) of the swabs taken from rabbits treated with nicotine were positive for virus, compared with 8.3% (53/639) of swabs taken from controls. Rabbits receiving nicotine exhibited a significantly (P < 0.0001) higher rate of ocular shedding than controls. The concentration of nicotine in the serum was determined at various times (0-24 hrs) after new patch replacement. Peak (average) serum level of nicotine was obtained 8 hours after patch replacement and exhibited a broad range of values (0.233 microg/mL-6.21 microg/mL). These results suggest that an initial systemic exposure to nicotine significantly increases HSV-1 reactivation. Further studies are needed to reveal any effects of nicotine dependency and nicotine withdrawal on herpesvirus
Tejaswi, Devireddy Venkata; Prabhuji, M L V; Khaleelahmed, Shaeesta
Diclofenac sodium is a nonsteroidal anti-inflammatory drug and is effective in the management of pain following periodontal surgery. However, oral administration of diclofenac can lead to gastrointestinal (GI) complications. To overcome these drawbacks, diclofenac is formulated as a transdermal patch, which delivers the drug into systemic circulation through skin. Twenty patients were selected for root coverage procedures with subepithelial connective tissue grafts bilaterally. Following the surgical procedure on the control sites, oral diclofenac sodium 100 mg was administered QD for 3 days. Following the surgical procedure on the contralateral test site, a transdermal diclofenac patch (TDP) was applied every 24 hours for 3 days. The TDP was effective in postoperative pain control following root coverage procedures with subepithelial connective tissue grafts. Pain tolerance was higher with the TDP as compared to oral administration, as it did not cause any GI complications.
Viscusi, Eugene R; Ding, Li; Phipps, J Bradley; Itri, Loretta M; Schauer, Philip R
Postoperative pain management can be challenging in patients with a high body mass index (BMI) especially as a result of poor venous access and delayed ambulation that can result in serious complications. Fentanyl iontophoretic transdermal system (ITS) is a needle-free, patient-controlled analgesic method available for use in acute postoperative pain. The primary objective of these analyses was to determine if there were any differences between patients with high BMI (>40 kg/m(2)) and lower BMIs (<30 kg/m(2) and 35-40 kg/m(2)) in terms of efficacy or safety. Data from three registration, placebo-controlled trials and three active-comparator trials using fentanyl ITS (IONSYS(®), The Medicines Company, Parsippany, NJ) for the management of postoperative pain were analyzed using BMI categories of <35 kg/m(2), 35-40 kg/m(2), and >40 kg/m(2). The majority of patients had lower abdominal or orthopedic surgery. For these analyses, the primary efficacy variables were assessed via patient global assessment of pain control (PGA) at 24 h and investigator global assessment (IGA) at study discharge. PGA and IGA are categorical 4-point scales (excellent, good, fair, or poor) with treatment "success" defined as either excellent or good. Safety was evaluated via treatment emergent adverse events (TEAEs). There were 1403 patients randomly assigned and treated with fentanyl ITS for at least 3 h (BMI <35 kg/m(2): 1180; 35-40 kg/m(2): 136, BMI >40 kg/m(2): 85; and 2 missing). PGA treatment success, which evaluates the method of pain control, at 24 h was consistent in the high and low BMI groups in patients treated with fentanyl ITS (<35 kg/m(2): 946/1180 [80.2%]; 35-40 kg/m(2): 103/136 [75.7%]; and >40 kg/m(2): 65/85 [76.5%]). The IGA results at study discharge were similar to the PGA. Safety appeared similar with fentanyl ITS across the BMI groups. In these analyses, fentanyl ITS was as efficacious, as assessed by the PGA ratings of treatment "success", in patients
Viscusi, Eugene R; Grond, Stefan; Ding, Li; Danesi, Hassan; Jones, James B; Sinatra, Raymond S
This analysis compared opioid-related adverse events (ORADEs) observed with fentanyl iontophoretic transdermal system (ITS) versus morphine intravenous (iv.) patient-controlled analgesia (PCA) in the management of postoperative pain. Safety data from four Phase IIIB randomized, active-comparator trials were pooled for this analysis (n = 1288 fentanyl ITS and 1313 morphine iv. PCA patients). Treatment-emergent adverse events were collected via spontaneous report. In this post hoc analysis, ORADEs were defined as apnea, confusion, constipation, dyspnea, hypotension, hypoventilation, hypoxia, ileus, nausea, pruritus, somnolence, tachycardia, urinary retention and vomiting. Odds ratios (OR) and 95% CI were calculated for all ORADEs and p-values were based on logistic regression with treatment as effect. There were fewer patients in the fentanyl ITS group compared with the morphine iv. PCA group who experienced at least one ORADE (52.7 vs 59.1%, respectively; OR: 0.772: 95% CI: 0.661-0.901; p = 0.0011). The ORADEs that occurred less frequently in the fentanyl ITS group than in the morphine iv. PCA group included hypotension (3.7 vs 5.5%, respectively; OR: 0.667; 95% CI: 0.459-0.969; p = 0.0338), hypoventilation (0.9 vs 1.9%, respectively; OR: 0.444; 95% CI: 0.217-0.906; p = 0.0256), nausea (40.3 vs 44.5%, respectively; OR: 0.842; 95% CI: 0.721-0.984; p = 0.0310), pruritus (5.5 vs 9.4%, respectively; OR: 0.559; 95% CI: 0.413-0.757; p = 0.0002) and tachycardia (1.6 vs 2.8%, respectively; OR: 0.489; 95% CI: 0.277-0.863; p = 0.0136). No ORADEs occurred more frequently in the fentanyl ITS group compared with the morphine iv. PCA group. Fentanyl ITS, in the management of acute postoperative pain, offered safety advantages in terms of ORADEs compared with morphine iv. PCA.
Toward evidence-based prescribing at end of life: a comparative analysis of sustained-release morphine, oxycodone, and transdermal fentanyl, with pain, constipation, and caregiver interaction outcomes in hospice patients.
Weschules, Douglas J; Bain, Kevin T; Reifsnyder, Joanne; McMath, Jill A; Kupperman, David E; Gallagher, Rollin M; Hauck, Walter W; Knowlton, Calvin H
The primary goal of this investigation was to examine selected outcomes in hospice patients who are prescribed one of three sustained-release opioid preparations. The outcomes examined include: pain score, constipation severity, and ability of the patient to communicate with caregivers. This study included 12,000 terminally ill patients consecutively admitted to hospices and receiving pharmaceutical care services between the period of July 1 and December 31, 2002. We retrospectively examined prescribing patterns of sustained-release morphine, oxycodone, and transdermal fentanyl. We compared individual opioids on the aforementioned outcome markers, as well as patient gender, terminal diagnosis, and median length of stay. Patients prescribed a sustained-release opioid had similar average ratings of pain and constipation severity, regardless of the agent chosen. Patients prescribed transdermal fentanyl were reported to have more difficulty communicating with friends and family when compared with patients prescribed either morphine or oxycodone. On average, patients prescribed transdermal fentanyl had a shorter length of stay on hospice as compared with those receiving morphine or oxycodone. There was no difference in observed pain or constipation severity among patients prescribed sustained-release opioid preparations. Patients receiving fentanyl were likely to have been prescribed the medication due to advanced illness and associated dysphagia. Diminished ability to communicate with caregivers and a shorter hospice course would be consistent with this profile. Further investigation is warranted to examine the correlation between a patient's ability to interact with caregivers and pain control achieved.
Güngör, Sevgi; Bektaş, Ayşegül; Alp, F Ilkay; Uydeş-Doğan, B Sönmez; Ozdemir, Osman; Araman, Ahmet; Ozsoy, Yildiz
The objectives of this study were to develop matrix-type transdermal patches of verapamil hydrochloride (VRP) with pectin as a matrix polymer to investigate the influence of several terpenes on in vitro permeation of VRP through rat skin and to evaluate pharmacodynamic activity of transdermal formulations in rats. Matrix-type transdermal patches containing VRP were prepared using pectin as a matrix agent and propylene glycol as a plasticizer agent. Terpenes such as nerolidol, d-limonene, eucalpytol, menthone, and menthol were also used as a chemical enhancer to improve the skin penetration of VRP. The permeation studies were performed using Franz-type diffusion cells and full-thickness excised abdominal rat skin. Effects of terpenes on the permeation parameters of VRP were evaluated. In vitro skin permeation studies showed that nerolidol was the most promising enhancer among the enhancers examined in the present study, followed by d-limonene. Pharmacodynamic activity of the transdermal patches containing nerolidol or d-limonene was evaluated in rats by the measurement of systolic blood pressure for 360 min with the use of the tail cuff method. VRP transdermal patches significantly decreased the systolic blood pressure after 30 min and transdermal patches containing nerolidol and d-limonene maintained the decrease in blood pressure during the observation of 360 min.
Pongjanyakul, Thaned; Prakongpan, Sompol; Priprem, Aroonsri
Nicotine transdermal patches (NTPs) were fabricated using an acrylic pressure sensitive adhesive emulsion to form a transparent matrix film. An automated thin layer chromatography (TLC) plate scraper was used to control the thickness of the cast nicotine matrix film. The in vitro release behavior and permeation of nicotine across abdominal human epidermis (HE) from the NTPs was studied using United States Pharmacopeia (USP) dissolution apparatus 5 (paddle over disk) and modified Franz-diffusion cell, respectively. The release of nicotine from the NTPs showed a good linear correlation with the square root of time (R2 > 0.99). This indicated a matrix diffusion controlled-release mechanism. The surface morphology of the matrix of the NTP was uniform and nonporous before and after release, indicating that the dried adhesive nicotine matrix was a homogeneous single-phase film. Neither the nicotine content in the range 4.70-8.41% w/w nor the film thicknesses of the NTPs affected the apparent diffusion coefficient of nicotine in the acrylic matrix. A good relationship between the amount of nicotine permeated across the HE and the square root of time was also observed with R2 > 0.98. This study also showed that the NTPs provided a good delivery system with more than 65% of the nicotine delivery being controlled by the device. Moreover, the release of nicotine from six production batches met the criteria of USP 24. This finding presented a good potential of this method for upscaling to industrial manufacturing.
Lemke, John; Sardariani, Edmond; Phipps, Joseph Bradley; Patel, Niki; Itri, Loretta M; Caravelli, James; Viscusi, Eugene R
Fentanyl iontophoretic transdermal system (fentanyl ITS, IONSYS(®)) is a patient-controlled analgesia system used for the management of acute postoperative pain, designed to be utilized in a hospital setting. The objective of the two studies was to determine if fentanyl ITS could be safely used with X-rays, computerized tomography (CT) scans and radiofrequency identification (RFID) devices. The ITS system has two components: controller and drug unit; the studies utilized ITS systems without fentanyl, referred to as the ITS Placebo system. The first study evaluated the effect of X-radiation on the operation of an ITS Placebo system. Five ITS Placebo systems were exposed to X-rays (20 and 200 mSv total radiation dose-the 200 mSv radiation dose represents a tenfold higher exposure than in clinical practice) while operating in the Ready Mode and five were exposed while operating in the Dose Mode. The second study evaluated the effect of RFID (worst-case scenario of direct contact with an RFID transmitter) on the operation of an ITS Placebo system. During these tests, observations of the user interface and measurements of output voltage confirmed proper function throughout all operational modes (Ready Mode, Dose Mode, End-of-Use Mode, and End-of-Life Mode). The ITS Placebo system met all specifications and no functional anomalies were observed during and following X-ray exposure at two radiation dose levels or exposure at six different combinations of RFID frequencies and field strengths. The performance of the ITS system was unaffected by X-ray exposure levels well beyond those associated with diagnostic X-rays and CT scans, and by exposure to radiofrequency field strengths typically generated by RFID devices. These results provide added confidence to clinicians that the fentanyl ITS system does not need to be removed during diagnostic X-rays and CT scans and can also be utilized in close proximity to RFID devices. The studies and writing of this manuscript were
Nishikawa, Rona K; Bell, Suzanne C; Kraner, James C; Callery, Patrick S
Fentanyl is a potent opioid analgesic that is increasingly becoming a choice drug of abuse. Fentanyl transdermal patches (FTPs) are easily obtained and consumed by smoking the reservoir gel and/or the whole patch. This allows for an increased bioavailability when inhaled. A method using analytical pyrolysis was developed to identify possible biomarkers associated with smoked fentanyl and FTPs. Pyrolysis was carried out under anaerobic and aerobic conditions using helium and air coupled to a gas chromatograph-mass spectrometer. The presence of a trap enhanced recovery and afforded a positive identification of pyrolytic products. Anaerobic and aerobic pyrolysis of fentanyl and FTPs consistently yielded propionanilide as the major pyrolytic product along with pyridine and previously reported metabolites (norfentanyl and despropionyl fentanyl). Analysis of fentanyl resulted in chlorine-containing compounds, presumably formed from the HCl salt of fentanyl. Analysis of FTPs showed significant polymeric and hydrocarbon compounds and products likely derived from the gel matrix. Fentanyl in the FTPs was in the citrate salt form; therefore, the chlorine-containing pyrolytic products obtained with the neat drug were not observed. Based on this application, it may be possible to identify what salt form of the drug was smoked based on pyrolytic products and to target distinguishing metabolic products for future research.
Meine, Trip J; Patel, Manesh R; Washam, Jeffrey B; Pappas, Paul A; Jollis, James G
An analysis of smokers admitted with acute coronary syndrome who received transdermal nicotine therapy and those who did not was performed. Propensity analysis was used to match patients. Transdermal nicotine therapy appears safe and does not have an effect on the mortality of patients with acute coronary syndromes.
Gariti, P; Alterman, A I; Barber, W; Bedi, N; Luck, G; Cnaan, A
This study examined plasma cotinine replacement levels of 56 outpatient smokers administered a 21 mg/day transdermal nicotine patch (Nicoderm CQ ). The percentage of cotinine replacement ranged from 35 to 232% (mean 107%; median 90.5%). Four subject variables were found to be significantly correlated with percentage of cotinine replacement-baseline cotinine level, prior quit attempts, gender, and the Fagerström Tolerance Questionnaire score. A two-variable model consisting of baseline cotinine level and gender provided the most powerful predictor combination. The percentage of cotinine replacement was not predictive of post-treatment smoking. The relatively high levels of cotinine replacement obtained using the Nicoderm CQ 21 mg/day patch suggest cautious use of higher dose treatment with this particular patch.
Kurz, A; Farlow, M; Lefèvre, G
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
Ahmed, Osama A A; Afouna, Mohsen I; El-Say, Khalid M; Abdel-Naim, Ashraf B; Khedr, Alaa; Banjar, Zainy M
To optimize and use of glimepiride (GMD)-loaded self-nanoemulsifying delivery systems (SNEDs) for the preparation of transdermal patches. Mixture design was utilized to optimize GMD-loaded SNEDs in acidic and aqueous pH media. Optimized GMD-loaded SNEDs were used in the preparation of chitosan (acidic) and hydroxypropyl methyl cellulose (HPMC) (aqueous) films. The prepared optimized formulations were investigated for ex vivo skin permeation, for in vivo hypoglycemic activity and for their pharmacokinetic parameters using animal model. The optimized formulations showed flux value of (2.88 and 4.428 μg/cm(2)/h) through rat skin for chitosan and HPMC films, respectively. The pattern of GMD release from both formulations was in favor of Higuchi and approaching zero order models. The n values for Korsmeyer-Peppas equation were characteristic of anomalous (non-Fickian) release mechanism. Moreover, HPMC patches have shown significant reductions (p < 0.05) in blood glucose levels; (213.33 ± 15.19) mg/100 ml from the base-line measurement after 12 h of application. Optimized GMD SNEDs patches were found to improve GMD skin permeability and the essential pharmacokinetic parameters. Further extensive pre/clinical studies are necessary prior to use transdermal GMD as a valuable alternative to peroral dosage forms with improved bioavailability, longer duration of action and more patient convenience.
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
Song, Pan-Pan; Jiang, Li; Li, Xiu-Juan; Hong, Si-Qi; Li, Shuang-Zi; Hu, Yue
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.
Baik, Seong Wan; Kim, Kyung Hoon; Kim, Yong Chul; Lee, Sang Chul; Kim, Dong Ki; Jung, Jae Eun
According to the three step-ladder analgesics in patients with cancer pain, adjuvant drugs are required for pain relief according to the pain character and also to reduce side effects of opioids. Pain clinicians sometimes want to decide to jump directly from naive and mild opioid to transdermal therapeutic system (TTS) fentanyl with less side effects. We investigated the safety, efficacy, and satisfaction of the patients of TTS fentanyl converting from opioid-naive and mild-opioid with adjuvant drug medications in related to dose cascade of TTS fentanyl. Both opioid-naive (n=3) and opioid-using (n=34) patients started with TTS fentanyl in the lowest available delivery rate (25 microg/hr) with rescue medication. A numeric rating scale (NRS, from 0=no pain to 10=worst pain imaginable), satisfaction of the patients with the transdermal therapy and side effects were recorded everyday during 29 days. Average reductions of NRS scores were 1.79 and 2.77, and the mean doses were 35.14 and 44.12 microg/hr on the 15th and 29th day, respectively. Reported level of satisfaction with the transdermal patch and generalized pain management were 'completely satisfied' and 'satisfied'. Frequent side effects were nausea, vomiting, and constipation. In conclusion, initial application of TTS fentanyl with proper adjuvant medications is effective, safe, and well tolerated.
Sutou, Ichiro; Nakatani, Toshihiko; Hashimoto, Tatsuya; Saito, Yoji
Opioids are not generally deemed to have an analgesic ceiling effect on cancer pain. However, there have been occasional reports of tolerance to opioid development induced by multiple doses of fentanyl. The authors report a case of suspected tolerance to the analgesic effect of opioid, in which an increasing dose of fentanyl failed to relieve the patient's cancer pain symptoms, but opioid switching to oxycodone injections enabled a dose reduction to below the equivalent dose conversion ratio. The patient was a 60-year-old man diagnosed with pancreatic body carcinoma with multiple metastases. The base dose consisted of 12 mg/day of transdermal fentanyl patches (equivalent to 3.6 mg/day, 150 μg/h fentanyl injection), and rescue therapy consisted of 10 mg immediate-release oxycodone powders. Despite the total daily dose of fentanyl reaching 5.6 mg (equivalent to 560 mg oral morphine), the analgesic effect was inadequate; thus, an urgent adjustment was necessary. Due to the moderate dose of fentanyl, the switch to oxycodone injection was done incrementally at a daily dose equivalent to 25% of the fentanyl injection. The total dose of oxycodone was replaced approximately 53.5% of the dose of fentanyl prior to opioid switching.
Schmidt, Reinhold; Alf, Claude; Bancher, Christian; Benke, Thomas; Berek, Klaus; Dal-Bianco, Peter; Führwürth, Gerhard; Imarhiagbe, Douglas; Jagsch, Christian; Lechner, Anita; Rainer, Michael; Reisecker, Franz; Rotaru, Juliana; Uranüs, Margarete; Walter, Andreas; Winkler, Andreas; Wuschitz, Albert
We performed a 6-month open-label study on the use of the transdermal rivastigmine patch in clinical routine in 103 patients with Alzheimer's disease from 25 outpatient services in Austria. After baseline, safety and tolerability of the 10 cm2--rivastigmine patch was assessed at week 4, 12 and 24 in all patients. A Mini Mental State Examination was done at baseline and at week 12 and 24. Skin adherence of the patch was very good or good in 85% of study participants. Only 2.9% of patients had gastrointestinal adverse events. Local skin reactions occurred in 23% of individuals. Skin alteration were mostly mild in severity. In only 6.8% of subjects did they result in termination of treatment. At the earliest skin reactions were observed after 3 months of treatment. Cognitive functioning of patients improved comparable to the controlled trial which led to approval of the rivastigmine patch. In daily routine the safety profile of the rivastigmine patch is favourable, as is the response to treatment. Local, mostly mild skin reactions affect approximately every fifth patient, and they occur relatively late in the course of therapy. Patients and their caregivers should receive detailed information about skin reactions to omit unnecessary drop outs to treatment.
Krinsky, Clarissa S; Lathrop, Sarah L; Zumwalt, Ross
Fentanyl is a synthetic opioid agonist used for pain control. Often administered as a transdermal patch, it is an interesting drug for study of postmortem redistribution. We hypothesized that fentanyl concentrations would increase over time after death, as measured in blood drawn on the day prior to autopsy and in blood drawn at the time of autopsy in ten cases where fentanyl patches were identified at the scene. Concentrations were compared, and heart blood to femoral blood ratios were calculated as markers of postmortem redistribution. Fentanyl concentrations measured in peripheral blood drawn the day of autopsy (peripheral blood 2 [PB2]) were higher than those drawn the day prior to autopsy (peripheral blood 1 [PB1]) with a mean ratio (PB2/PB1) of 1.80. The ratio of heart blood concentrations (HB) to femoral blood concentrations drawn at autopsy (PB2) had a mean ratio (HB/PB2) of 1.08. Some cases had blood from the same source analyzed at two different laboratories, and concentrations of fentanyl in those samples showed inter- and intralaboratory differences up to 25 ng/mL. Postmortem fentanyl concentrations may be affected by antemortem factors, postmortem redistribution, and laboratory variability. Forensic pathologists must use caution in interpreting fentanyl levels as part of death investigation.
Kovács, G; Zelei, T; Vokó, Z
Transdermal hormone replacement therapy is preferred for menopausal vasomotor symptoms. Our purpose was to compare the efficacy and local tolerability of a patch and a metered-dose transdermal spray that have never been directly compared. The relative change in the number of hot flushes between baseline and week 12 was selected as an efficacy indicator and the frequency of local skin reactions as a tolerability indicator. A network meta-analysis was performed to compare efficacy. Application site tolerability was compared descriptively. Overall 46 studies were identified. In the efficacy analysis, eight active treatment arms and a placebo arm were determined based on the estradiol daily dose (from 14 μg to 50 μg). All but one had a significantly higher effect on relative change in the number of hot flushes than did the placebo. We found no evidence for different efficacy of the patch and the metered-dose transdermal spray. The latter performed better in terms of local skin reactions. The patch and the metered-dose transdermal spray seem to have the same efficacy on vasomotor symptoms in estradiol hormone replacement. The local tolerability of the metered-dose transdermal spray is favorable.
Martinez, S A; Wilson, M G; Linton, D D; Newbound, G C; Freise, K J; Lin, T-L; Clark, T P
A prospective, double-blinded, positive-controlled, multicenter, noninferiority study was conducted to evaluate the safety and effectiveness of transdermal fentanyl solution (TFS) compared with oxymorphone for the control of postoperative pain in dogs. Five hundred and two (502) client-owned dogs were assigned to a single dose of TFS (2.7 mg/kg) applied 2–4 h prior to surgery or oxymorphone hydrochloride (0.22 mg/kg) administered subcutaneously 2–4 h prior to surgery and q6h through 90 h. Pain was evaluated over 4 days by blinded observers using a modified Glasgow composite pain scale, and the a priori criteria for treatment failure was a pain score ≥8 or adverse event necessitating withdrawal. Four TFS- and eight oxymorphone-treated dogs were withdrawn due to lack of pain control. Eighteen oxymorphone-treated, but no TFS-treated dogs were withdrawn due to severe adverse events. The one-sided upper 95% confidence interval of the difference between TFS and oxymorphone treatment failure rates was −5.3%. Adverse events associated with oxymorphone were greater in number and severity compared with TFS. It was concluded that a single administration of TFS was safe and noninferior to repeated injections of oxymorphone for the control of postoperative pain over 4 days at the dose rates of both formulations used in this study. PMID:24344787
Jia, Shu-Shan; Shang, Li; Li, Ming-E; Zhao, Dong-Mei; Xu, Wen-Hua; Wang, Yao-Qi
The aim of this study was to identify predictive factors for higher conversion ratio in opioid switching from oral oxycodone to transdermal fentanyl (TDF) in patients with cancer pain. The participants of this study were 156 hospitalized cancer patients who underwent opioid switching from oral oxycodone to TDF at the Affiliated Hospital of Binzhou Medical University between January 1st, 2010 and March 31st, 2014. Patient characteristics, modified Glasgow Prognostic Score (mGPS), daily oxycodone dose, and reasons for opioid switching were retrospectively collected. The effect of variables on the conversion ratio was analyzed by multiple regression analysis to identify the predictive factors for higher conversion ratio in opioid switching from oral oxycodone to TDF. The results showed that the mGPS (odds ratio [OR], 2.358; 95% CI 1.379-4.031; P = 0.002), the reason for opioid switching (OR, 0.497; 95% CI, 0.298-0.828; P = 0.007) and equivalent oral morphine dose (OR, 1.700; 95% CI, 1.008-2.867; P = 0.046) were found to be significant predictors requiring higher conversion ratio in opioid switching. This study indicates that higher mGPS, poor pain control before switching and higher equivalent oral morphine dose are significant predictors of a need for higher conversion ratio in opioid switching from oral oxycodone to TDF. These results could contribute to the establishment of evidence-based medicine in cancer pain relief. PMID:26221306
Liu, Nannan; Song, Wenting; Song, Tian; Fang, Liang
The aim of this study was to design a novel felbinac (FEL) patch with significantly higher (P < 0.05) skin permeation amount than the commercial product SELTOUCH® using ion-pair and chemical enhancer strategy, overcoming the disadvantage of the large application area of SELTOUCH®. Six complexes of FEL with organic amines diethylamine (DEA), triethylamine (TEA), N-(2'-hydroxy-ethanol)-piperdine (HEPP), monoethanolamine (MEtA), diethanolamine (DEtA), and triethanolamine (TEtA) were prepared by ion-pair interaction, and their formation were confirmed by differential scanning calorimetry (DSC), powder X-ray diffraction (pXRD), infared spectroscopy (IR), and proton nuclear magnetic resonance spectroscopy ((1)H-NMR). Subsequently, the effect of ion-pair complexes and chemical enhancers were investigated through in vitro and in vivo experiments using rabbit abdominal skin. Results showed that FEL-TEA was the most potential candidate both in isopropyl palmitate (IPP) solution and transdermal patches. Combining use of 10% N-dodecylazepan-2-one (Azone), the optimized FEL-TEA patch achieved a flux of 18.29 ± 2.59 μg/cm(2)/h, which was twice the amount of the product SELTOUCH® (J = 9.18 ± 1.26 μg/cm(2)/h). Similarly, the area under the concentration curve from time 0 to time t (AUC0-t ) in FEL-TEA patch group (15.94 ± 3.58 h.μg/mL) was also twice as that in SELTOUCH® group (7.31 ± 1.16 h.μg/mL). Furthermore, the in vitro skin permeation results of FEL-TEA patch was found to have a good correlation with the in vivo absorption results in rabbit. These findings indicated that a combination of ion-pair and chemical enhancer strategy could be useful in developing a novel transdermal patch of FEL.
Derry, Sheena; Stannard, Cathy; Cole, Peter; Wiffen, Philip J; Knaggs, Roger; Aldington, Dominic; Moore, R Andrew
Opioid drugs, including fentanyl, are commonly used to treat neuropathic pain, and are considered effective by some professionals. Most reviews have examined all opioids together. This review sought evidence specifically for fentanyl, at any dose, and by any route of administration. Other opioids are considered in separate reviews. To assess the analgesic efficacy of fentanyl for chronic neuropathic pain in adults, and the adverse events associated with its use in clinical trials. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase from inception to June 2016, together with the reference lists of retrieved articles, and two online study registries. We included randomised, double-blind studies of two weeks' duration or longer, comparing fentanyl (in any dose, administered by any route, and in any formulation) with placebo or another active treatment in chronic neuropathic pain. Two review authors independently searched for studies, extracted efficacy and adverse event data, and examined issues of study quality and potential bias. We did not carry out any pooled analyses. We assessed the quality of the evidence using GRADE. Only one study met our inclusion criteria. Participants were men and women (mean age 67 years), with postherpetic neuralgia, complex regional pain syndrome, or chronic postoperative pain. They were experiencing inadequate relief from non-opioid analgesics, and had not previously taken opioids for their neuropathic pain. The study used an enriched enrolment randomised withdrawal design. It was adequately blinded, but we judged it at unclear risk of bias for other criteria.Transdermal fentanyl (one-day fentanyl patch) was titrated over 10 to 29 days to establish the maximum tolerated and effective dose (12.5 to 50 µg/h). Participants who achieved a prespecified good level of pain relief with a stable dose of fentanyl, without excessive use of rescue medication or intolerable adverse events ('responders
Funke, Adrian Peter; Günther, Clemens; Müller, Rainer Helmut; Lipp, Ralph
The aim of this study was to develop matrix-type transdermal systems (TDSs) containing the highly lipophilic (log P = 5.82) antiestrogen (AE) and the permeation enhancers propylene glycol and lauric acid. For that purpose, permeation of AE from various adhesive matrices through excised skin of hairless mice was evaluated. It was found that pretreatment of the skin with permeation enhancers raised the transdermal flux of subsequently applied antiestrogen. Highest steady-state transdermal fluxes (1.1 microg cm(-2) h(-1)) were obtained from Gelva, polyacrylate adhesive, followed by 0.55 microg cm(-2) h(-1) from Oppanol polyisobutylene, 0.31 microg cm(-2) h(-1) from BIO-PSA silicone, and 0.12 microg cm(-2) h(-1) from Sekisui polyacrylate matrices. In order to develop TDS with high content of fluid permeation enhancer propylene glycol, two different strategies were investigated. One strategy was the addition of hydroxypropyl cellulose (HPC) as thickening agent to Gelva matrices. This allowed for propylene glycol loading levels of up to 30%, resulting in transdermal AE fluxes of 0.09 microg cm(-2) h(-1). On the other hand, a fleece-laminated backing foil was loaded with the described permeation enhancer formulation and laminated with polyacrylate adhesive layer, resulting in transdermal AE fluxes of 0.06 microg cm(-2) h(-1). However, application of these TDSs on skin pretreated with permeation enhancers raised the fluxes to 2.6 microg cm(-2) h(-1) from Gelva/HPC and 0.46 microg cm(-2) h(-1) from fleece/Sekisui.
Reñé, R; Ricart, J; Hernández, B
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.
Arai, Tsutomu; Kashimoto, Yuji; Ukyo, Yoshifumi; Tominaga, Yushin; Imanaka, Keiichiro
To evaluate the efficacy and safety of fentanyl 1 day patch in opioid-naïve patients with non-cancer chronic pain insufficiently relieved by non-opioid analgesics. Two phase III placebo-controlled, double-blind, group-comparison, randomized withdrawal studies were conducted in patients with osteoarthritis and/or low back pain (N01 study) and post-herpetic neuralgia, complex regional pain syndrome, or chronic postoperative pain (N02) in Japan. Both studies consisted of period I (10-29 days of titration, fentanyl 12.5-50.0 µg/h) and period II (12 weeks double-blind). N01, NCT01008618; N02, NCT01008553 MAIN OUTCOME MEASURES: The primary endpoint was the number of days until study discontinuation due to insufficient pain relief in period II, and secondary endpoints included pain scored on visual analog scale (VAS), subject's overall assessment, the number of rescue dose, brief pain inventory short form score, score on short-form 36-item health survey version 2.0, physician's overall assessment, and assessment of adverse events. Of the 218 (N01) and 258 (N02) subjects who entered period I, 150 and 163 subjects entered period II, respectively. In the N01 study, the between-group difference was significant in the VAS score (95% CI: 7.3 [1.1, 13.5] mm, P = 0.0215) but not in the primary endpoint (P = 0.0846, log-rank test). In the N02 study, both primary efficacy (P = 0.0003) and VAS (8.7 [2.4, 15.0] mm, P = 0.0071) results showed that fentanyl was more effective than placebo. The major adverse events were nervous system and gastrointestinal disorders typically associated with opioid analgesic use. The incidence of adverse events in the fentanyl group was 68.5% to 85.7%. Although the primary efficacy results showed significant effects of fentanyl in the N02 but not the N01 study, overall results showed that fentanyl 1 day patch is effective and well tolerated.
Ah, Young-Chang; Choi, Jin-Kyu; Choi, Yang-Kyu; Ki, Han-Moi; Bae, Joon-Ho
A monolithic drug-in-adhesive (MDIA) type patch containing meloxicam (MX) was designed with an acrylic adhesive, a solubility modulator increasing MX solubility, and enhancers. MDIA patches having one adhesive layer between the backing and the release liner give high productivity and improve patient compliance. The biggest problem to prepare MDIA patch including MX was poor solubility of MX. In this research, solubility modulators to increase solubility of MX and acrylic adhesives and skin permeation enhancers were investigated through solubility tests, in vitro skin permeation tests, and stability tests. Consequently, the composition of sodium methoxide (SM), an acrylic adhesive containing poly(vinyl pyrrolidone) blocks (MAS683), polyoxyethylene cetylether (BC-2), and diisopropanolamine (DIPA) made it possible for MX to be contained in an adhesive layer at a concentration of as much as 15 wt% without MX crystal and with high skin permeation over 400 microG/cm(2). Finally, the patch formulation containing MX (MX-patch) selected through our in vitro study was characterized by in vivo using an animal study to acquire pharmacokinetic (PK) parameters and to confirm the anti-inflammatory efficacy of MX-patch. In the animal study, MX-patch was compared with a commercially available piroxicam patch (PX-patch). The amount of MX delivered from MX-patch to the skin surface was believed to be higher than the amount of MX diffused from the skin tissue to circulatory system because the plasma concentration of MX continuously increased up to 32 h, the end time of PK study, although the patch samples were detached at 24 h. PX-patch produced a C(max) at 8 h. MX-patch showed better significant efficacy than PX-patch in adjuvant arthritis model. 2009 Elsevier B.V. All rights reserved.
Han, Hyun Jeong; Lee, Jeong Ju; Park, Sun A.; Park, Hyun Young; Kim, Jeong Eun; Shim, Young Soo; Shim, Dong-Seok; Kim, Eun-Joo; Yoon, Soo Jin
Background and Purpose The goal of this study was to estimate the efficacy and safety of the rivastigmine transdermal patch in patients with probable Alzheimer's disease (AD) who cannot tolerate or do not respond to oral cholinesterase inhibitors (ChEIs). Methods A 24-week, prospective, open-label, single-arm, multicenter study was conducted from June 2009 to June 2010 in patients with probable AD. The enrolled patients had either a poor response or a decline in global function after treatment with oral ChEIs, or they were not able to tolerate treatment with oral ChEIs due to adverse events such as nausea or vomiting. A poor response was defined as a decrease of at least 2 points on the Korean version of the Mini-Mental State Examination (K-MMSE) within the previous 6 months (the decline in global function was determined by the investigator or caregiver). The efficacy of treatment was assessed using a follow-up Clinical Global Impression of Change (CGIC) assessment and K-MMSE conducted after 24 weeks, and safety was measured by the occurrence of adverse events and patient disposition. Results In total, 164 patients aged 74.7±7.52 years (mean±SD) and with 5.12±3.64 years of education were included. The study was completed by 70% of the patients (n=116), with 12.2% discontinuing due to adverse events. The most frequently reported adverse events (11%) were skin lesions, such as erythema or itching, followed by gastrointestinal problems (1.2%). Either an improvement or no decline in CGIC scores was reported for 82% of the patients. Conclusions The immediate switching of patients from an oral ChEI to the rivastigmine transdermal patch without a washout period was safe and well tolerated by the probable-AD patients in this study. PMID:22087207
Baldwin, Claudine M; Keating, Gillian M
*Oxybutynin inhibits contraction of the detrusor muscle in the overactive bladder by binding to muscarinic M(3) receptors and blocking acetylcholinergic activation. *The transdermal oxybutynin system, applied twice weekly, delivers continuous oxybutynin over a 96-hour patch wear period. The transdermal route of administration avoids the extensive first-pass metabolism of oxybutynin to its active metabolite, N-desethyloxybutynin. *In two well designed trials in patients with overactive bladder, transdermal oxybutynin 3.9 mg/day decreased the number of incontinence episodes and increased average voided volume to a significantly greater extent than placebo. Urinary frequency was improved to a significantly greater extent with transdermal oxybutynin than with placebo in one trial but not the other. *There was no significant difference between transdermal oxybutynin and extended-release oral tolterodine for any of these endpoints. *Health-related quality-of-life improvements with transdermal oxybutynin were shown in patients with overactive bladder in the open-label MATRIX trial, as demonstrated by significant improvements in all domains of the King's Health Questionnaire. *Transdermal oxybutynin is generally well tolerated in patients with overactive bladder. The majority of patients who discontinued transdermal oxybutynin treatment in two pivotal trials did so because of application-site reactions. However, none discontinued treatment because of dry mouth.
Viscusi, Eugene R; Ding, Li; Itri, Loretta M
Acute postoperative pain management in the geriatric patient can be challenging, including their response to medications. The purpose of this analysis was to evaluate whether the efficacy and safety profile of fentanyl iontophoretic transdermal system (ITS) (IONSYS(®)) was similar in geriatric (≥65 years) and non-geriatric (<65 years) patients. Efficacy and safety data from three randomized, double-blind, placebo-controlled trials and four randomized, open-label, active-comparator trials were utilized for this analysis. Efficacy was assessed via the patient global assessment (PGA) and the investigator global assessment (IGA) scales. The PGA and IGA are categorical 4-point scales (excellent, good, fair, or poor) with treatment success defined as excellent or good. Safety was evaluated via adverse events. A total of 1763 patients were assigned to the fentanyl ITS treatment group. Of the 1763 patients in the fentanyl ITS group, 499 patients were ≥65 years of age; 65.1% were 65-74 years of age, 31.7% were 75-84 years of age, and 3.2% were ≥85 years of age. In the fentanyl ITS treatment groups, there were no statistically significant differences between the non-geriatric and geriatric patients in terms of patients reporting success on the PGA at 24 h (80.0 vs. 83.0%, respectively; p = 0.3415). There were no statistically significant differences between the groups in success rates on the IGA at study discharge (82.8 vs. 87.5%, respectively; p = 0.1195). The safety profile was similar between the age groups. Overall, efficacy and safety of the fentanyl ITS were similar between the geriatric and non-geriatric patients.
Soler, L I; Boix, A; Lauroba, J; Colom, H; Domenech, J
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.
Nelson, Anita L
The first contraceptive patch with ethinyl estradiol (EE) and norelgestromin in the United States demonstrated that there was a tremendous interest in topical methods, which could provide patient convenience, steady-state hormonal levels and reassurance of ongoing coverage, while maintaining efficacy and good bleeding patterns. Unfortunately, concerns about increased risk of venous thromboembolism (VTE) risk diminished its popularity. Another version in Europe and Canada had slightly lower estrogen doses, but questions were raised about its VTE risk too based on its progestin. To fill that gap, two new contraceptive patches with lower estrogen levels have been developed and extensively tested. This article provides a short overview of the first set of patches followed by discussions of the pharmacokinetics of the two experimental patches as well as the results of their clinical trials, including information about efficacy, bleeding patterns and tolerability. Given the recent increased use of first tier contraceptive methods (Intrauterine devices and implants), there may be interest in new patches. Price will influence their popularity. However, a new nondaily delivery system with lower estrogen levels will provide an important option to women.
Sobue, Satoshi; Sekiguchi, Kaneo; Kikkawa, Hironori; Irie, Shin
The transdermal nicotine patch, which contains 25 mg nicotine per 30 cm(2), is designed to deliver approximately 15 mg nicotine to the blood circulation in 16 hours of application for the treatment of smoking cessation. It was applied to 3 different skin sites (upper arm, abdomen, and back) to examine regional variations in percutaneous nicotine absorption in a single-dose, 3-period, crossover study involving 9 healthy male Japanese smokers. Nicotine pharmacokinetics during once-daily application of the transdermal nicotine patch for 5 days was also investigated in 10 healthy smokers. There were statistically significant effects of application sites on percutaneous nicotine absorption. The ratios (90% confidence intervals) of AUC and C(max) for comparison to the upper arm were 102% (88, 117%) and 106% (95, 119%) for the back and 75% (65, 87%) and 75% (66, 84%) for the abdomen, respectively. These suggest that systemic exposure after application to the upper arm was greater compared with the abdomen but equivalent to the back. Following multiple doses, linear pharmacokinetics and no significant accumulation of nicotine concentrations were observed, and steady state was reached by day 2. Only mild itching and erythema were observed at the application sites. The transdermal nicotine patch was well tolerated in both studies.
Cinciripini, Paul M.; And Others
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…
Archer, D F; Furst, K; Tipping, D; Dain, M P; Vandepol, C
To determine whether a continuous estradiol-norethindrone acetate transdermal delivery system reduces incidence of endometrial hyperplasia in postmenopausal women more than transdermal estradiol (E2) alone. Six hundred twenty-five postmenopausal women were assigned randomly to one of four treatments, transdermal E2 50 microg/day, or transdermal E2-norethindrone acetate with 50 microg E2 and 140, 250, or 400 microg/day of norethindrone acetate. Follow-up visits to collect information on safety and efficacy were scheduled at 3, 6, 9, and 12 months after initiation of treatment. Endometrial biopsy for histologic evaluation was done at baseline and upon exit from the study (completion or withdrawal). Endometrial histology was evaluated by two independent gynecologic pathologists. In the event of a disparate reading, a third gynecologic pathologist evaluated the tissue using predetermined criteria. Endometrial hyperplasia was found in 37.9% (39 of 103) in the E2 alone group versus 0.8% (one of 123), 1% (one of 98), and 1.1% (one of 89) in the E2-norethindrone acetate 50-140, 50-250, and 50-400 groups, respectively (P < .001). Uterine bleeding was less frequent in the E2-norethindrone acetate 50-140 group than other treatments. The mean number of hot flushes per day decreased to less than one in each treatment group at endpoint. The E2-norethindrone acetate combination patch showed skin tolerance comparable to that of E2 alone. Continuous transdermal delivery of E2 combined with norethindrone acetate effectively prevented endometrial hyperplasia in healthy postmenopausal women. Continuous combined transdermal delivery systems provide increased dosing flexibility and might improve convenience and compliance with hormone replacement therapy.
Mukherjee, Biswajit; Mahapatra, Sushmita; Gupta, Ritu; Patra, Balaram; Tiwari, Amit; Arora, Priyanka
The present study was designed to develop a suitable matrix type transdermal drug delivery system (TDDS) of dexamethasone using blends of two different polymeric combinations, povidone (PVP) and ethylcellulose (EC) and Eudragit with PVP. Physical studies including moisture content, moisture uptake, flatness to study the stability of the formulations and in vitro dissolution of the experimental formulations were performed to determine the amount of dexamethasone present in the patches were performed and scanning electron microscopy (SEM) photographs of the prepared TDDS were taken to see the drug distribution pattern. Drug-excipient interaction studies were carried out using Fourier transform infrared (FTIR) spectroscopic technique. In vitro skin permeation study was conducted in a modified Franz's diffusion cell. All the formulations were found to be suitable for formulating in terms of physicochemical characteristics and there was no significant interaction noticed between the drug and polymers used. In vitro dissolution studies showed that the drug distribution in the matrix was homogeneous and the SEM photographs further demonstrated this. The formulations of PVP:EC provided slower and more sustained release of drug than the PVP:Eudragit formulations during skin permeation studies and the formulation PVP:EC (1:5) was found to provide the slowest release of drug. Based on the above observations, it can be reasonably concluded that PVP-EC polymers are better suited than PVP-Eudragit polymers for the development of TDDS of dexamethasone.
Sobue, Satoshi; Sekiguchi, Kaneo; Kikkawa, Hironori; Akasaki, Moriaki; Irie, Shin
Transdermal nicotine patch (TNP) contains approximately 16.6 and 24.9 mg of nicotine per 20 and 30 cm2 (TNP-20 and TNP-30). The aims of the study are to investigate linearity of nicotine pharmacokinetics after single application of different strengths of TNP and to directly compare plasma nicotine concentrations with those during cigarette smoking. Twelve healthy Japanese male smokers were randomly allocated to 1 of 2 cohorts consisting of 6 subjects each. Cohort 1 subjects received 1 sheet of TNP-20 (TNP-20x1) in period 1, and 2 sheets of TNP-20 (TNP-20x2) in period 3. Cohort 2 subjects were received 1 sheet of TNP-30 (TNP-30x1) in period 2, and smoked a total of 12 cigarettes at 1 h intervals in period 4. Each TNP was applied to the upper arm for 16 h. After TNP-20x1 or TNP-20x2 treatment in cohort 1, the amount of nicotine delivered from TNP (Dose) was proportional to surface area of TNP. Cmax and AUC of nicotine increased with the surface area (Dose), and tmax, t(1/2), CL/F and percentage of dose excreted in urine were almost the same between both treatments. These suggest the linear pharmacokinetics of nicotine in proportion to the surface area and Dose following single application of TNP in identical subjects. In cohort 2, the plasma nicotine concentrations after TNP-30x1 treatment were approximately half those just before each smoking.
Salinas-Casado, J; Esteban-Fuertes, M; Serrano, O; Galván, J
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.
Lee, Jae-Hong; Sevigny, Jeff
The rationale for the development of the rivastigmine transdermal patch was to improve upon an efficacious therapy by mitigating certain adverse events, such as nausea and vomiting. This may be particularly important in Alzheimer disease patients with low body weights, who may be more susceptible to these adverse events. This analysis compared the effect of body weight on tolerability in Alzheimer disease patients receiving rivastigmine capsules or rivastigmine patch. Using data from a 24-week trial, adverse events and discontinuations were evaluated in patients stratified on the basis of extreme low weight (<50 kg), medium weight (50 to 80 kg), and high weight (>80 kg) at baseline. Rivastigmine patch was generally well tolerated, regardless of patient body weight. Among patients receiving rivastigmine patch, lower body weight, as stratified, was not associated with a higher adverse event rate; however, there was an association between a higher adverse event rate and low body weight among patients receiving rivastigmine capsules. Discontinuations because of adverse events were not directly related to weight. A lower incidence of adverse events was apparent with transdermal delivery of rivastigmine compared with oral administration.
Langley, Ruth E.; Godsland, Ian F.; Kynaston, Howard; Clarke, Noel W.; Rosen, Stuart D.; Morgan, Rachel C.; Pollock, Philip; Kockelbergh, Roger; Lalani, El-Nasir; Dearnaley, David; Parmar, Mahesh; Abel, Paul D.
OBJECTIVE To assess the hormonal effects of Fem7® (Merck, KGaA, Darmstadt, Germany) 100 μg transdermal oestrogen patches on men undergoing first-line androgen-deprivation therapy for prostate cancer. PATIENTS AND METHODS PATCH is a multicentre, randomized, phase II trial for men with locally advanced or metastatic prostate cancer, comparing luteinizing hormone-releasing hormone agonist therapy with oestrogen patches. To assess the dosing schedule for the patches, as this was the first time that this brand of patch had been used in men, and to reassure patients and participating clinicians, the Independent Data Monitoring Committee agreed to early release of hormonal data from this study. RESULTS Oestradiol, testosterone and prostate-specific antigen (PSA) levels are presented for the first group of 14 patients who received the patches (with 1 withdrawal) and for whom there were ≥12 weeks of follow-up by March 2007. After 12 weeks, testosterone levels (nmol/L) in eight of the 13 patients were <1.7, two were 1.7–2 and three were >2. The median (range) serum oestradiol levels was 442 (52.1–1542) pmol/L and all patients had a PSA response, with eight having a PSA level of <4 ng/mL. CONCLUSION These results confirm that oestrogen patches produce castrate levels of testosterone and concomitant PSA responses. They also highlighted the potential differences between different brands of oestrogen patches, and the need to monitor hormonal response, toxicity and efficacy until more experience with oestrogen patches for this clinical indication is obtained. The number of patches recommended in the PATCH study has now been increased. PMID:18422771
Shi, Yongli; Xu, Shuxin; Dong, Anjie; Zhang, Jianhua
To improve the poor compatibility among different components of Drug-in-adhesive type patch, two novel plasters (Drug-in-fiber and Drug-in-adhesive/fiber) were developed based on ibuprofen (IBU)-loaded fiber mats. These fibrous mats were fabricated via electrospinning of cellulose acetate/poly(vinylpyrrolidone) composites in a binary solvent of N,N-dimethyl acetamide/acetone. Physical status studies suggested that Drug-in-fiber could inhibit IBU re-crystallization, but the active ingredients were released at a relatively slow rate due to the dual-resistance of fiber mat and adhesive matrix. To overcome this shortcoming, Drug-in-adhesive/fiber was designed by coupling medicated hydrophilic pressure sensitive adhesive and IBU-loaded fiber mat. This method endowed Drug-in-adhesive/fiber a fast IBU release rate and high permeated drug amount though simulative skins. This design separated enhancer from adhesive matrix, which guaranteed Drug-in-adhesive/fiber excellent adhesion forces. Hence, the plasters based on medicated fiber mats improved the compatibility among patch components.
Zhang, Chao; Li, Haiyan; Xiong, Xin; Zhai, Suodi; Wei, Yudong; Zhang, Shuang; Zhang, Yuanyuan; Xu, Lin; Liu, Li
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 (Cmax), extended time to reach the Cmax 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. PMID:28331292
Zhang, Chao; Li, Haiyan; Xiong, Xin; Zhai, Suodi; Wei, Yudong; Zhang, Shuang; Zhang, Yuanyuan; Xu, Lin; Liu, Li
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 (Cmax), extended time to reach the Cmax 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.
Hill, Kevin P.; Toto, Lindsay H.; Lukas, Scott E.; Weiss, Roger D.; Trksak, George H.; Rodolico, John M.; Greenfield, Shelly F.
We assessed the feasibility of a new cognitive behavioral therapy (CBT) manual, plus transdermal patch nicotine replacement therapy (NRT), to treat co-occurring nicotine and cannabis dependence. Seven of twelve (58.3%) adults with DSM-IV diagnoses of both nicotine and cannabis dependence completed 10 weeks of individual CBT and NRT. Participants smoked 12.6 ± 4.9 tobacco cigarettes per day at baseline, which was reduced to 2.1 ± 4.2 at the end of treatment (F = 23.5, p<0.0001). The reduction in cannabis use from 10.0 ± 5.3 inhalations per day at baseline to 8.0 ± 5.3 inhalations per day at 10 weeks was not significant (F = 1.12, p=.37). There was a significant decrease from the mean baseline Fagerstrom Test for Nicotine Dependence scores at weeks 4, 6, 8, and 10 of treatment (F = 19.8, p<0.001) and mean Client Satisfaction Questionnaire scores were uniformly high (30.6 ± 1.9). A CBT plus NRT treatment program significantly reduced tobacco smoking but did not significantly reduce cannabis use in individuals with co-occurring nicotine and cannabis dependence. There was no compensatory increase in cannabis use following the reduction in tobacco smoking, suggesting that clinicians can safely pursue simultaneous treatment of co-occurring nicotine and cannabis dependence. The intervention was well-liked by the 7 of the 12 enrollees who completed the study. PMID:23617864
Ise, Yuya; Wako, Tetsuya; Miura, Yoshihiko; Katayama, Shirou; Shimizu, Hisanori
The present study was undertaken to determine the pharmacoeconomics of switching from sustained-release morphine tablet to matrix type (MT) of transdermal fontanel or sustained-release Oxycodone tablet. Cost-effective analysis was performed using a simulation model along with decision analysis. The analysis was done from the payer's perspective. The cost-effective ratio/patient of transdermal MT fontanel (22, 539 yen)was lower than that of sustained -release Oxycodone tablet (23, 630 yen), although a sensitivity analysis could not indicate that this result was reliable. These results suggest the possibility that transdermal MT fontanel was much less expensive than a sustained-release Oxycodone tablet.
Harrison, Lester I; Zurth, Christian; Gunther, Clemens; Karara, Adel H; Melikian, Armen; Lipp, Ralph
A new drug-in-adhesive transdermal patch was developed to deliver both estradiol and levonorgestrel through the skin over a 7-day period, but at different rates. This report elucidates the in vitro and in vivo biopharmaceutical studies that were necessary during the development of this product. Three test patches had to be manufactured, all delivering estradiol at the same rate, but delivering levonorgestrel at three different rates so that a levonorgestrel dose response could be studied in the clinic. An in vitro hairless mouse skin model (HMS) using modified Franz diffusion cells was used to select the test products delivering levonorgestrel in the order of 1:2:3. HMS experiments also demonstrated that the presence of estradiol did not affect the flux of levonorgestrel. Two in vivo studies in postmenopausal women showed that at steady state (four weeks of once-weekly dosing) the three test products all delivered estradiol at comparable rates. Similarly, the levonorgestrel deliveries for the three test products were in the order expected. The target fluxes of both drugs were achieved in these three test products by varying the drug loads and patch size. That this approach was successful is evidence of the value of using the HMS penetration experiments in transdermal product development and should provide useful insights for other formulations having to develop complex systems. One of the test products is now marketed as Climara Pro.
Suzuki, Yoshiki; Kamijo, Yoshito; Yoshizawa, Tomohiro; Fujita, Yuji; Usui, Kiyotaka; Kishino, Tohru
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.
Wang, Wei; Song, Tian; Wan, Xiaocao; Liu, Chao; Zhao, Hanqing; Fang, Liang
The aim of this study was to develop a controlled release drug-in-adhesive patch containing escitalopram (ESP) using ion-pair technique. Special attention was paid on the mechanism of how counter ion controlled the release of ESP. Five organic acids were chosen as the counter ions. Formulation factors including adhesive matrix, drug loading and permeation enhancers were investigated through in vitro experiments using rat skin and the optimized patch was evaluated using in vivo pharmacokinetic study. Drug-counter ion-PSA interactions were characterized by FT-IR, molecular modeling and DSC at molecular level. The optimized patch prepared with ESP-BA showed zero-order skin permeation profile and a satisfied permeation amount of three days (1059±104.9μg/cm(2)) in vitro, which also showed a steady-state drug plasma concentration lasting 36h in vivo and the Cmax was significantly controlled compared with the control group. The controlled release of ESP was attributed to the interactions among ESP-counter ion-PSA by hydrogen bonding, and counter ion enhanced the interaction between ESP and PSA molecule, which acted as a "bridge" between them. In conclusion, a controlled release ESP transdermal patch was developed and a novel insight of ion-pair controlled release was proposed at molecular level. Copyright © 2017 Elsevier B.V. All rights reserved.
Schutter, U; Ritzdorf, I; Heckes, B
The transdermal 7-day buprenorphine matrix patch provides a constant and user-friendly pain management when chronic musculoskeletal pain requires opioids. This analysis of clinical routine data evaluated the benefit of this treatment for patients previously receiving oral long-term treatment with weak opioids alone. Data of 310 patients previously treated with tramadol or tildate/naloxone and part of a multicentre observational study with 3295 patients were analyzed. In 89.7% of the 310 patients oral treatment with weak opioids was replaced by the 7-day buprenorphine patch due to insufficient analgesia. During treatment with the 7-day buprenorphine patch there was a clinically significant decrease of the mean pain intensity at rest during the day from 5.7 to 2.9, on physical effort during the day from 7.3 to 3.8 and at night from 5.2 to 2.3 (11-point NRS scale, p < or = 0.001). In addition, quality of life aspects such as mobility, self-reliance and quality of sleep improved, which are relevant for individual patient satisfaction with pain management. For patients with previous long-term tramadol or tilidate/naloxone treatment the switch to the 7-day buprenorphine matrix patch proved to be effective and safe for the management of chronic pain. The user-friendly 7-day application interval contributes to improving compliance and a reducing exposure to tablets.
... any of the following symptoms: irritability, hyperactivity, abnormal sleep, high-pitched cry, uncontrollable shaking of a part ... palonosetron (Aloxi); selective serotonin-reuptake inhibitors such as citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac, Sarafem, in Symbyax), ...
... drugs (NSAIDs). It works by stopping the body's production of a substance that causes pain. ... in Twynsta), and valsartan (in Exforge HCT); certain antibiotics; beta blockers such as atenolol (Tenormin, in Tenoretic), ...
... certain medical conditions, including disorders of the testicles, pituitary gland, (a small gland in the brain), or ... heart attack, heart failure, or other heart problems; stroke and mini-stroke; liver disease; seizures; or mental ...
... difficulty breathing If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online (http://www.fda.gov/Safety/MedWatch) or by phone (1-800-332-1088).
... 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 ...
... exposed adhesive layer should be avoided to prevent contamination of fingers with scopolamine. Temporary blurred vision and ... may make you drowsy. Do not drive a car or operate machinery until you know how scopolamine ...
... changes in mood and personality) in people with Alzheimer's disease (a brain disease that slowly destroys the memory ... of these abilities, but it does not cure Alzheimer's disease or dementia in people with Parkinson's disease. Continue ...
David, S P; Munafò, M R; Murphy, M F G; Proctor, M; Walton, R T; Johnstone, E C
Smokers of European ancestry (n=720) who participated in a double-blind, randomised, placebo-controlled trial of transdermal nicotine replacement therapy, were genotyped for two functional polymorphisms (variable number of tandem repeats (VNTR) and a C to T transition at position -521 (C-521T)) in the dopamine D4 receptor gene (DRD4) gene. Logistic regression models of abstinence at 12- and 26-week follow-ups were carried out separately for each polymorphism. For the DRD4 VNTR models, the main effect of treatment was significant at both 12-week (P=0.001) and 26-week (P=0.006) follow-ups, indicating an increased likelihood of successful cessation on active nicotine replacement therapy transdermal patch relative to placebo. The main effect of DRD4 VNTR genotype was associated with abstinence at 12-week follow-up (P=0.034), with possession of one or more copies of the long allele associated with reduced likelihood of cessation (17 vs 23%), but this effect was not observed at 26-week follow-up. For the DRD4 C-521T models, no main effect or interaction terms involving genotype were retained in the models at either 12- or 26-week follow-up. These data are consistent with observations from studies of the DRD2 gene that genetic variants related to relatively decreased dopaminergic tone in the mesocorticolimbic system are associated with increased risk for relapse to smoking following a cessation attempt.
López-Cervantes, Miriam; Escobar-Chávez, José Juan; Casas-Alancaster, Norma; Quintanar-Guerrero, David; Ganem-Quintanar, Adriana
Mycetoma is a chronic, degenerative, and incapacitating infection of the skin and subcutaneous tissue. This study focuses on developing a kanamycin-based auxiliary system intended to be used in the treatment of mycetoma caused by Actinomadura madurae. Transdermal patches (with two different formulations: one with free kanamycin [K] and the other one with kanamycin adsorbed in silica [K-SG]) and an emulgel were developed. Both patches were prepared by the casting-evaporation technique. To characterize them, differential scanning calorimetry, bioadhesion, post-moisture detachment, strength and rupture distance, gas exchange, water uptake, and dissolution studies were carried out. The emulgel (containing 0.57% of kanamycin) was prepared from an oil-in-water emulsion, which was then incorporated to a gel. the patches with the best characteristics contained 22.9% of silica and 14.6% of kanamycin. Dissolution studies indicated that 8.8% of kanamycin released from K and 3.2% from K-SG at 24h. The emulgel containing 0.57% of kanamycin showed good technological characteristics for its application to the skin (viscosity, 44.9 +/- 1.4 poises; pH, 6.9 +/- 0.4; and penetrability, 52.7 +/- 5.1). The optimal patches were those containing 15.9% of freely dispersed kanamycin (K) and 14.6% of kanamycin adsorbed in silica (K-SG), which corresponds to the batch 2-0.8. The assessments performed to both pharmaceutical forms (patches and emulgel) show that they have the adequate technological characteristics for being used as an auxiliary in the treatment of actinomycetoma caused by A. madurae.
Hsueh, Shu-Chun; Hsueh, Kuang-Chieh; Chou, Ming-Yueh; Tu, Ming-Shium
`Varenicline use has been shown to produce greater long-term smoking cessation rates than bupropion but has no clear differences compared to the transdermal nicotine patch. We performed this study to compare the effectiveness of varenicline with the nicotine patch at 3 and 6 months of follow-up of patients in an outpatient smoking cessation program provided by a hospital in Southern Taiwan. The sample consisted of 463 patients who attended the smoking cessation program at the outpatient family medicine clinic at Kaohsiung Veterans General Hospital between March 2006 and December 2008. All patients were aged ≥18 years and either smoked ≥10 cigarettes per day or scored ≥4 on the Fagerström Test for Nicotine Dependence. Patients were seen by a physician for up to 8 sessions in 90 days. Medication use was guided by patient preference (208 opted for varenicline and 255 for the nicotine patch). The primary outcomes of the study were self-reported 7-day point prevalence abstinence rates at 3 and 6 months from the first clinic visit. Varenicline users had a significantly higher abstinence rate than those using nicotine patch at 3-month (47.1% vs. 30.6%; odds ratio [OR] = 2.02, 95% confidence interval [CI] = [1.38, 2.96]) and 6-month follow-up (41.3% vs. 30.6%; OR = 1.60, 95% CI [1.09, 2.32]). Both groups had similar incidences of adverse events. Varenicline use in a sample of treatment-seeking-dependent smokers was associated with significantly higher abstinence rates than the nicotine patch.
Ikeda, Ken; Hirayama, Takehisa; Takazawa, Takanori; Kawabe, Kiyokazu; Iwasaki, Yasuo
Objective Parkinson's disease (PD) is characterized by the progressive degeneration of the nigrostriatal dopaminergic neurons. Rotigotine is a non-ergot dopamine receptor agonist (DA). Its transdermal patch maintains the effective concentrations for 24 hours. Freezing of gait (FOG) is a common and devastating symptom in PD patients. Little is known about therapeutic effects of rotigotine on FOG in PD patients. Herein we compared how three non-ergot DAs of rotigotine, pramipexole LA and ropinirole CR influence FOG, besides classical motor deficits in PD patients. Methods Rotigotine (maintenance doses of 9-27 mg/day) was administered in 51 patients, 36 patients received pramipexole LA (1.5-4.5 mg/day) and 35 patients received ropinirole CR (8-16 mg/day). The Unified PD Rating Scale (UPDRS) parts I-IV, FOG questionnaire (16 items) and wearing off time were examined from baseline to 7 months after DA administration. UPDRS parts I-IV were evaluated during on time and FOG was recorded during off time if patients experienced wearing off. Results A total of 111 patients completed the study. UPDRS parts II-III scores and wearing off time were significantly reduced after each DA treatment compared to baseline. FOG was found in 54 patients (49%). Most patients developed FOG during off time only. FOG scores were significantly decreased at 2 months after rotigotine treatment whereas pramipexole LA and ropinirole treatment did not alter FOG scores. Conclusion The present study indicates that transdermal patch of rotigotine attenuated the FOG off time. The similar binding affinities to dopamine receptors between rotigotine and dopamine, and 24 hours steady hemodynamics could contribute to the therapeutic mechanism of rotigotine on FOG in PD patients with wearing off. PMID:27725534
Hadebe, Silindile I.; Ngubane, Phikelelani S.; Serumula, Metse R.; Musabayane, Cephas T.
Purpose Studies in our laboratory are concerned with developing optional insulin delivery routes based on amidated pectin hydrogel matrix gel. We therefore investigated whether the application of pectin insulin (PI)-containing dermal patches of different insulin concentrations sustain controlled release of insulin into the bloodstream of streptozotocin (STZ)-induced diabetic rats with concomitant alleviation of diabetic symptoms in target tissues, most importantly, muscle and liver. Methods Oral glucose test (OGT) responses to PI dermal matrix patches (2.47, 3.99, 9.57, 16.80 µg/kg) prepared by dissolving pectin/insulin in deionised water and solidified with CaCl2 were monitored in diabetic rats given a glucose load after an 18-h fast. Short-term (5 weeks) metabolic effects were assessed in animals treated thrice daily with PI patches 8 hours apart. Animals treated with drug-free pectin and insulin (175 µg/kg, sc) acted as untreated and treated positive controls, respectively. Blood, muscle and liver samples were collected for measurements of selected biochemical parameters. Results After 5 weeks, untreated diabetic rats exhibited hyperglycaemia and depleted hepatic and muscle glycogen concentrations. Compared to untreated STZ-induced diabetic animals, OGT responses of diabetic rats transdermally applied PI patches exhibited lower blood glucose levels whilst short-term treatments restored hepatic and muscle glycogen concentrations. Plasma insulin concentrations of untreated diabetic rats were low compared with control non-diabetic rats. All PI treatments elevated plasma insulin concentrations of diabetic rats although the levels induced by high doses (9.57 and 16.80 µg/kg) were greater than those caused by low doses (2.47 and 3.99 µg/kg) but comparable to those in sc insulin treated animals. Conclusions The data suggest that the PI hydrogel matrix patch can deliver physiologically relevant amounts of pharmacologically active insulin. Novelty of the Work A new
Menten, J; Desmedt, M; Lossignol, D; Mullie, A
This open compassionate-use prospective registration study evaluated the tolerability, ease of use and applied doses of transdermal (TTS) fentanyl in adult patients with cancer-related pain requiring strong opioid analgesia. Elderly patients were particularly focussed on. Previous pain medication was converted to an appropriate dose of TTS-fentanyl. Immediate-release morphine rescue medication was allowed as needed for breakthrough pain. Dose adjustments of TTS-fentanyl, rescue morphine requirements, the ease of use and side-effects were assessed monthly, with special emphasis paid to the severity of constipation and the use of laxatives. A total of 663 patients with cancer-related pain, including 8% opioid-naive patients, were enrolled; 661 patients used at least 1 patch of TTS-fentanyl. Of these, 455 subjects were assessed at baseline and at 1 post-baseline visit at least. Individual treatment ranged from a few days to 2 1/2 years; TTS-fentanyl doses ranged from 25 to 950 microg/h. The major reason for study termination was non-drug-related death (61%). Approximately 40% of patients reported constipation. The frequency of constipation depended on the rescue morphine dose used, but no dose-relationship was found for TTS-fentanyl. Patient acceptance of the patches was high; around 85% of patients rated convenience as good to excellent The ease of use and tolerability of TTS-fentanyl in the elderly patients were comparable to that in the total population, except for a slight increase of non-serious adverse events. TTS-fentanyl can be applied as long-term therapy to patients with cancer-related pain, including the elderly.
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-->.
Zhao, Chunyi; Quan, Peng; Liu, Chao; Li, Qiaoyun; Fang, Liang
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 (Tg) 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.
Schulz, Martin; Fussnegger, Bernhard; Bodmeier, Roland
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
Development of a drug-in-adhesive patch combining ion pair and chemical enhancer strategy for transdermal delivery of zaltoprofen: pharmacokinetic, pharmacodynamic and in vitro/in vivo correlation evaluation.
Cui, Hongxia; Quan, Peng; Zhou, Zhuang; Fang, Liang
The aim of the study was to develop a drug-in-adhesive patch system for transdermal delivery of zaltoprofen (ZAL). The formulation was designed in combination with the ion pair and chemical enhancer strategy. Seven organic amines were chosen as counter ions, and the prepared ion pairs were characterized by Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC). The in vivo pharmacokinetic performance of ZAL was studied on rabbits following transdermal and intravenous administration. A deconvolution method was applied to determine the correlation between the in vitro permeation and the in vivo absorption. Acetic acid-induced writhing response was conducted on mice to evaluate the analgesic effect. In vitro permeation results showed that both ion pairs and chemical enhancers were effective in modulating ZAL skin permeation from patches. The enhancement ratio was negatively correlated to the polar surface area (PSA) of counter ions, and was positively correlated to the octanol-water partition coefficient (log Ko/w) of chemical enhancers, respectively. The optimized formulation contained 10% (w/w) ZAL-triethylamine and 10% (w/w) isopropyl myristate, with DURO-TAK® 87-4098 as the pressure sensitive adhesive matrix. Furthermore, the in vitro permeation data were well correlated with the in vivo absorption data. The analgesic effect of the optimized patch was comparable to the commercial indometacin plasters. In conclusion, it was feasible for transdermal delivery of ZAL by the synergistic action of ion pair and chemical enhancer, and the in vitro permeation data were indicative of the in vivo performance for the developed patches.
Pergolizzi, Joseph V; Ben-Joseph, Rami; Chang, Chun-Lan; Hess, Gregory
Medication prescribing information provides guidance to healthcare providers on how to prescribe a drug properly. Oftentimes patient factors in addition to the prescribing information are considered when selecting medications. Utilizing real-world pharmacy and medical claims data, this study assessed US practitioner prescribing practices of US approved transdermal buprenorphine system (BTDS) in relation to BTDS's full prescribing information (FPI) as well as the relationship between patient factors and initial BTDS dose. Patients aged ≥18 years initiating BTDS between 1 January 2011 and 30 November 2011 were identified in the IMS Pharmacy and Private Practitioner Medical Claims databases. The index date was defined as the first filled BTDS prescription. Demographics, chronic pain-related medical conditions in the 12 months pre-index and prior medication use in the 6 months pre-index were assessed. Initial BTDS dosing strength, receipt of approved initial BTDS dose per the FPI, and concomitant medications were assessed in the post-index 6 month period. The study included 10,457 patients newly treated with BTDS. The majority of patients were female (69.9%) with a mean (±SD) age of 54.5 (±15.2) years. Within the 6 months prior to the index BTDS prescription, 91.7% of the patients used opioids. Overall, 48.9% of patients were prescribed the FPI approved BTDS dose. When stratified, 73.5% of opioid-naïve patients received the FPI approved initial dose compared to 46.0% of those with prior opioid experience of ≤80 mg morphine-equivalent daily dose. Patients on BTDS alone (i.e. monotherapy) had a higher rate of receiving the FPI approved initial BTDS dose compared to patients on BTDS concomitant regimens (p < 0.05). Practitioners demonstrated that they prescribe in accordance with BTDS's prescribing information in the majority of opioid-naïve patients and in approximately half of opioid-experienced patients. The initial opioid dose is a critical step in
Schug, Stephan A; Ting, Sonya
Fentanyl is a synthetic, highly selective opioid with many desirable physicochemical properties, including a high lipophilicity and predictable pharmacokinetics. These properties have an established record in the management of pain in a variety of settings, particularly acute pain and breakthrough cancer pain. Fentanyl was initially developed for parenteral use; however, this is invasive and impractical in the outpatient setting. Unfortunately, the high first-pass metabolism of fentanyl makes oral formulations unfeasible. However, its high lipophilicity allows fentanyl to be absorbed via a number of other routes. Thus new formulations were designed to allow non-invasive methods of administration. Transmucosal and transdermal fentanyl formulations are well established, and have proven useful in the settings of breakthrough cancer pain, emergencies and in the paediatric population. The iontophoretic transdermal system was developed to provide a needle-free system of delivering bolus doses of fentanyl on demand, a novel way of delivering patient-controlled opioid analgesia. Transpulmonary administration of fentanyl remains experimental. The aim of this review is to provide an update on current non-parenteral fentanyl formulations, with attention to their particular pharmacokinetics and features relevant to clinical use in pain management.
T., 2000. Beneficial effects of topical anti - inflammatory drugs against sulfur mustard-induced ocular lesions in rabbits. J Appl Toxicol 20 Suppl 1...nibble at food and readily consume fresh fruits and vegetables , although like most animals they exhibit individual preferences. Evidence of a lack of
Chen, Hsing-Kang; Lan, Tsuo-Hung; Wu, Bo-Jian
There have been many studies of smoking cessation using nicotine replacement therapy (NRT) with schizophrenic patients, but none exploring the smoking-reduction effects of varying doses of NRT in long-stay patients with schizophrenia. This study aimed to examine the effect of different doses of the nicotine transdermal patch on smoking-reduction and cessation outcomes in long-term hospitalized schizophrenic patients. A total of 184 subjects participated in a randomized, controlled, double-blind 8-week clinical trial. Participants were randomized into two groups using two different doses of NRT: a high-dose NRT group (31.2 mg for the first 4 weeks, then 20.8 mg for 4 weeks, n = 92) or a low-dose NRT group (20.8 mg for 8 weeks, n = 92). The 7-day point prevalence of abstinence was 2.7 % (5/184). Participants in the low-dose NRT group reduced smoking by 3.1 more cigarettes on average than those in the high-dose group (p = 0.005). However, a repeated measures analysis of variance revealed that the main effect of changes in the number of cigarettes smoked, comparing the two types of treatment across periods, was not significant (p = 0.35, partial eta square = 0.018). In summary, among a cohort of chronic institutionalized schizophrenic patients, smoking cessation and reduction outcomes were not correlated with NRT dose, and the cessation rate was much lower than rates in similar studies. It indicates that long-term hospitalized schizophrenic patients have more difficulties with quitting smoking. More effective integrative smoking cessation programs should be addressed for these patients.
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
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.
Subramony, J Anand; Sharma, Ashutosh; Phipps, J B
Transdermal drug delivery via iontophoresis is reviewed with special focus on the delivery of lidocaine for local anesthesia and fentanyl for patient controlled acute therapy such as postoperative pain. The role of the microprocessor controller in achieving dosimetry, alternating/reverse polarity, pre-programmed, and sensor-based delivery is highlighted. Unique features such as the use of tactile signaling, telemetry control, and pulsatile waveforms in iontophoretic drug delivery are described briefly.
Krinsky, Clarissa S; Lathrop, Sarah L; Crossey, Michael; Baker, Ginger; Zumwalt, Ross
Since its approval in the United States, fentanyl has become increasingly popular for the medical management of pain and as a substance of abuse. Fentanyl is unique among the opioids in its widespread use with a transdermal delivery system, which contributes to its unique pharmacokinetics and abuse potential. We examined the demographics of deaths with fentanyl identified on toxicologic analysis and reviewed specific challenges in the laboratory detection of postmortem fentanyl levels. The New Mexico Office of the Medical Investigator database was searched for all cases from January 1986 through December 2007 with fentanyl reported as present or quantified. Those deaths with a cause of death identified as drug overdose were then analyzed separately. From 1986 to 2007, 154 cases were identified with fentanyl present in postmortem samples, with 96 of the cases identified as fentanyl-related drug overdoses. The number of fentanyl-related deaths has increased over the past 20 years, corresponding to both statewide increases in the medical use of fentanyl and the abuse of prescription opioids. The demographics of these fentanyl-related overdoses showed that subjects were more likely to be female, white non-Hispanic, and older than those in previously described overdose deaths. Several cases were identified with central and peripheral blood samples and antemortem and postmortem samples available for fentanyl quantification. Given the uncharacteristic demographics of fentanyl-related deaths and the complexity of the laboratory analysis of fentanyl, forensic scientists must use caution in both the detection and interpretation of fentanyl concentrations.
Winkler, Julia; Goldammer, Mark; Ludwig, Matthias; Rohde, Beate; Zurth, Christian
Pharmacokinetic (PK) interactions between the cytochrome P450 3A4 (CYP3A4) pathway and transdermally administered ethinyl estradiol (EE) and gestodene (GSD) were investigated. This paper reports the findings of three open-label, intra-individual, one-way crossover, Phase I trials. In two studies, women used a novel contraceptive patch for 3 weeks during two 4-week study periods; in the second period, the CYP3A4 inhibitors erythromycin (Study 1) or ketoconazole (Study 2) were administered concurrently. In a third study, women received single doses of the CYP3A4 model substrate midazolam, alone and after 3 weeks of concurrent patch application. In each period, the EE/GSD patch (delivering low EE and GSD doses resulting in the same systemic exposure as a combined oral contraceptive containing 0.02 mg EE and 0.06 mg GSD) was applied once weekly for 3 weeks, with one patch-free week. Erythromycin, ketoconazole, and midazolam were administered orally. Main outcome measures were area under the curves (AUCs) and maximum plasma concentration (C max) of EE, and total and unbound GSD (Studies 1 and 2). AUC and C max of midazolam (Study 3). Co-administration of CYP3A4 inhibitors did not affect EE metabolism, and had only weak effects on the PK of total and unbound GSD. The patch had no clinically relevant effect on metabolism of the CYP3A4 substrate midazolam.
Andresen, T; Staahl, C; Oksche, A; Mansikka, H; Arendt-Nielsen, L; Drewes, A M
Chronic pain and hyperalgesia can be difficult to treat with classical opioids acting predominately at the µ-opioid receptor. Buprenorphine and its active metabolite are believed to act through µ-, κ- and δ-receptors and may therefore possess different analgesic and anti-hyperalgesic effects compared with pure µ-receptor agonists, for example, fentanyl. Here, we have compared the analgesic and anti-hyperalgesic effects of buprenorphine and fentanyl. Twenty-two healthy volunteers were randomized to treatment with transdermal buprenorphine (20 µg·h(-1), 144 h), fentanyl (25 µg·h(-1), 72 h) or placebo patches in a double-blind, cross-over experimental pain study. The experimental pain tests (phasic pain, sensitization) involved pressure at the tibial bone, cutaneous electrical and thermal stimulation, intramuscular nerve growth factor, UVB light burn injury model and intradermal capsaicin-induced hyperalgesia. Pain testing was carried out at baseline, 24, 48, 72 and 144 h after application of the drugs. Compared with placebo, buprenorphine, but not fentanyl, significantly attenuated pressure at the tibial bone as well as pressure pain in the primary hyperalgesic area induced by UVB light The two drugs were equipotent and better than placebo against cutaneous thermal pain stimulation), but failed to show significant analgesic effect to cutaneous electrical stimulation, nerve growth factor-induced muscle soreness and to capsaicin-induced hyperalgesia. Buprenorphine, but not fentanyl, showed analgesic effects against experimentally induced, bone-associated pain and primary hyperalgesia compared with placebo. These tissue- and modality-differentiated properties may reflect the variable effects of opioid drugs observed in individual patients. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.
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
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
New England Journal of Medicine , Vol. 307(17), 1982, p 1079. 9. Johnson, P., Hansen, D., Matarazzo, D., Peterson, L...Swisher, C., and Trappolini, A.; Transderm Scop Patches for Prevention of Motion Sickness, New England Journal of Medicine , Vol. 311(7), 1984, p 468. 10...Meyboom, R.M.B.; More on Transderm Scop Patches; New England Journal of Medicine , Vol. 311(21), 1984, p 1377. 11. Osterholm, R.K. and Camoriano,
Gupta, Himanshu; Babu, R J
Transdermal drug delivery is an attractive alternative to the oral and parenteral drug delivery. Drugs which are prone to first-pass metabolism can be delivered easily in small doses with sustained blood levels through this method. An update to available products along with a review of clinical trials and patents are discussed in this study. In this review, we have compiled 16 drugs, i.e. Buprenorphine, Clonidine, Estradiol, Fentanyl, Granisetron, Lidocaine, Methylphenidate, Nicotine, Nitroglycerin, Oxybutynin, Rivastigmine, Rotigotine, Scopolamine, Selegiline, Testosterone, Influenza virus vaccine (Microneedle) and covering about 22 marketed products on the transdermal system. We present instrumental information on them along with the compilation of current clinical trials on transdermal systems. We summarize the contents of patents granted in last 5 years under different pharmacological categories. This article serves, accordingly as a source of available information focused on transdermal drug delivery research.
... Basics Understanding the Epidemic Overdose Prevention Prescription Opioids Heroin Fentanyl Data Opioid Data Analysis Drug Overdose Death Data Prescribing Data Prescription Opioid Overdose Data Heroin Overdose Data Synthetic Opioid Data Fentanyl Encounters Data ...
Bista, Sudeep R; Haywood, Alison; Norris, Ross; Good, Phillip; Tapuni, Angela; Lobb, Michael; Hardy, Janet
Fentanyl is widely used to relieve cancer pain. However there is great interpatient variation in the dose required to relieve pain and little knowledge about the pharmacokinetic and pharmacodynamic (PK/PD) relationship of fentanyl and pain control. Patients with cancer are fragile and there is reluctance on the part of health professionals to take multiple plasma samples for PK/PD studies. The relationship between plasma and saliva fentanyl concentrations was investigated to determine whether saliva could be a valid substitute for plasma in PK/PD studies. One hundred sixty-three paired plasma and saliva samples were collected from 56 patients prescribed transdermal fentanyl (Durogesic, Janssen-Cilag Pty Limited, NSW, Australia) at varying doses (12-200 µg/h). Pain scores were recorded at the time of sampling. Fentanyl and norfentanyl concentrations in plasma and saliva were quantified using HPLC-MS/MS. Saliva concentrations of fentanyl (mean = 4.84 μg/L) were much higher than paired plasma concentrations of fentanyl (mean = 0.877 μg/L). Both plasma and saliva mean concentrations of fentanyl were well correlated with dose with considerable interpatient variation at each dose. The relationship between fentanyl and norfentanyl concentrations was poor in both plasma and saliva. No correlation was observed between fentanyl concentration in plasma and saliva (r(2) = 0.3743) or free fentanyl in plasma and total saliva concentrations (r(2) = 0.1374). Pain scores and fentanyl concentration in either of the matrices were also not correlated. No predictive correlation was observed between plasma and saliva fentanyl concentration. However the detection of higher fentanyl concentrations in saliva than plasma, with a good correlation to dose, may allow saliva to be used as an alternative to plasma in PK/PD studies of fentanyl in patients with cancer. Copyright © 2015 Elsevier HS Journals, Inc. All rights reserved.
Foegh, Marie; Archer, David F; Stanczyk, Frank Z; Rubin, Arkady; Mishell, Daniel R
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.
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.
Junge, Wolfgang; Heger-Mahn, Doris; Trummer, Dietmar; Merz, Martin
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.
... derived and synthetic drugs that interact with opium receptors in the brain. They are used to treat moderate to severe chronic pain pain when a continuous, around-the-clock opioid analgesic is required for an extended period of time.) ...
Stiasny-Kolster, Karin; Berg, Daniela; Hofmann, Werner E; Berkels, Reinhard; Grieger, Frank; Lauterbach, Thomas; Schollmayer, Erwin; Bachmann, Cornelius G
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.
Bista, Sudeep R; Lobb, Michael; Haywood, Alison; Hardy, Janet; Tapuni, Angela; Norris, Ross
Monitoring fentanyl concentration in saliva and plasma may be useful in pharmacokinetic/pharmacodynamic studies. Salivettes(®) have been used widely for collecting saliva samples. However due to its lipophilicity, fentanyl adsorbs to the cotton dental bud (CDB) used in this device. Furthermore, due to dry mouth being a common adverse effect seen in patients treated with opioids, obtaining enough saliva for analysis is often a challenge. Hence, a simple simultaneous method to quantify fentanyl and its metabolite in both human plasma and saliva was developed and validated. A novel extraction method was also developed and validated to recover fentanyl in saliva directly from the CDB. This extraction method utilises acetonitrile to recover the fentanyl directly from the CDB rather than recovery by centrifugation, which is not always possible. Reverse phase chromatographic separation was performed on a Shimadzu LC 20A HPLC system using gradient elution. The electrospray ion source (ESI) was operated in positive ion mode using an Applied Biosystems API 3200 LC/MS/MS as detector. Deuterated fentanyl (D5) and nor-fentanyl (D5) were used as internal standards (IS). The retention times for fentanyl and nor-fentanyl were 3.70 min and 3.20 min respectively. The lower limit of quantitation (LLOQ) was determined to be 0.030 μg/L in plasma and 0.045 in saliva for fentanyl and nor-fentanyl. Acceptable linearity for fentanyl and nor-fentanyl in both plasma and saliva was demonstrated from 0.02 to 10 μg/L (R(2) 0.9988-0.9994). Accuracy for fentanyl and nor-fentanyl in both plasma and saliva samples was between 96% and 108%. Total imprecision expressed as the co-efficient of variation was between 1.0 and 15.5% for both analytes in both matrices. The validated method was applied successfully in 11 paired plasma and saliva samples obtained from patients with cancer pain receiving transdermal fentanyl (Duragesic(®)) at doses from 25 μg to 100 μg.
Archer, David F; Stanczyk, Frank Z; Rubin, Arkady; Foegh, Marie
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
Mystakidou, Kyriaki; Befon, Sofia; Tsilika, Eleni; Dardoufas, Kostas; Georgaki, Stavroula; Vlahos, Lambros
Up to now, a transdermal therapeutic system (TTS) of fentanyl has been applied to cancer patients on opioid analgesics previously treated with mild opioids or morphine. The aim of this study was to investigate the efficacy and safety of TTS fentanyl (patch) administration as an analgesic to patients treated with opioid analgesics for moderate-to-severe cancer pain, with immediate-release oral morphine only as rescue medication. The prior analgesic medication of the patients did not include mild or strong opioids. The study group consisted of 113 patients (54 men and 59 women; age range: 21-87 years, mean +/- SD 61.3 +/- 14.84 years) with undertreated chronic cancer pain. The study period was 42 days. The patients were hospitalized for the first 3 days of the study; thereafter they were transferred to their home for the rest of the study. Daily cards were completed, noting their pain score (0-10 VAS), nausea, vomiting, constipation, skin reactions, dizziness or any other complaints. Vital signs were also recorded. Data assessments were made at baseline, on days 1, 2 and 3 (during hospitalization) and thereafter on days 7, 14, 21, 28, 35, and 42 after hospital discharge. The initial TTS fentanyl delivery rate was chosen depending on the patient's analgesic requirements. All patients were given an oral morphine solution (5-10 mg), every 4-6 h, for the first 12 h, as rescue medication. Baseline pain score was between 6 and 10 (mean +/- SD 7.1 +/- 1.7). The initial TTS fentanyl delivery rate was between 25 and 50 microg/h (mean +/- SD 36.5 +/- 15.7). On day 3, 95 patients (84%) reported a pain score < or = 3 (mean +/- SD 0.5 +/- 0.8), 14 patients (12.4%) a pain score of 4 and 4 patients (3.5%) of 5-8. No adverse effects suggesting the discontinuation of the study were reported. From day 7 until the completion of the study, the mean pain score was between 1.3 and 0.16 while the TTS fentanyl delivery rate on day 42 was between 25 and 400 microg/h (mean +/- SD 122.1 +/- 81
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.
Kim, Ho-Joong; Ahn, Hyo Sae; Nam, Yunjin; Chang, Bong-Soon; Lee, Choon-Ki; Yeom, Jin S
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.
Burns, Glenn; DeRienz, Rebecca T; Baker, Daniel D; Casavant, Marcel; Spiller, Henry A
There has been a significant spike in fentanyl-related deaths from illicit fentanyl supplied via the heroin trade. Past fentanyl access was primarily oral or dermal via prescription fentanyl patch diversion. One factor potentially driving this increase in fatalities is the change in route of administration. Rapid intravenous (IV) fentanyl can produce chest wall rigidity. We evaluated post-mortem fentanyl and norfentanyl concentrations in a recent surge of lethal fentanyl intoxications. Fentanyl related deaths from the Franklin County coroner's office from January to September 2015 were identified. Presumptive positive fentanyl results were confirmed by quantitative analysis using liquid chromatography tandem mass spectrometry (LC/MS/MS) and were able to quantify fentanyl, norfentanyl, alfentanyl, and sufentanyl. 48 fentanyl deaths were identified. Mean fentanyl concentrations were 12.5 ng/ml, (range 0.5 ng/ml to >40 ng/ml). Mean norfentanyl concentrations were 1.9 ng/ml (range none detected to 8.3 ng/ml). No appreciable concentrations of norfentanyl could be detected in 20 of 48 cases (42%) and were less than 1 ng/ml in 25 cases (52%). Elevated fentanyl concentrations did not correlate with rises in norfentanyl levels. In several cases fentanyl concentrations were strikingly high (22 ng/ml and 20 ng/ml) with no norfentanyl detected. The lack of any measurable norfentanyl in half of our cases suggests a very rapid death, consistent with acute chest rigidity. An alternate explanation could be a dose-related rapid onset of respiratory arrest. Deaths occurred with low levels of fentanyl in the therapeutic range (1-2 ng/ml) in apparent non-naïve opiate abusers. Acute chest wall rigidity is a well-recognized complication in the medical community but unknown within the drug abuse community. The average abuser of illicit opioids may be unaware of the increasing fentanyl content of their illicit opioid purchase. In summary we believe sudden onset chest
... who are taking regularly scheduled doses of another narcotic (opiate) pain medication, and who are tolerant (used to the effects of the medication) to narcotic pain medications. Fentanyl is in a class of ...
... who are taking regularly scheduled doses of another narcotic (opiate) pain medication, and who are tolerant (used to the effects of the medication) to narcotic pain medications. Fentanyl is in a class of ...
Quality-of-life outcomes from the Prostate Adenocarcinoma: TransCutaneous Hormones (PATCH) trial evaluating luteinising hormone-releasing hormone agonists versus transdermal oestradiol for androgen suppression in advanced prostate cancer.
Gilbert, Duncan C; Duong, Trinh; Kynaston, Howard G; Alhasso, Abdulla A; Cafferty, Fay H; Rosen, Stuart D; Kanaga-Sundaram, Subramanian; Dixit, Sanjay; Laniado, Marc; Madaan, Sanjeev; Collins, Gerald; Pope, Alvan; Welland, Andrew; Nankivell, Matthew; Wassersug, Richard; Parmar, Mahesh K B; Langley, Ruth E; Abel, Paul D
To compare quality-of-life (QoL) outcomes at 6 months between men with advanced prostate cancer receiving either transdermal oestradiol (tE2) or luteinising hormone-releasing hormone agonists (LHRHa) for androgen-deprivation therapy (ADT). Men with locally advanced or metastatic prostate cancer participating in an ongoing randomised, multicentre UK trial comparing tE2 versus LHRHa for ADT were enrolled into a QoL sub-study. tE2 was delivered via three or four transcutaneous patches containing oestradiol 100 μg/24 h. LHRHa was administered as per local practice. Patients completed questionnaires based on the European Organisation for Research and Treatment of Cancer quality of life questionnaire 30-item core (EORTC QLQ-C30) with prostate-specific module QLQ PR25. The primary outcome measure was global QoL score at 6 months, compared between randomised arms. In all, 727 men were enrolled between August 2007 and October 2015 (412 tE2, 315 LHRHa) with QoL questionnaires completed at both baseline and 6 months. Baseline clinical characteristics were similar between arms: median (interquartile range) age of 74 (68-79) years and PSA level of 44 (19-119) ng/mL, and 40% (294/727) had metastatic disease. At 6 months, patients on tE2 reported higher global QoL than those on LHRHa (mean difference +4.2, 95% confidence interval 1.2-7.1; P = 0.006), less fatigue, and improved physical function. Men in the tE2 arm were less likely to experience hot flushes (8% vs 46%), and report a lack of sexual interest (59% vs 74%) and sexual activity, but had higher rates of significant gynaecomastia (37% vs 5%). The higher incidence of hot flushes among LHRHa patients appear to account for both the reduced global QoL and increased fatigue in the LHRHa arm compared to the tE2 arm. Patients receiving tE2 for ADT had better 6-month self-reported QoL outcomes compared to those on LHRHa, but increased likelihood of gynaecomastia. The ongoing trial will evaluate clinical efficacy and longer term
Bentley, J B; Borel, J D; Nenad, R E; Gillespie, T J
Fentanyl pharmacokinetics was compared in two groups of adult patients, one group (n = 5) aged less than 50 years, and one group (n = 4) aged greater than 60 years. Despite equivalent doses of fentanyl (10 microgram/kg IV), serum drug concentrations were significantly higher in the older patient group. This was reflected by a prolonged terminal elimination half-life in the elderly compared with the younger patients (945 versus 265 minutes, respectively, p less than 0.005). Volumes of the central compartment and volumes of drug distribution were similar in both patient groups. However, drug clearance was markedly decreased in the elderly (265 versus 991 ml/min, p less than 0.005). These data suggest that a given dose of fentanyl will be clinically effective for a longer period in older patients than in younger patients.
Hadgraft, Jonathan; Lane, Majella E
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.
Zerem, Ayelet; Nishri, Daniella; Yosef, Yael; Blumkin, Lubuv; Lev, Dorit; Leshinsky-Silver, Esther; Kivity, Sara; Lerman-Sagie, Tally
We report resolution of an epileptic encephalopathy by administration of transdermal nicotine patches in an adolescent with severe nonlesional refractory frontal lobe epilepsy. The 18.5-year-old female patient had refractory epilepsy from the age of 11. Recurrent electroencephalography (EEG) recordings showed mostly generalized activity, albeit with right frontal predominance. Almost all antiepileptic medications failed to provide benefit. She developed an encephalopathic state with cognitive decline. The nonlesional frontal lobe epilepsy and a family history of a cousin with nocturnal epilepsy with frontal origin suggested genetic etiology. Transdermal nicotine patches brought complete resolution of the seizures, normalization of the EEG, and a significant improvement in her thinking process and speech organization. Sequencing of the CHRNB2 and CHRNA4 genes did not detect a mutation. Transdermal nicotine patches should be considered in severe pharmacoresistant frontal lobe epilepsy.
Prevention of nausea and vomiting (N&V) in cancer patients receiving high-dose cisplatin. Assessment of the potential antiemetic activity of transdermal fentanyl (TTS-F) compared to standard antiemetic treatment in acute and delayed N&V: first clinical report.
Mantovani, G; Curreli, L; Macciò, A; Massa, E; Massa, D; Mulas, C; Succu, G; Contu, P
A single-institution, prospective, open crossover study was performed to compare the effectiveness and tolerability of transdermal fentanyl (TTS-F) vs intravenous (i.v.) ondansetron (OND), both combined with i.v. DEX, in the prevention of acute nausea and vomiting (N&V), and TTS-F vs metoclopramide (M), both combined with intramuscular (i.m.) DEX, in the prevention of delayed N&V in patients with advanced stage head and neck squamous cell carcinoma receiving high-dose (> or = 100 mg/m2) cisplatin. This is the first report on the clinical use of TTS-F in this setting. All patients were adequately informed of the study characteristics and gave their written informed consent before study entry. The antiemetic treatment for acute N&V consisted of A) OND 8 mg plus DEX 20 mg (i.v.) or B) TTS-F 75 micrograms/h plus DEX 20 mg i.v. For prevention of delayed N&V, patients receiving TTS-F for acute N&V were given TTS-F at the same dosage (75 micrograms/h) on days 2-5, whereas patients receiving OND for acute N&V were treated with M 20 mg orally every 6 h on days 2-5, starting 24 h after CDDP. All patients received DEX 8 mg i.m. every 12 h on days 2 and 3, 4 mg i.m. every 12 h on days 4 and 5, starting 24 h after CDDP. From November 1997 to April 1998, 15 consecutive patients entered the study and were assigned to one of the two alternative treatments for acute N&V. All of them were evaluable. Twelve patients were evaluable for delayed N&V. Seven patients were assigned to Group 1 starting with treatment A (OND + DEX) and 8 patients were assigned to Group 2 starting with treatment B (TTS-F + DEX). In the prevention of acute N&V, the overall efficacy of OND + DEX was statistically significantly higher than that of TTS-F + DEX in achieving Complete Response (CR) and Major Efficacy (ME = CR + Major Response, MaR). As for delayed N&V, the overall efficacy of M + DEX, both in achieving CR and ME, although higher, was statistically not significantly different from that of TTS-F + DEX
A two-centre, open-label, randomised study of ovulation inhibition with three transdermal contraceptive patches, each containing different amounts of ethinyl estradiol and gestodene in healthy, young women.
Waellnitz, K; Duijkers, I; Klipping, C; Rautenberg, T; Rohde, B; Zurth, C
Here we report the findings of a two-centre, open-label, randomised, Phase IIa study designed to investigate whether an ethinyl estradiol (EE)/gestodene (GSD) patch that has been developed (referred to herein as the 'EE/GSD patch') reliably inhibits ovulation in comparison with patches delivering lower doses of these hormones. The study rationale was to provide justification of the doses of EE and GSD selected for the EE/GSD patch. Healthy women, aged 18-35 years, were randomised to receive treatment with either the EE/GSD patch, a 'reduced-GSD patch' (delivering similar amounts of EE and approximately half the amount of GSD) or a 'reduced-EE/GSD patch' (delivering half the amount of EE and GSD). Treatment was administered for three 28-day cycles (three × 7 patch-wearing days, plus a 7-day patch-free interval). The primary pharmacodynamic variable was the percentage of women with ovulation in at least one of Cycles 2 and/or 3, as indicated by Hoogland score. Pharmacokinetic parameters for EE and GSD were also measured. Results indicated that the EE/GSD patch effectively suppressed ovulation, while patches delivering lower doses of EE and GSD were less effective for this purpose. All three patches showed comparable tolerability.
There is some suggestion of a link between sexual dysfunction in postmenopausal women and low circulating concentrations of testosterone.1 This underlies the development of a new transdermal testosterone patch (black triangle down Intrinsa - Procter & Gamble) that has recently been licensed in the UK for the treatment of women who have hypoactive sexual desire disorder (HSDD) following a menopause induced by surgery (i.e. bilateral salpingooophorectomy and hysterectomy) and who are receiving concomitant oestrogen replacement therapy.2 Here we discuss the diagnosis of HSDD, as well as the evidence for using transdermal testosterone patches in women in whom this diagnosis is made.
Ham, Anthony S; Buckheit, Robert W
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
Ham, Anthony S; Buckheit, Robert W
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.
Ebrahimzadeh, H; Yamini, Y; Gholizade, A; Sedighi, A; Kasraee, S
A single-drop liquid-liquid-liquid microextraction (LLLME) method coupled with high-performance liquid chromatography (HPLC) was developed for the determination of fentanyl in biological (plasma and urine) and wastewater samples. Fentanyl is a potent synthetic narcotic analgesic administered in the form of a transdermal patch for the management of chronic pain. Fentanyl was extracted from 0.01 M NaOH solution (donor phase) into a thin layer of organic phase (100 muL), then back-extracted into 5 muL of the acidic acceptor microdrop (1 x 10(-3)M HClO(4)) immersed in the organic membrane from the tip of a 25-muL HPLC syringe. After the extraction, the microdrop was withdrawn into the syringe and injected directly into a HPLC system for analysis. The parameters influencing the extraction efficiency including the organic solvent and its volume, acceptor microdrop volume, composition of the donor and acceptor phases, stirring rate, temperature, salt addition and pre- and back-extraction times were investigated and optimized. At the most appropriate conditions (100 muL of n-octane, 3.6 mL of the donor phase maintained at 0.01 M NaOH, 5 muL of 1 x 10(-3)M HClO(4) as the acceptor microdrop, stirring rate of 1000 rpm for pre-extraction and 700 rpm for back-extraction, 30 degrees C, no salt addition, 30 min for pre-extraction and 20 min for back-extraction), an enrichment factor (EF) of 355 was obtained. The limit of detection (LOD) was 0.1 ngmL(-1) (based on S/N=3) and intra- and inter-day relative standard deviations less than 9% were obtained. The calibration graph was linear within the range of 0.5-1000 ngmL(-1) with the correlation coefficient (r) of 0.9999. Finally, the feasibility of the proposed method was evaluated by extraction and determination of fentanyl in plasma, urine and wastewater samples and satisfactory results were obtained.
Rawat, Swati; Vengurlekar, Sudha; Rakesh, B.; Jain, S.; Srikarti, G.
Recently there has been an increased interest in using iontophoretic technique for the transdermal delivery of medications, both ionic and nonionic. This article is an overview of the history of iontophoresis and factors affecting iontophoretic drug transfer for the systemic effects and laws for development of Transdermal delivery system are discussed. PMID:20390073
Strasinger, Caroline; Raney, Sam G; Tran, Doanh C; Ghosh, Priyanka; Newman, Bryan; Bashaw, Edward D; Ghosh, Tapash; Shukla, Chinmay G
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) ; Hadgraft and Lane (2006) ). 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.
Wilens, Timothy E.; Boellner, Samuel W.; Lopez, Frank A.; Turnbow, John M.; Wigal, Sharon B.; Childress, Ann C.; Abikoff, Howard B.; Manos, Michael J.
A study investigated the impact of variable wear times of the methylphenidate transdermal system in children with attention-deficit/hyperactivity disorder (ADHD). It was concluded that duration of medication effect was directly related to the wear time of the methylphenidate transdermal system patch.
Wilens, Timothy E.; Boellner, Samuel W.; Lopez, Frank A.; Turnbow, John M.; Wigal, Sharon B.; Childress, Ann C.; Abikoff, Howard B.; Manos, Michael J.
A study investigated the impact of variable wear times of the methylphenidate transdermal system in children with attention-deficit/hyperactivity disorder (ADHD). It was concluded that duration of medication effect was directly related to the wear time of the methylphenidate transdermal system patch.
Ishida, Takuya; Naito, Takafumi; Sato, Hikaru; Kawakami, Junichi
This study aimed to evaluate the relationship between the concentrations of plasma fentanyl and serum 4β-hydroxycholesterol based on CYP3A5 genotype and gender in cancer patients. Thirty-three Japanese cancer patients treated with transdermal fentanyl were enrolled. The concentrations of plasma fentanyl and norfentanyl, and serum 4β-hydroxycholesterol and total cholesterol were determined at day 8 or later after starting the medication. The plasma fentanyl concentration was significantly higher in the CYP3A5*3/*3 group than in the *1 allele carrier group. The *3/*3 group had a lower metabolic ratio of fentanyl. The serum 4β-hydroxycholesterol concentration and its ratio to total cholesterol were significantly lower in the CYP3A5*3/*3 group than in the *1 allele carrier group. The concentrations of plasma fentanyl and serum 4β-hydroxycholesterol were significantly higher in women than in men. Gender did not affect the metabolic ratio of fentanyl or the concentration ratio of 4β-hydroxycholesterol. The plasma fentanyl concentration was not correlated with the serum 4β-hydroxycholesterol concentration, while the metabolic ratio of fentanyl was slightly correlated with the serum concentration ratio of 4β-hydroxycholesterol. In conclusion, CYP3A5*3 and gender affected the plasma fentanyl and serum 4β-hydroxycholesterol concentrations in cancer patients. However, the plasma disposition of fentanyl was not determined using the serum 4β-hydroxycholesterol concentration. Copyright © 2016 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.
Notelovitz, M; Cassel, D; Hille, D; Furst, K W; Dain, M P; VandePol, C; Skarinsky, D
This study was undertaken to evaluate the efficacy and tolerability of a combination estradiol plus norethindrone acetate transdermal delivery system given in a continuous sequential regimen with transdermal estradiol versus placebo in the treatment of vasomotor symptoms of menopause. This was a 12-week double-blind trial of 220 healthy postmenopausal women with > or = 8 moderate to severe hot flushes and sweating episodes per day. Women were randomly assigned to wear transdermal placebo patches or a transdermal patch releasing 50 microg/d 17beta-estradiol alone (Vivelle) for days 1 to 14 of each cycle and a combination patch releasing 50 microg/d 17beta-estradiol plus 1 of 3 dosage levels (140, 250, or 400 microg/d) of norethindrone acetate (CombiPatch) for days 15 through 28. There was a significant (P <.001) reduction by the second week in the mean number of daily hot flushes from baseline to end point with all 3 doses of estradiol plus norethindrone acetate compared with placebo. Significant (P <.001) reductions in the mean intensity of hot flushes and sweating were also noted with estradiol plus norethindrone acetate compared with placebo. The incidences of adverse events with all 3 doses of estradiol plus norethindrone acetate and with placebo were comparable. An estradiol plus norethindrone acetate transdermal delivery system administered in a continuous sequential regimen with transdermal estradiol was well tolerated and effective for the treatment of moderate to severe vasomotor symptoms in postmenopausal women.
Cunningham, Susan M; Haikal, Nabila A; Kraner, James C
Among the new psychoactive substances encountered in forensic investigations is the opioid, acetyl fentanyl. The death of a 28-year-old man from recreational use of this compound is reported. The decedent was found in the bathroom of his residence with a tourniquet secured around his arm and a syringe nearby. Postmortem examination findings included marked pulmonary and cerebral edema and needle track marks. Toxicological analysis revealed acetyl fentanyl in subclavian blood, liver, vitreous fluid, and urine at concentrations of 235 ng/mL, 2400 ng/g, 131 ng/mL, and 234 ng/mL, respectively. Acetyl fentanyl was also detected in the accompanying syringe. Death was attributed to recreational acetyl fentanyl abuse, likely through intravenous administration. The blood acetyl fentanyl concentration is considerably higher than typically found in fatal fentanyl intoxications. Analysis of this case underscores the need for consideration of a wide range of compounds with potential opioid-agonist activity when investigating apparent recreational drug-related deaths. © 2015 American Academy of Forensic Sciences.
Pharmacokinetics and adhesion of a transdermal patch containing ethinyl estradiol and gestodene under conditions of heat, humidity, and exercise: A single-center, open-label, randomized, crossover study.
Zurth, Christian; Schuett, Barbara; Casjens, Manuela; Ludwig, Matthias; Waellnitz, Katrin
In this open-label, randomized study, 36 women (18-45 years) applied an ethinyl estradiol/gestodene contraceptive patch once-weekly for 3 weeks followed by a 1-week, patch-free interval, in 3 treatment periods. The primary objective was to evaluate the pharmacokinetics of ethinyl estradiol and gestodene under conditions of heat, humidity, and exercise. The secondary objective was to evaluate patch adhesion under the same conditions. Weeks 1 and 2 of each period comprised "standardized normal activity" (SNA); in week 3, SNA continued or women used a sauna, whirlpool, swimming pool, or performed an exercise combination. Thirty-one women completed the study; 23 yielded evaluable pharmacokinetic data. Analyses were exploratory and conducted using an analysis of variance. Area under the concentration-time curve from 0 to 168 hours (AUC0-168 ) for gestodene and ethinyl estradiol during sauna, swimming, and whirlpool was equivalent to previous SNA recordings. For exercise combination, the gestodene AUC0-168 was 12% lower compared with SNA, albeit not considered clinically relevant. Two women lost a total of 3 patches during sporting activities; other detachments during this week were not correlated with sporting activity. Overall, hormone delivery using the ethinyl estradiol/gestodene patch under conditions of heat, humidity, and exercise corresponded to delivery under normal conditions.
Modepalli, Naresh; Shivakumar, H N; Kanni, K L Paranjothy; Murthy, S Narasimha
Iron deficiency anemia is one of the major nutritional deficiency disorders. Iron deficiency anemia occurs due to decreased absorption of iron from diet, chronic blood loss and other associated diseases. The importance of iron and deleterious effects of iron deficiency anemia are discussed briefly in this review followed by the transdermal approaches to deliver iron. Transdermal delivery of iron would be able to overcome the side effects associated with conventional oral and parenteral iron therapy and improves the patient compliance. During preliminary investigations, ferric pyrophosphate and iron dextran were selected as iron sources for transdermal delivery. Different biophysical techniques were explored to assess their efficiency in delivering iron across the skin, and in vivo studies were carried out using anemic rat model. Transdermal iron delivery is a promising approach that could make a huge positive impact on patients suffering with iron deficiency.
Cherukuri, Suneetha; Batchu, Uma Rajeswari; Mandava, Kiranmai; Cherukuri, Vidhyullatha; Ganapuram, Koteswara Rao
Transdermal drug delivery system (TDDS) was designed to sustain the release and improve the bioavailability of drug and patient compliance. Among the various types of transdermal patches, matrix dispersion type systems disperse the drug in the solvent along with the polymers and solvent is allowed to evaporate forming a homogeneous drug-polymer matrix. The objective of the present study was to design and formulate TDDS of topiramate (TPM) and to evaluate their extended release in vitro and ex vivo. In the present study, an attempt has been made to develop a matrix-type transdermal therapeutic system comprising TPM with different ratios of hydrophilic and hydrophobic polymeric combinations using solvent casting technique. The physicochemical compatibility of the drug and the polymers was studied by Fourier transform infrared spectroscopy. The results obtained showed no physical-chemical incompatibility between the drug and the polymers. The patches were further subjected to various physical evaluations along with the ex vivo permeation studies using pig ear skin. On the basis of results obtained from the physical evaluation and ex vivo studies the patches containing the polymers, that is, Eudragit L 100 and polyvinylpyrrolidone, with oleic acid as the penetration enhancer were considered as the best formulations for the transdermal delivery of TPM.
Cherukuri, Suneetha; Batchu, Uma Rajeswari; Mandava, Kiranmai; Cherukuri, Vidhyullatha; Ganapuram, Koteswara Rao
Background: Transdermal drug delivery system (TDDS) was designed to sustain the release and improve the bioavailability of drug and patient compliance. Among the various types of transdermal patches, matrix dispersion type systems disperse the drug in the solvent along with the polymers and solvent is allowed to evaporate forming a homogeneous drug-polymer matrix. The objective of the present study was to design and formulate TDDS of topiramate (TPM) and to evaluate their extended release in vitro and ex vivo. Materials and Methods: In the present study, an attempt has been made to develop a matrix-type transdermal therapeutic system comprising TPM with different ratios of hydrophilic and hydrophobic polymeric combinations using solvent casting technique. Results: The physicochemical compatibility of the drug and the polymers was studied by Fourier transform infrared spectroscopy. The results obtained showed no physical-chemical incompatibility between the drug and the polymers. The patches were further subjected to various physical evaluations along with the ex vivo permeation studies using pig ear skin. Conclusions: On the basis of results obtained from the physical evaluation and ex vivo studies the patches containing the polymers, that is, Eudragit L 100 and polyvinylpyrrolidone, with oleic acid as the penetration enhancer were considered as the best formulations for the transdermal delivery of TPM. PMID:28405574
Ziesenitz, Victoria C; König, Sonja K; Mahlke, Nina S; Skopp, Gisela; Haefeli, Walter E; Mikus, Gerd
Fentanyl is primarily metabolized by CYP3A, but has also been suggested to act as a weak inhibitor of CYP3A. We investigated the influence of CYP3A inhibition by ketoconazole on the pharmacokinetics of intravenously administered fentanyl and the effect of fentanyl on CYP3A activity. A prospective, open-label, randomized, monocentre, crossover study was conducted in 16 healthy volunteers. They received fentanyl alone (5 microgram per kilogram) or fentanyl plus ketoconazole (200 milligram orally B.I.D. over 2 days). Naloxone (2 × 0.2 milligram i.v.) was given simultaneously with fentanyl to mitigate any opioid effect. Midazolam was administered as a CYP3A probe drug. Fentanyl and its metabolites were quantified by LC/MS/MS in blood and urine samples obtained over 24 hour. Exposure of fentanyl (AUC0- ∞ ) was significantly increased to 133% and systemic clearance was reduced to 78% by ketoconazole, norfentanyl formation was significantly delayed and partial metabolic clearance decreased to 18%. Fentanyl had no influence on midazolam exposure and CYP3A activity whereas ketoconazole decreased CYP3A activity to 13%. Although fentanyl N-dealkylation is substantially inhibited by ketoconazole, exposure of fentanyl itself increased by one third only. Clinically fentanyl dosage adjustments may become necessary when ketoconazole or other strong CYP3A inhibitors are given simultaneously. Fentanyl itself does not influence CYP3A activity.
Lee, David T; Jenkins, Nelson L; Anastasopulos, Alexandra J; Volpe, A George; Lee, Bernard T; Lalikos, Janice F
Postoperative nausea and vomiting (PONV) is a common complaint after plastic and reconstructive surgery. Transdermal scopolamine is a commonly used agent for prevention of PONV. Anisocoria from transdermal scopolamine use is an adverse effect that has not been reported in the plastic surgery literature. We present a series of 3 craniofacial patients in which ipsilateral mydriasis occurred and spontaneously resolved after removal of the scopolamine patch. Given the various causes and potentially grave implications of unilateral mydriasis, we discourage the use of transdermal scopolamine in craniofacial surgery, and especially in orbital surgery. However, if transdermal scopolamine is decided to be used for PONV prophylaxis, we recommend educating the patient, the operating room staff, and the surgical team regarding this potential adverse effect and to avoid finger-to-eye contamination after patch manipulation.
Padula, Cristina; Nicoli, Sara; Aversa, Vincenzo; Colombo, Paolo; Falson, Françoise; Pirot, Fabrice; Santi, Patrizia
This paper describes an innovative transdermal drug delivery system, a monolaminated bioadhesive film in which the usual constituents of transdermal patches (backing, drug and adhesive) have been condensed in one single layer, denominated Patch-non-Patch. The main characteristics of the film is that it is not self-adhesive in the dry state but becomes adhesive only when applied on wet skin. This characteristic is due to the presence of a small amount of adhesive, unable to make the system self-adhesive, but capable of restoring the adhesiveness in contact with a small amount of water. From the results obtained to date, it appears that the technology Patch-non-Patch has the potentiality to be successfully applied to the pharmaceutical and cosmetic market. On the skin the film is flexible, invisible and adapts to all skin irregularities. The system has been shown to be highly efficient, releasing a high percentage of the active included in most cases. Additionally, the inclusion of other excipients can modulate drug delivery, thus improving the versatility of the product. Finally, the second generation Patch-non-Patch, made occlusive on the skin surface, can further broaden the potential application.
MacDiarmid, Scott A
Multiple antimuscarinic agents are available for the treatment of overactive bladder. Many of the agents have undergone reformulation in an attempt to improve patient adherence and drug tolerability. Oxybutynin evolved from an immediate-release pill to a once-daily oral preparation, and is now available as a transdermal patch and gel. This article discusses the clinical impact of oxybutynin reformulation and reviews the evolution and benefits of transdermal therapy. PMID:19609406
MacDiarmid, Scott A
Multiple antimuscarinic agents are available for the treatment of overactive bladder. Many of the agents have undergone reformulation in an attempt to improve patient adherence and drug tolerability. Oxybutynin evolved from an immediate-release pill to a once-daily oral preparation, and is now available as a transdermal patch and gel. This article discusses the clinical impact of oxybutynin reformulation and reviews the evolution and benefits of transdermal therapy. PMID:19390669
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
Moseley, H; Johnston, S; Allen, A
It has been alleged that the exposure of a transdermal delivery system to leakage of microwave radiation from a domestic microwave oven can result in the user receiving a second-degree burn in the area of the patch. Several transdermal delivery systems were exposed to microwave radiation from an Electro Medical Supplies Microtron 200 microwave diathermy unit. Temperature rises of up to 2.2 degrees C were recorded at a maximum power density of 800 W/m2. These temperature rises were considered insignificant compared to that required to produce a burn. The exposure of transdermal delivery systems to a microwave diathermy field or lower level leakage radiation from a microwave oven is unlikely to cause direct thermal injury to the wearer.
Wisner, Katherine L.; Sit, Dorothy K.Y.; Moses-Kolko, Eydie L.; Driscoll, Kara E.; Prairie, Beth; Stika, Catherine S.; Eng, Heather F.; Dills, John L; Luther, James F.; Wisniewski, Stephen R.
Postpartum depression occurs in 14.5% of women in the first three months after birth. This study was an 8 week acute phase randomized trial with three cells (transdermal estradiol (E2), sertraline, and placebo) for the treatment of postpartum major depressive disorder. However, the study was stopped after batch analysis revealed that the E2 serum concentrations were lower than pre-study projections. This paper explores our experiences that will inform future investigations of therapeutic E2 use. Explanations for the low E2 concentrations were: 1) Study patch non-adhesion, which did not explain the low concentrations across the entire sample. 2) Ineffective transdermal patch preparations, although two different patch preparations were used and no significant main effect of patch type on E2 concentrations was found. 3) Obesity, at study entry, E2-treated women had mean ± SD BMI=32.9 ±7.4. No pharmacokinetic data comparing E2 concentrations from transdermal patches in obese women vs. normal weight controls are available. 4) Induction of Cytochrome P450 (CYP450) 3A4 and other E2 elimination pathways in pregnancy. CYP4503A4 is induced in pregnancy and is a pathway for the metabolism of E2. Conversion to estrone and Phase II metabolism via glucuronidation and sulfation, which also increase in pregnancy, are routes of E2 elimination. The time required for these pathways to normalize after delivery has not been elucidated. The observation that transdermal E2 doses greater than 100 mcg/day did not increase serum concentrations was unexpected. Another hypothesis consistent with this observation is suppression of endogenous E2 secretion with increasing exogenous E2 dosing. PMID:26061609
Kerımoğlu, Oya; Şahbaz, Sevınç; Şehırlı, Özer; Ozdemır, Zarıfe Nıgar; Çetınel, Şule; Dortunç, Betül; Şener, Göksel
The objective of this study was to evaluate pharmacodynamical properties of transdermal therapeutic systems (TTS) containing captopril together with synthetic and pH independent polymers, Eudragit RL 100 and RS 100. Optimum formulation was chosen according to the results of our previous study regarding in vitro dissolution and ex vivo diffusion rate studies through excised human skin by using Franz Diffusion Cell. Control group, hypertension group (HT) and TTS containing captopril hypertension group (HT-CAP) were assessed for the pharmacodynamic activity of the study. Pharmacodynamic activity of transdermal patches containing captopril was evaluated in rats by the measurement of systolic blood pressure for 24 h with the use of the tail cuff method. Blood pressure, heart rate, body and heart weight, heart and body weight ratio were determined. Lactate dehydrogenase (LDH), creatinine phosphokinase (CPK), glutathione (GSH), malondialdehyde (MDA), myeloperoxidase (MPO) and Na+, K(+)-ATPase were measured in the serum of rats. Histopathological evaluation of the heart tissue was conducted in order to determine any tissue damage. Blood pressure values of the TTS containing captopril hypertension group were decreased significantly and became almost similar with the blood pressure values of the control group. These results indicated that matrix type transdermal patches prepared with Eudragit RL 100 and RS 100 polymers containing captopril can be considered as transdermal therapeutic systems for chronical treatment of hypertension and congestive heart failure. However, further in vivo pharmacokinetic studies should be performed in order to determine the blood level of the drug.
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
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
Wang, D M; Lin, F C; Chen, L Y; Lai, J Y
In this study, asymmetric poly(4-methyl-1-pentene) (TPX) membranes, fabricated by the dry/wet inversion method, were applied to transdermal delivery of nitroglycerin (NTG), a drug for treating angina pectoris. The flux of NTG through the TPX membrane was measured in vitro by a Franz cell. The results indicate that the NTG flux through asymmetric TPX membranes is strongly dependent on the membrane structure, which can be varied by adding nonsolvents in the casting solution. By adding different kinds of nonsolvents and adjusting the added amounts, membranes with different NTG release rates can be fabricated. It was also found that, with suitable drug formula, the NTG dissolution rate of a prototype TPX patch is comparable to that of a commercial patch, Transderm-Nitro. In addition, the data of NTG flux through a composite of TPX membrane and pig skin are also presented.
Transdermal drug delivery offers several advantages, including avoidance of erratic absorption, absence of gastric irritation, painlessness, noninvasiveness, as well as improvement in patient compliance. With this mode of drug administration, there is no pre-systemic metabolism and it is possible to increase drug bioavailability and half-life. However, only a few molecules can be delivered across the skin in therapeutic quantities. This is because of the hindrance provided by the stratum corneum. Several techniques have been developed and used over the last few decades for transdermal drug delivery enhancement. These include sonophoresis, iontophoresis, microneedles, and electroporation. Electroporation, which refers to the temporary perturbation of the skin following the application of high voltage electric pulses, has been used to increase transcutaneous flux values by several research groups. In this review, transdermal electroporation is discussed and the use of the technique for percutaneous transport of low and high molecular weight compounds described. This review also examines our current knowledge regarding the mechanisms of electroporation and safety concerns arising from the use of this transdermal drug delivery technique. Safety considerations are especially important because electroporation utilizes high voltage pulses which may have deleterious effects in some cases. PMID:26999191
Kopper, Nathan W; Gudeman, Jennifer; Thompson, Daniel J
Vasomotor symptoms (VMS) associated with menopause can cause significant discomfort and decrease the quality of life for women in the peri-menopausal and post-menopausal stages of life. Hormone therapy (HT) is the mainstay of treatment for menopausal symptoms and is currently the only therapy proven effective for VMS. Numerous HT options are available to treat VMS, including estrogen-only and estrogen-progestogen combination products to meet the needs of both hysterectomized and nonhysterectomized women. In addition to selecting an appropriate estrogen or estrogen-progestogen combination, consideration should be given to the route of administration to best suit the needs of the patient. Delivery systems for hormone therapy include oral tablets, transdermal patches, transdermal topical (nonpatch) products, and intravaginal preparations. Oral is currently the most commonly utilized route of administration in the United States. However, evidence suggests that oral delivery may lead to some undesirable physiologic effects caused by significant gut and hepatic metabolism. Transdermal drug delivery may mitigate some of these effects by avoiding gut and hepatic first-pass metabolism. Advantages of transdermal delivery include the ability to administer unmetabolized estradiol directly to the blood stream, administration of lower doses compared to oral products, and minimal stimulation of hepatic protein production. Several estradiol transdermal delivery technologies are available, including various types of patches, topical gels, and a transdermal spray. PMID:19920906
Cohn, Joshua A.; Brown, Elizabeth T.; Reynolds, W. Stuart; Kaufman, Melissa R.; Milam, Douglas F.; Dmochowski, Roger R.
Antimuscarinic medications are used to treat nonneurogenic overactive bladder refractory to nonpharmacologic therapy. Side effects such as dry mouth, constipation, blurred vision, dizziness, and impaired cognition limit the tolerability of therapy and are largely responsible for high discontinuation rates. Oxybutynin is a potent muscarinic receptor antagonist whose primary metabolite after first-pass hepatic metabolism is considered largely responsible for its associated anticholinergic side effects. Transdermal administration of medications bypasses hepatic processing. Specifically with oxybutynin, whose low molecular weight permits transdermal administration, bioavailability of the parent drug with oral administration is less than 10%, whereas with transdermal delivery is a minimum of 80%. The result has been an improved side effect profile in multiple clinical trials with maintained efficacy relative to placebo; however, the drug may still be discontinued by patients due to anticholinergic side effects and application site reactions. Transdermal oxybutynin is available as a patch that is changed every 3–4 days, a gel available in individual sachets, or via a metered-dose pump that is applied daily. The transdermal patch was briefly available as an over-the-counter medication for adult women, although at this time all transdermal formulations are available by prescription only. PMID:27034721
Petersen, Kristian Kjær; Rousing, Mark Lillelund; Jensen, Carina; Arendt-Nielsen, Lars; Gazerani, Parisa
Skin permeability and local blood perfusion are important factors for transdermal drug delivery. Application of heat is expected to enhance microcirculation and local perfusion and/or blood vessel permeability, thus facilitating drug transfer to the systemic circulation. In addition, heating prior to or during topical application of a drug may facilitate skin penetration, increase kinetic energy, and facilitate drug absorption. The aim of the present study was to investigate whether application of controlled local heat would enhance transdermal delivery from the nicotine patch mounted on the upper arm of ten healthy non-smoking male Caucasian subjects. Local skin perfusion was monitored using Laser Doppler Imaging (LDI) at baseline (32 °C) and following application of local controlled heat (43 °C) on the upper arm, where the patch was placed. The residue of the nicotine patches was then examined by High-Performance Liquid Chromatography (HPLC) to indicate the uptake of nicotine from the patch due to the local controlled heat. Controlled heat application (43°C) caused significant cutaneous hyperaemia (up to 9 folds increase in skin perfusion) with an increase in nicotine uptake (up to 13 folds). The method was well tolerated without causing any pain or discomfort. These data suggest that controlled heat application, which is a simple, non-invasive method, can significantly enhance local skin perfusion and drug uptake from patches.
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
Invernale, Michael A; Tang, Benjamin C; York, Royce L; Le, Long; Hou, David Yupeng; Anderson, Daniel G
Here, efforts toward the development of a microneedle-based glucose sensor or "smart patch" for intradermal glucose sensing are described. Metallic microneedle array electrodes, conducting polymers, and glucose oxidase form the sensor platform. This work represents the first steps toward the development of painless, transdermal-sensing devices for continuous glucose monitoring.
Shaw, Greg L; Patel, Hiten Rh
Overactive bladder is a common and disabling problem. The mainstay of pharmacological treatment is with oral anticholinergic drugs. Anticholinergic side effects are common and include dry mouth and constipation. Compliance is limited by these side effects. Transdermal administration of oxybutynin has been shown to be as effective as oral treatment while minimising the anticholinergic side effects. Skin reactions occur frequently, necessitating changes of application site. Despite this, the preparation is a useful element in the armamentarium to treat overactive bladder. It is likely to be particularly useful in those in whom side effects of oral medication are intolerable or in whom oral administration of drug is not possible. Here, the pharmacokinetics, pharmacodynamics, efficacy and safety of transdermal oxybutynin are reviewed.
Sevast'ianov, V I; Salomatina, L A; Kuznetsova, E G; Iakovleva, N V; Shumakov, V I
A possibility is studied of the transdermal delivery of insulin by using a mixture of synthetic analogues of phosphoglycerides (SAP), as a potential activator of hormone diffusion, through the skin. Experimentally in vitro, it was proven that the diffusion of insulin through the skin of two types of transdermal therapeutic form (TTF)--matrix-type and matrix-hydrogel-type--is possible only in presence of activator SAP-M-99. The detected optimal composition of insulin matrix TTF with the area of 40 sq cm enabled a trandermal hormone diffusion speed of 0.26 UNITS/h, which is compatible with the secretion of insulin by the pancreas of an adult (0.25-1.5 UNITS/h). A change-over for the matrix-hydrogel system of insulin delivery based on a 40 sq cm collagenous sponge enabled to increase the insulin diffusion up to 0.54 UNITS/h.
Kalluri, Haripriya; Banga, Ajay K
Transdermal delivery of peptides and proteins avoids the disadvantages associated with the invasive parenteral route of administration and other alternative routes such as the pulmonary and nasal routes. Since proteins have a large size and are hydrophilic in nature, they cannot permeate passively across the skin due to the stratum corneum which allows the transport of only small lipophilic drug molecules. Enhancement techniques such as chemical enhancers, iontophoresis, microneedles, electroporation, sonophoresis, thermal ablation, laser ablation, radiofrequency ablation and noninvasive jet injectors aid in the delivery of proteins by overcoming the skin barrier in different ways. In this review, these enhancement techniques that can enable the transdermal delivery of proteins are discussed, including a discussion of mechanisms, sterility requirements, and commercial development of products. Combination of enhancement techniques may result in a synergistic effect allowing increased protein delivery and these are also discussed.
Somerset is developing a selegiline transdermal system (STS) for potential use in the treatment of depression. It has also been developed for Alzheimer's disease (AD), Parkinson's disease and attention-deficit hyperactivity disorder (ADHD) , although no development has been reported for AD or ADHD in recent years. Somerset claims the transdermal system could be more effective than the oral formulation of selegiline already marketed . In May 2001, Somerset filed an NDA with the US FDA for STS for the treatment of depression , however, in March 2002, the company received a 'non-approvable' letter from the FDA requesting additional efficacy data. At this time, Somerset had scheduled a meeting with the FDA to review and clarify their comments . Selegiline will be co-promoted in the US by Watson, under the terms of a previous agreement .
Tidey, Jennifer W; O'Neill, Suzanne C; Higgins, Stephen T
This study was conducted to examine the effects of contingent monetary reinforcement (CM) for smoking reduction, with and without transdermal nicotine, on cigarette smoking in individuals with schizophrenia. Fourteen outpatients participated in each of 3 conditions: (a) CM combined with 21 mg transdermal nicotine, (b) CM combined with placebo patch, and (c) noncontingent reinforcement combined with placebo patch. Each condition lasted 5 days. Carbon monoxide levels were measured 3 times daily, and nicotine withdrawal symptoms were measured once daily in each condition. Results indicated that CM reduced smoking but that 21 mg transdermal nicotine did not enhance that effect. These results offer further evidence supporting the efficacy of CM for reducing smoking among people with schizophrenia, but higher doses of nicotine replacement therapy, or another pharmacotherapy, may be needed to enhance that effect.
Lazzarini, Rosana; Duarte, Ida; Ferreira, Alessandra Lindmayer
Patch tests were introduced as a diagnostic tool in the late nineteenth century. Since then, they have improved considerably becoming what they are today. Patch tests are used in the diagnostic investigation of contact dermatitis worldwide. Batteries or series previously studied and standardized should be used in patch testing. The methodology is simple, but it requires adequate training for the results to be correctly interpreted and used. Despite having been used for over a century, it needs improvement like all other diagnostic techniques in the medical field.
Lazzarini, Rosana; Duarte, Ida; Ferreira, Alessandra Lindmayer
Patch tests were introduced as a diagnostic tool in the late nineteenth century. Since then, they have improved considerably becoming what they are today. Patch tests are used in the diagnostic investigation of contact dermatitis worldwide. Batteries or series previously studied and standardized should be used in patch testing. The methodology is simple, but it requires adequate training for the results to be correctly interpreted and used. Despite having been used for over a century, it needs improvement like all other diagnostic techniques in the medical field. PMID:24474094
Iqbal, Nimra; Vitorino, Carla; Taylor, Kevin M G
The development of a transdermal nanocarrier drug delivery system with potential for the treatment of psychiatric disorders, such as schizophrenia and bipolar disorder, is described. Lipid nanocarriers (LN), encompassing various solid:liquid lipid compositions were formulated and assessed as potential nanosystems for transdermal delivery of olanzapine. A previously optimized method of hot high pressure homogenization (HPH) was adopted for the production of the LN, which comprised solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC) and nanoemulsions (NE). Precirol( ®) was selected as the solid lipid for progression of studies. SLN exhibited the best performance for transdermal delivery of olanzapine, based on in vitro release and permeation studies, coupled with results from physicochemical characterization of several solid:liquid lipid formulations. Stability tests, performed to give an indication of long-term storage behavior of the formulations, were in good agreement with previous studies for the best choice of solid:liquid lipid ratio. Overall, these findings highlight the SLN-based formulation as promising for the further inclusion in and production of transdermal patches, representing an innovative therapeutic approach.
Lee, Hyunjae; Song, Changyeong; Baik, Seungmin; Kim, Dokyoon; Hyeon, Taeghwan; Kim, Dae-Hyeong
Transdermal drug delivery is a prospective drug delivery strategy to complement the limitations of conventional drug delivery systems including oral and injectable methods. This delivery route allows both convenient and painless drug delivery and a sustained release profile with reduced side effects. However, physiological barriers in the skin undermine the delivery efficiency of conventional patches, limiting drug candidates to small-molecules and lipophilic drugs. Recently, transdermal drug delivery technology has advanced from unsophisticated methods simply relying on natural diffusion to drug releasing systems that dynamically respond to external stimuli. Furthermore, physical barriers in the skin have been overcome using microneedles, and controlled delivery by wearable biosensors has been enabled ultimately. In this review, we classify the evolution of advanced drug delivery strategies based on generations and provide a comprehensive overview. Finally, the recent progress in advanced diagnosis and therapy through customized drug delivery systems based on real-time analysis of physiological cues is highlighted. Copyright © 2017 Elsevier B.V. All rights reserved.
Ashare, Rebecca L; Baschnagel, Joseph S; Hawk, Larry W
The subjective experience of nicotine, which may be influenced by personality traits as well as environmental factors, may be important for understanding the factors associated with the initiation and maintenance of nicotine dependence. The present study examined the effects of 7 mg transdermal nicotine among a relatively large sample (n = 91; 44 women) of college-aged nonsmokers. Using a placebo controlled, double-blind, within-subjects design, nicotine's effects were examined at rest and again after participants completed a sustained attention task. Sex and personality factors (Behavioral Inhibition and Behavioral Approach; BIS/BAS Scales; Carver & White, 1994) were examined as potential moderators. Overall, the effects of nicotine were generally modest and unpleasant. In the context of the cognitive task, nicotine increased nausea and negative affect but reduced fatigue, relative to placebo. In contrast, effects of nicotine during the initial 4 hr of patch administration, in which participants were in their natural environments, were moderated by individual differences in behavioral approach. Neither behavioral inhibition nor gender reliably moderated any subjective effects of nicotine. The present work suggests transdermal nicotine exerts only modest, mostly negative effects among nonsmokers. Future work should examine both contextual and personality moderators in large samples of participants who are exposed to nicotine through multiple routes of administration.
Shaw, J.; Ferry, D.; Pethica, D.; Brenner, D.; Tucker, I.
OBJECTIVE—To assess nicotine patch use in smokers who purchased the product as a non-prescription medicine from pharmacies. DESIGN—A questionnaire administered at the time of purchase. SETTING—Community pharmacies throughout New Zealand. SUBJECTS—A total of 805 male and female purchasers of nicotine patches aged 18 through 87 years. MAIN OUTCOME MEASURES—Patterns of usage including self-reported smoking history, previous quit-smoking attempts, previous and current use of transdermal nicotine and other products, side effects, and concomitant smoking. RESULTS—Most respondents (74%) had attempted to quit smoking previously, many of whom (53%) had used a non-prescription nicotine replacement product. Approximately 60% of purchasers were first-time users. For those continuing a course of treatment, there was no evidence of use for longer than the manufacturer's recommendation (12 weeks). Twenty-eight per cent of respondents reported continuing smoking while using transdermal nicotine, although the number of cigarettes smoked was much less than in the reported smoking history. Side effects were reported by 24% of patch users in the current course, but there was no evidence of significant safety problems. CONCLUSIONS—This survey provides preliminary data on the non-prescription usage of transdermal nicotine when purchased through pharmacies. Keywords: nicotine replacement therapy; nicotine skin patch; transdermal nicotine; over-the-counter medication PMID:9789935
Aurilio, C; Pace, M C; Pota, V; Sansone, P; Barbarisi, M; Grella, E; Passavanti, M B
Due to tolerance development and adverse side effects, chronic pain patients frequently need to be switched to alternative opioid therapy To assess the efficacy and tolerability of an alternative transdermally applied (TDS) opioid in patients with chronic cancer pain receiving insufficient analgesia using their present treatment. A total of 32 patients received alternative opioid therapy, 16 were switched from buprenorphine to fentanyl and 16 were switched from fentanyl to buprenorphine. The dosage used was 50% of that indicated in equipotency conversion tables. Pain relief was assessed at weekly intervals for the next 3 weeks Pain relief as assessed by VAS, PPI, and PRI significantly improved (p < 0.0001) in all patients at all 3 follow up visits. After 3 weeks of treatment, the reduction in the mean VAS, PPI, and PRI scores in the fentanyl and buprenorphine groups was 68, 77, 74, and 69, 79, and 62%, respectively. Over the same time period the use of oral morphine as rescue medication was reduced from 27.5 +/- 20.5 (mean +/- SD) to 3.75 +/- 8.06, and 33.8 +/- 18.9 to 3.75 +/- 10.9 mg/day in the fentanyl and buprenorphine groups, respectively. There was no significant difference in either pain relief or rescue medication use between the two patient groups The number of patient with adverse events fell during the study. After the third week of the treatment the number of patients with constipation was reduced from 11 to 5, and 10 to 4 patients in the fentanyl and buprenorphine groups, respectively. There was a similar reduction in the incidence of nausea and vomiting. No sedation was seen in any patient after one week of treatment. Opioid switching at 50% of the calculated equianalgesic dose produced a significant reduction in pain levels and rescue medication. The incidence of side effects decreased and no new side effects were noted. Further studies are required to provide individualized treatment for patients according to their different types of cancer.
Aurilio, C; Pace, MC; Pota, V; Sansone, P; Barbarisi, M; Grella, E; Passavanti, MB
Background Due to tolerance development and adverse side effects, chronic pain patients frequently need to be switched to alternative opioid therapy Objective To assess the efficacy and tolerability of an alternative transdermally applied (TDS) opioid in patients with chronic cancer pain receiving insufficient analgesia using their present treatment. Methods A total of 32 patients received alternative opioid therapy, 16 were switched from buprenorphine to fentanyl and 16 were switched from fentanyl to buprenorphine. The dosage used was 50% of that indicated in equipotency conversion tables. Pain relief was assessed at weekly intervals for the next 3 weeks Results Pain relief as assessed by VAS, PPI, and PRI significantly improved (p < 0.0001) in all patients at all 3 follow up visits. After 3 weeks of treatment, the reduction in the mean VAS, PPI, and PRI scores in the fentanyl and buprenorphine groups was 68, 77, 74, and 69, 79, and 62%, respectively. Over the same time period the use of oral morphine as rescue medication was reduced from 27.5 ± 20.5 (mean ± SD) to 3.75 ± 8.06, and 33.8 ± 18.9 to 3.75 ± 10.9 mg/day in the fentanyl and buprenorphine groups, respectively. There was no significant difference in either pain relief or rescue medication use between the two patient groups The number of patient with adverse events fell during the study. After the third week of the treatment the number of patients with constipation was reduced from 11 to 5, and 10 to 4 patients in the fentanyl and buprenorphine groups, respectively. There was a similar reduction in the incidence of nausea and vomiting. No sedation was seen in any patient after one week of treatment. Conclusion Opioid switching at 50% of the calculated equianalgesic dose produced a significant reduction in pain levels and rescue medication. The incidence of side effects decreased and no new side effects were noted. Further studies are required to provide individualized treatment for patients according
Starkman, Jonathan S; Dmochowski, Roger R
In clinical trials, transdermal oxybutynin (OXY-TDS) has shown comparable efficacy and improved tolerability when compared with conventional pharmacotherapy. Systemic anticholinergic adverse effects are comparable to those with placebo, most likely owing to avoidance of first-pass hepatic metabolism and conversion of oxybutynin to N-desethyloxybutynin. OXY-TDS has predictable pharmacokinetic absorption and elimination parameters, as shown in both in vitro and in vivo studies. Consistent plasma concentrations of oxybutynin avoid labile peak and trough concentrations seen with immediate-release formulations, paralleling extended-release drug delivery. This novel drug delivery system has unique dermatologic skin application site reactions, including erythema and pruritus. Skin reactions are usually mild and can be minimized by varying the site of patch application. Most eczematous dermatologic reactions can be appropriately treated with a moderately potent topical corticosteroid cream. A small percentage of patients will discontinue therapy as a result of bothersome application site skin reactions. PMID:17043706
Liu, Xingyan; Liu, Hong; Liu, Jianqiang; He, Zhiwei; Ding, Congcong; Huang, Guoliang; Zhou, Weihua; Zhou, Leshan
Background The purpose of this study was to develop a transdermal ligustrazine patch containing a stable formulation and with good entrapment efficiency, release rate, and transdermal absorption. Methods Ligustrazine ethosomes were prepared by ethanol injection-sonication, with entrapment efficiency as an indicator. Using acrylic resin as the primary constituent, the ligustrazine ethosome patch was prepared by adding succinic acid as a crosslinking agent and triethyl citrate as a plasticizer. In vitro release and transdermal permeation studies were carried out. Finally, a pharmacokinetic study was carried out in rats to explore relative bioavailability. The formulations of ligustrazine ethosome were 1% (w/v) phospholipid, 0.4% (w/v) cholesterol, and 45% (v/v) ethanol. Results Ligustrazine ethosomes were obtained with an average particle size of 78.71 ± 1.23 nm and an average entrapment efficiency of 86.42% ± 1.50%. In vitro transdermal testing of the ligustrazine ethosome patches showed that the cumulative 24-hour amount of ligustrazine was up to 183 ± 18 μg/cm2. The pharmacokinetic results revealed that the relative bioavailability was 209.45%. Conclusion Compared with conventional ligustrazine administration, ligustrazine ethosome patches could promote better drug absorption and increase bioavailability. This study demonstrates that the transdermal action of the ligustrazine ethosome patch was comparatively good. PMID:21499422
Fort, Chelsea; Curtis, Byron; Nichols, Clay; Niblo, Cheryl
Acetyl fentanyl is an illicit fentanyl analog recently appearing in forensic casework. A quantitative method was created for measuring acetyl fentanyl in various biological matrices acquired post-mortem due to recent positive screening results in casework. Initial detection by immunoassay and standard gas chromatography mass spectrometry (GC/MS) methods have been previously reported for acetyl fentanyl and are examined further here. A Selective Ion Monitoring (SIM) method was created using a GC/MS for quantitation. In two separate cases, acetyl fentanyl was found to be in similar concentrations to those previously reported and ruled to be the cause of death. Acetyl fentanyl concentrations were determined in blood samples, liver, brain, vitreous humor, and urine. Individual 1 had acetyl fentanyl concentrations as follows: heart blood-285 ng/mL, femoral blood-192 ng/mL, liver-1,100 ng/g, brain-620 ng/g, and urine-3,420 ng/mL. Individual 2 had acetyl fentanyl concentrations as follows: heart blood-210 ng/mL, femoral blood-255 ng/mL, urine-2,720 ng/mL and vitreous humor-140 ng/mL. Experimental conditions for screening and quantitation are provided, using immunoassay and GC/MS methods. Due to the recent emergence of acetyl fentanyl, more data will need to be generated to fully differentiate recreational and fatal concentrations of acetyl fentanyl to assist toxicologists accurately understanding its physiological impact. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: email@example.com.
Lera dos Santos, Marcos Eduardo; Maluf-Filho, Fauze; Chaves, Dalton Marques; Matuguma, Sergio Eiji; Ide, Edson; Luz, Gustavo de Oliveira; de Souza, Thiago Ferreira; Pessorrusso, Fernanda C Simões; de Moura, Eduardo Guimarães Hourneaux; Sakai, Paulo
AIM: To compare deep sedation with propofol-fentanyl and midazolam-fentanyl regimens during upper gastrointestinal endoscopy. METHODS: After obtaining approval of the research ethics committee and informed consent, 200 patients were evaluated and referred for upper gastrointestinal endoscopy. Patients were randomized to receive propofol-fentanyl or midazolam-fentanyl (n = 100/group). We assessed the level of sedation using the observer’s assessment of alertness/sedation (OAA/S) score and bispectral index (BIS). We evaluated patient and physician satisfaction, as well as the recovery time and complication rates. The statistical analysis was performed using SPSS statistical software and included the Mann-Whitney test, χ2 test, measurement of analysis of variance, and the κ statistic. RESULTS: The times to induction of sedation, recovery, and discharge were shorter in the propofol-fentanyl group than the midazolam-fentanyl group. According to the OAA/S score, deep sedation events occurred in 25% of the propofol-fentanyl group and 11% of the midazolam-fentanyl group (P = 0.014). Additionally, deep sedation events occurred in 19% of the propofol-fentanyl group and 7% of the midazolam-fentanyl group according to the BIS scale (P = 0.039). There was good concordance between the OAA/S score and BIS for both groups (κ = 0.71 and κ = 0.63, respectively). Oxygen supplementation was required in 42% of the propofol-fentanyl group and 26% of the midazolam-fentanyl group (P = 0.025). The mean time to recovery was 28.82 and 44.13 min in the propofol-fentanyl and midazolam-fentanyl groups, respectively (P < 0.001). There were no severe complications in either group. Although patients were equally satisfied with both drug combinations, physicians were more satisfied with the propofol-fentanyl combination. CONCLUSION: Deep sedation occurred with propofol-fentanyl and midazolam-fentanyl, but was more frequent in the former. Recovery was faster in the propofol-fentanyl group
Rao, Qian; Lin, Yu; Liu, Xin; Ma, Lian-Ju; Sheng, Fang-Fang; Xiao, Ke
To screen the matrix and permeation enhancer of Duliang Patches. Based on L9 (3(4)) orthogonal experimental design, the content of imperatorin of the release rate and transdermal osmolality were regarded as evaluation indexes to optimize the matrix and permeation enhancer of patches suing of Drug dissolution tester and Franz diffusion cell. The best prescriplion of sustained-release patch of Duliang was: the quality percentage content of the starch, sodium carboxymethyl cellulose, glycerin, azone, propylene glycol and PEG400 was 6%, 2%, 30%, 1%, 15% and 2.5% respectively. The release behavior of sustained-release patches of Duliang tallied with Higuchi equation and the effect of sustained-release was apparent. The sustained-release patches of Duliang have good property of sustained-release and transdermal in vitro and the stability of patches is also sound while the release in vivo awaits further inspection.
Morissette, Sandra B.; Gulliver, Suzy Bird; Kamholz, Barbara W.; Spiegel, David A.; Tiffany, Stephen T.; Barlow, David H.
Transdermal nicotine almost doubles tobacco cessation rates; however little is known about what happens to smokers during the quit process when they are wearing the nicotine patch and confronted with high-risk smoking triggers. This is particularly important for smokers with psychological disorders who disproportionately represent today’s smokers and have more trouble quitting. Using a mixed between- and within-subjects design, smokers with anxiety disorders (n = 61) and smokers without any current Axis I disorders (n = 38) received transdermal nicotine (21 mg) or a placebo patch over two assessment days separated by 48 hours. Urge to smoke was evaluated during a 5-hour patch absorption period (reflecting general smoking deprivation) and during imaginal exposure to theoretically high-risk triggers containing smoking cues, anxiety cues, both, or neutral cues. No differences were observed between smokers with and without anxiety disorders. Significant Patch X Time and Patch X Cue Content interactions were found. Both patch conditions experienced an increase in urge during the deprivation period, but post-absorption urge was significantly higher in the placebo condition, suggesting that transdermal nicotine attenuated the degree to which urge to smoke increased over time. During the cue reactivity trials, when participants received the nicotine patch, they experienced significantly lower urge in response to both smoking-only and neutral cues, but not when anxiety cues were present (alone or in combination with smoking cues). These data suggest that transdermal nicotine alleviates urge only under certain circumstances, and that adjunctive interventions are likely necessary to address smoking urges in response to spikes in distress among smokers trying to quit. PMID:22686966
Morissette, Sandra B; Gulliver, Suzy Bird; Kamholz, Barbara W; Spiegel, David A; Tiffany, Stephen T; Barlow, David H
Transdermal nicotine almost doubles tobacco cessation rates; however, little is known about what happens to smokers during the quit process when they are wearing the nicotine patch and are confronted with high-risk smoking triggers. This is particularly important for smokers with psychological disorders who disproportionately represent today's smokers and have more trouble quitting. Using a mixed between- and within-subjects design, smokers with anxiety disorders (n=61) and smokers without any current Axis I disorders (n=38) received transdermal nicotine (21 mg) or a placebo patch over two assessment days separated by 48 hr. Urge to smoke was evaluated during a 5-hr patch absorption period (reflecting general smoking deprivation) and during imaginal exposure to theoretically high-risk triggers containing smoking cues, anxiety cues, both, or neutral cues. No differences were observed between smokers with and without anxiety disorders. Significant Patch×Time and Patch×Cue Content interactions were found. Both patch conditions experienced an increase in urge during the deprivation period, but postabsorption urge was significantly higher in the placebo condition, suggesting that transdermal nicotine attenuated the degree to which urge to smoke increased over time. During the cue reactivity trials, when participants received the nicotine patch, they experienced significantly lower urge in response to both smoking-only and neutral cues, but not when anxiety cues were present (alone or in combination with smoking cues). These data suggest that transdermal nicotine alleviates urge only under certain circumstances and that adjunctive interventions are likely necessary to address smoking urges in response to spikes in distress among smokers trying to quit.
Transdermal drug administration has a number of advantages that cannot be leveraged for therapeutic benefits because of the robust barrier provided by the stratum corneum. One of the promising techniques for circumventing the stratum corneum is sonophoresis - the use of ultrasound for facilitating transdermal drug delivery. In this review, the mechanisms underlying sonophoresis and the utilization of the technique for transdermal delivery are discussed. The challenges of this mode of drug administration have also been highlighted and insight from a number of toxicological studies is described.
Azagury, Aharon; Khoury, Luai; Enden, Giora; Kost, Joseph
Transdermal drug delivery offers an attractive alternative to the conventional drug delivery methods of oral administration and injections. However, the stratum corneum serves as a barrier that limits the penetration of substances to the skin. Application of ultrasound (US) irradiation to the skin increases its permeability (sonophoresis) and enables the delivery of various substances into and through the skin. This review presents the main findings in the field of sonophoresis in transdermal drug delivery as well as transdermal monitoring and the mathematical models associated with this field. Particular attention is paid to the proposed enhancement mechanisms and future trends in the fields of cutaneous vaccination and gene therapy.
Donnelly, Ronald F
Fentanyl is used to manage pain because it is a potent lipophilic opiate agonist. The stability of fentanyl in polyolefin bags when diluted to either 10 µg/mL or 50 µg/mL with sodium chloride 0.9% has not been studied. The chemical stability of fentanyl 50 µg/mL packaged in polyvinyl chloride bags has been studied, however, the stability in polyolefin bags is lacking. Polyolefin bags were aseptically filled with either 10-µg/mL or 50-µg/mL fentanyl solution. Containers were then stored at either 5°C and protected from light or 22°C and exposed to light for 93 days. Fentanyl peaks were monitored using a stability-indicatin high-performance liquid chromatographic method. Changes to color, clarity, and pH were also monitored. There were no signs of chemical degradation of fentanyl packaged in polyolefin bags at either 5°C or 22°C after storage for 93 days. Over the course of the study, all solutions remained colorless and clear. The pH showed a slight decrease during the 93 days of storage. The stability of both undiluted (50-µg/mL) and diluted (10-µg/mL) fentanyl solutions when packaged in polyolefin bags was 93 days when stored at either 5°C or 22°C. Copyright© by International Journal of Pharmaceutical Compounding, Inc.
Donny, Eric C; Jones, Melissa
Sensorimotor smoking stimuli are important determinants of cigarette use. The present study aimed to determine whether denicotinized cigarettes lose their reinforcing and/or subjective effects over a 9-day outpatient period when they are smoked with or without concurrent transdermal nicotine. After a preferred brand baseline, 68 participants were randomized into one of four conditions based on the dose (mg) of transdermal nicotine and the type of cigarettes (dose/cigarette): 0/nicotine, 0/denicotinized, 7/denicotinized, and 21/denicotinized. Under placebo patch conditions, participants smoked a similar number of nicotine and denicotinized cigarettes and no group differences emerged over repeated testing. The total volume of smoke inhaled was lower in the denicotinized group, although this decrease dissipated over time. Denicotinized cigarettes were rated as having low positive and high negative subjective effects. Compared to placebo, transdermal nicotine decreased the number of denicotinized cigarette smoked, produced a lasting decrease in the total volume of denicotinized cigarette smoke inhaled, but had little effect on the subjective effects of denicotinized cigarettes. Transdermal nicotine attenuated withdrawal during initial smoking abstinence; however, once participants were allowed to smoke withdrawal symptoms were relatively low regardless of patch condition. The persistent use of denicotinized cigarettes may result from the presence of nicotine withdrawal and/or the degree to which smoking becomes somewhat independent of the outcome of the behavior (i.e., habit learning). Additional studies would be useful to determine what factors drive continued use of denicotinized cigarettes, whether their use subsides as withdrawal dissipates, and whether they address motives for smoking distinct from current pharmacotherapy.
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.
Dima, Delia; Tomuleasa, Ciprian; Frinc, Ioana; Pasca, Sergiu; Magdo, Lorand; Berindan-Neagoe, Ioana; Muresan, Mihai; Lisencu, Cosmin; Irimie, Alexandru; Zdrenghea, Mihnea
Pain is commonly diagnosed with respect to cancer and heart diseases, being a major symptom in most neoplastic diseases. Uncontrolled pain leads to a decrease in the quality of life and an increase in the morbidity of the patient. Opioids represent the best analgetic supportive therapy and are frequently used in patients suffering from cancer and experiencing a high level of pain. Opioid treatment starts with a gradual titration of the dose until the minimum effective dose and the maximum tolerated dose are determined. Opioid rotation refers to the switch from one opioid to another in order to get a better response to analgetic therapy and reduce side effects. Fentanyl therapy is recommended to be continued during chemotherapy, radiotherapy, or in the case of surgical intervention. Rotation to fentanyl patches is an efficient and elegant solution for cancer patients, with reduced side effects. Opioid rotation, especially to fentanyl, was shown to increase the quality of life in patients with malignant disease. Finally, rotation to fentanyl is also advantageous from an economic point of view.
Dima, Delia; Tomuleasa, Ciprian; Frinc, Ioana; Pasca, Sergiu; Magdo, Lorand; Berindan-Neagoe, Ioana; Muresan, Mihai; Lisencu, Cosmin; Irimie, Alexandru; Zdrenghea, Mihnea
Pain is commonly diagnosed with respect to cancer and heart diseases, being a major symptom in most neoplastic diseases. Uncontrolled pain leads to a decrease in the quality of life and an increase in the morbidity of the patient. Opioids represent the best analgetic supportive therapy and are frequently used in patients suffering from cancer and experiencing a high level of pain. Opioid treatment starts with a gradual titration of the dose until the minimum effective dose and the maximum tolerated dose are determined. Opioid rotation refers to the switch from one opioid to another in order to get a better response to analgetic therapy and reduce side effects. Fentanyl therapy is recommended to be continued during chemotherapy, radiotherapy, or in the case of surgical intervention. Rotation to fentanyl patches is an efficient and elegant solution for cancer patients, with reduced side effects. Opioid rotation, especially to fentanyl, was shown to increase the quality of life in patients with malignant disease. Finally, rotation to fentanyl is also advantageous from an economic point of view. PMID:28223843
Amanatkar, Hamid Reza; Grossberg, George Thomas
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.
Omray, L K; Kohli, S; Khopade, A J; Patil, S; Gajbhiye, Asmita; Agrawal, G P
The mesophasic microreservoir comprises lyotrophic liquid crystals. The liquid crystals were prepared of Brij-35, cetosteryl alcohol and propranolol and evaluated for parameters viz. anisotropy, size and size distribution and drug entrapment efficiency. Subsequent to this liquid crystals based transdermal drug delivery system (TDS) was prepared by incorporating liquid crystals in previously prepared matrix based transdermal patch and evaluated for stability studies like temperature, humidity and aging. The system was also studied for tensile strength, moisture content, water vapor transmission, drug content, anisotropy and In vitro drug release studies.
Bang, Lynne M; Easthope, Stephanie E; Perry, Caroline M
Oxybutynin binds to the M(3) muscarinic receptors on the detrusor muscle of the bladder, preventing acetylcholinergic activation and relaxing the muscle. The transdermal system delivers oxybutynin over a 3- to 4-day period after application to intact skin. Peak plasma concentrations of oxybutynin and the major active metabolite, N-desethyloxybutynin, are reached 24 - 48 hours after a single application and therapeutic concentrations are maintained throughout the dosage interval. In a large, randomised, double-blind trial, transdermal oxybutynin 3.9 mg/day significantly decreased the median number of incontinence episodes per week compared with placebo (-19 vs -15, p = 0.0165) in patients with overactive bladder. In addition, the micturition frequency was reduced and average voided volume was increased by transdermal oxybutynin treatment. Significant reductions in incontinence episodes following transdermal oxybutynin treatment were also observed in two further studies and the clinical efficacy was similar to that of oral tolterodine or oral oxybutynin. Transdermal oxybutynin was well tolerated in clinical trials. Application site reactions were the most common adverse effect; however, the majority were mild to moderate in severity. Adverse events associated with anticholinergic drugs (e.g. dry mouth) were less frequently reported in patients treated with transdermal oxybutynin than in those receiving orally administered oxybutynin or tolterodine.
Poklis, Justin; Poklis, Alphonse; Wolf, Carl; Hathaway, Cindie; Arbefeville, Elise; Chrostowski, Leszek; Devers, Kelly; Hair, Laura; Mainland, Mary; Merves, Michele; Pearson, Julia
We present the case histories, autopsy findings and toxicology findings of two fatal intoxications involving the designer drug, butyryl fentanyl. The quantitative analysis of butyryl fentanyl in postmortem fluids and tissues was performed by an ultrahigh-performance liquid chromatography tandem mass spectrometry method. In the first case, butyryl fentanyl was the only drug detected with concentrations of 99 ng/mL in peripheral blood, 220 ng/mL in heart blood, 32 ng/mL in vitreous humor, 590 ng/mL in gastric contents, 93 ng/g in brain, 41 ng/g in liver, 260 ng/mL in bile and 64 ng/mL in urine. The cause of death was ruled fatal intoxication by butyryl fentanyl. In the second case, butyryl fentanyl was detected along with acetyl fentanyl, alprazolam and ethanol. The butyryl fentanyl concentrations were 3.7 ng/mL in peripheral blood, 9.2 ng/mL in heart blood, 9.8 ng/mL in vitreous humor, 4,000 ng/mL in gastric contents, 63 ng/g in brain, 39 ng/g in liver, 49 ng/mL in bile and 2 ng/mL in urine. The acetyl fentanyl concentrations were 21 ng/mL in peripheral blood, 95 ng/mL in heart blood, 68 ng/mL in vitreous humor, 28,000 ng/mL in gastric contents, 200 ng/g in brain, 160 ng/g in liver, 330 ng/mL in bile and 8 ng/mL in urine. In addition, the alprazolam concentration was 40 ng/mL and the ethanol concentration was 0.11 g/dL, both measured in peripheral blood. The cause of death in the second case was ruled a mixed drug intoxication. In both cases, the manner of death was accident.
Lindauer, Allison; Sexson, Kathryn; Harvath, Theresa A
: 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.
Ziv, I; Versano, D; Ruach, M; Izraeli, S; Almog, S; Alhalel, A; Alkalay, M; Menahem, S; Tochner, Z
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
Mao, Yan-Ting; Hua, Hai-Ying; Zhang, Xiang-Guo; Zhu, Dong-Xue; Li, Feng; Gui, Zhen-Hua; Zhao, Yong-Xing
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.
Manno, Maurizio; Di Renzo, Gianfranco; Bianco, Pasquale; Sbordone, Carmine; De Matteis, Francesco
We report the case of a 62-year-old woman who developed a withdrawal syndrome after using a standard 1.5-mg transdermal scopolamine (TDS) patch behind the ear to prevent motion sickness during sailing. The patient, who had used TDS occasionally for years without significant adverse effects, more recently, having worn a patch continuously for 7 days, approximately 24 to 36 hours after removing the patch developed dizziness, nausea, sweating, fatigue, and drowsiness. All symptoms disappeared without therapy in about 2 days. Approximately 1 year after the first episode, though, a very similar, more severe disabling reaction developed on 2 occasions. Drowsiness and malaise were accompanied by severe asthenia, orthostatic sweating, inability to stand, and hypotension. All clinical tests (electrocardiogram; spirometry; blood cell count; plasma levels of cortisol, sodium, and potassium; and liver and kidney function tests) were negative, and symptoms disappeared slowly, after several days. Although we are certain that scopolamine was responsible for the symptoms, we are less clear as to the nature of the disorder. The effects being more severe after a more prolonged use of the TDS patch, the increase in severity each successive time, and the time lag between removing the patch and appearance of symptoms all indicated a withdrawal syndrome for which several mechanisms may be suggested.
Faymonville, M E; Libbrecht, D
Our understanding of the pathophysiologic mechanisms of chronic pain progresses; the complexity of the problem justifies our need for new molecules and new ways of administration that will help to further optimise and better individualize our pharmacologic therapies. Whereas acute pain can be considered an alarm signal, chronic pain constitutes, per se, a syndrome that requires a meticulous selection of the analgesic drug(s). Since pain is permanent, the continuous administration of the analgesic is recommended rather than an on demand administration. Transdermic modes of administration are of value for the treatment of chronic pain because they allow a progressive delivery of the active compound together with the maintenance of stable plasma levels of the drug. Buprenorphine is a semi-synthetic opioid that is available in the sublingual, injectable, or transdermic forms. The matrix patch of buprenorphine represents a major asset for the treatment of chronic pain, whether it be cancerous in origin, or not. Its efficacy and safety have been clearly demonstrated in randomised double blind trials as well as in post-marketing surveillance observations. Buprenorphine, administered as a transdermal therapeutic system, induces a dose-related pain relief, whatever the nature of the pain and the age of the patient. Buprenorphine also exerts an analgesic action on neuropathic pain. It differs from other opioids by its affinity as a partial agonist on mu and kappa receptors, and as a complete agonist of ORL-1 receptors. Therefore, transdermal buprenorphine will be useful to all physicians having to control severe pain by powerful opioids.
Chen, Suting; Han, Yi; Yu, Daping; Huo, Fengmin; Wang, Fen; Li, Yunxu; Dong, Lingling; Liu, Zhidong; Huang, Hairong
Electro-phonophoresis (EP) has been used as a drug delivery approach in clinical fields. The objective of the present study is to evaluate the skin permeability of isoniazid and rifampin in guinea pigs by EP to provide reference basis for clinical applications of such transdermal delivery system in the treatment of patients with superficial tuberculosis. Isoniazid and rifampin solutions were delivered transdermally with or without EP in health guinea pigs for 0.5 h. Local skin and blood samples were collected serially at 0, 1/2, 1, 2, 4, 6 and 24 h after dosing. Drug concentrations in local skin and blood were evaluated by high-performance liquid chromatography. Isoniazid concentrations in local skin of guinea pigs receiving isoniazid through EP transdermal delivery were significantly higher than in animals receiving only isoniazid with transdermal patch. However, for rifampin, patches alone group presented almost uniform concentration versus time curve with that of EP group, and both groups had concentrations much higher than the therapeutic concentration of the drug over sustainable time. After EP transdermal delivery, the mean peak concentrations of isoniazid and rifampin in skin were 771.0 ± 163.4 μg/mL and 81.2 ± 17.3 μg/mL respectively. Neither isoniazid nor rifampin concentration in blood could be detected (below the lower detection limit of 1 μg/mL) at any time point. The present study showed that application of EP significantly enhanced INH penetration through skin in guinea pigs, while RIF patch alone obtained therapeutic concentration in local skin. Our work suggests several possible medication approaches for efficient treatment of superficial tuberculosis.
Stachowiak, Grzegorz; Pertyński, Tomasz; Pertyńska-Marczewska, Magdalena
Despite the undeniably positive effect on the quality of life of menopausal women, menopausal hormone therapy (HT) also has negative side-effects, which include, among others, thromboembolic complications. To assess the effect of a popular type of this therapy - transdermal HT on platelet hemostasis, which plays a significant role in intravascular coagulation. The study group consisted of 92 postmenopausal women: 1) group G1 (n=30), treated with transdermal HT (17β-estradiol 50 μg/day plus NETA 170 μg/day); 2) group G2 (n=31), treated with the above transdermal HT and low dosage of acetylsalicylic acid (ASA); 3) control group P (n=31). All the women qualified for the study had two or more risk factors for arterial thrombosis, such as: smoking, hypertension, visceral obesity, hypercholesterolaemia, hypertriglyceridaemia, elevated levels of PAI-1, and increased fibrinogen, increased activity of coagulation factor VII. After three months of therapy, in the G1 group there was a decrease in platelet count (p = 0.004) and a decrease in GP IIb/IIIa - a platelet receptor for fibrinogen (p = 0.022). In the G2 group, no changes in the tested parameters were observed. 1) Transdermal HT in the form of combined, estrogen-progestogen patches favourably modifies platelets haemostasis, reversing the adverse effects that occur after menopause. 2) The use of low ASA doses as a thromboprophylaxis in short-term transdermal HT is not necessary.
Mundada, A S; Avari, J G
Damar Batu (DB) is a novel film-forming biomaterial obtained from Shorea species, evaluated in this study for its potential application in transdermal drug delivery system. DB was characterized initially in terms of acid value, softening point, molecular weight (M(w)), polydispersity index (M(w)/M(n)), and glass transition temperature (T(g)). Neat, plasticized films of DB were investigated for mechanical properties. The biomaterial was further investigated as a matrix-forming agent for transdermal drug delivery system. Developed matrix-type transdermal patches were evaluated for thickness and weight uniformity, folding endurance, drug content, in vitro drug release study, and skin permeation study. On the basis of in vitro drug release and in vitro skin permeation performance, formulation containing DB/Eudragit RL100 (60 : 40) was found to be better than other formulations and was selected as the optimized formulation. IR analysis of physical mixture of drug and polymer and thin layer chromatography study exhibited compatibility between drug and polymer. From the outcome of this study, it can be concluded that applying suitable adhesive layer and backing membrane-developed DB/ERL100, transdermal patches can be of potential therapeutic use.
Shaikh, Shahida; Shaikh, Abdul Hameed; Akhter, Saleem; Isran, Basma
To determine the efficacy of transdermal Nitroglycerine patch in idiopathic pre-term labour and foetomaternal outcome. This quasi-experimental study was conducted at the Obstetrics Unit-II of Shaikh Zayed Hospital for Women, Chandka Medical College, Shaheed Mohtarma Benazir Bhutto Medical University, Larkana, from Jan 1 to June 30, 2010. Sixtyfive pregnant women at 28-34 weeks of gestation were recruited after they met the selection criteria based on non-probability consecutive sampling. Initially, 73 patients were selected, but 65 of them completed the treatment, while 8 patients refused to continue. Patients diagnosed with pre-term labour were given glyceryl trinitrate (GTN) 5 mg/12 hours transdermal patch which was applied on the anterior abdominal wall. The second patch of same dose was given after 12 hours. Arrest of labour, prolongation of pregnancy in days or weeks along with side effects of the agent were monitored. Patients were followed till delivery to know the foeto-maternal outcome. Dramatic effects were seen in around 60 (92.3%), of the total patients who had felt relief from premature labour pains within the first hour and only 5 (7.6%) patients could not go beyond 24 hours, as among them 3 (4.61%) had previous uterine scar and 2 (3.07%) developed ruptured membranes after 12 hours of admission and their babies also could not survive. Mean pregnancy prolongation was 15.35 +/- 9.45 days (min: 4 max: 35), so delivery was deferred up to 48 hours, 3 to 7 days and more than 7 days in 4 (6.15%), 6 (9.23%) and 50 (76.92%) respectively. Glyceryl trinitrate, trans dermal patch is effective and safe tocolytic in idiopathic preterm labour. By prolonging pregnancy it improves neonatal outcome.
Sleep disturbances are common among children and adolescents with attention deficit hyperactivity disorder. This study sought to evaluate the effects of individualizing wear times of the methylphenidate transdermal system on sleep parameters. In this open-label, randomized trial, 26 children with attention deficit hyperactivity disorder and sleep disturbances were randomized (after dose optimization) to one of four groups with different sequences of patch wear times (i.e., 9, 10, 11, and 12 hours per day wear times each for week in different sequences). The primary endpoint comprised sleep latency. Secondary endpoints included total sleep time, sleep quality, and attention deficit hyperactivity disorder and related signs (assessed with Attention Deficit Hyperactivity Disorder Rating Scale-IV and Connor's Global Impression-Parent). A mixed-effects regression model evaluated the effects of patch wear time on sleep and symptom measures. Patch wear time exerted no significant effect on sleep latency or total sleep time, although a trend toward improved sleep quality was evident (P = 0.059) with longer patch wear times. Sleep parameters were not adversely affected by longer methylphenidate transdermal system patch wear times. Thus, if replicated in larger samples, the individualization of patch wear times should be considered according to the needs and responses of patients. Copyright © 2011 Elsevier Inc. All rights reserved.
Lyon, Bradley; Aria, Adrianus Indrat; Gat, Amir; Cosse, Julia; Montemayor, Lauren; Beizaie, Masoud; Gharib, Morteza
By catalyst patterning, bundles of vertically-aligned carbon nanotubes (CNT) can be assembled to create 2D arrays of hollow micro-needles with feature size as small as a few microns. For transdermal drug delivery, the most challenging mechanical requirement is to make the CNT micro-needle small enough so that delivery is painless yet large enough so that the micro-needle can achieve skin penetration. By taking advantage of capillary action and the nanoporosity of CNT bundles, we can wick high strength polymer into the inter-spacing between nanotubes to augment the stiffness of our micro-needles. For low viscous polymers, the large ratio between the micron sized center hole of the micro-needle and the nanopores of the surrounding CNT allow us to wick polymer through the nanotubes while maintaining an open central hole for drug transport. For a transdermal patch prototype with a delivery area less than 1cm x 1cm square, we can fabricate 50 CNT micro-needles that produces a total flow rate up to 100 uL/s with actuation pressure provided by a mere finger tap. From in vitro experiments, we will demonstrate that CNT micro-needles provide a much faster convective delivery of drugs than conventional topical diffusion based patches. We acknowledge Zcube s.r.l for their support of this work.
Gentry, M V; Hammersley, J J; Hale, C R; Nuwer, P K; Meliska, C J
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.
Sutter, Mark E; Gerona, Roy R; Davis, M Thais; Roche, Bailey M; Colby, Daniel K; Chenoweth, James A; Adams, Axel J; Owen, Kelly P; Ford, Jonathan B; Black, Hugh B; Albertson, Timothy E
The current national opioid epidemic is a public health emergency. We have identified an outbreak of exaggerated opioid toxicity caused by fentanyl adulterated tablets purchased on the street as hydrocodone/acetaminophen. Over an 8-day period in late March 2016, a total of 18 patients presented to our institution with exaggerated opioid toxicity. The patients provided a similar history: ingesting their "normal dose" of hydrocodone/acetaminophen tablets but with more pronounced symptoms. Toxicology testing and analysis was performed on serum, urine, and surrendered pills. One of the 18 patients died in hospital. Five patients underwent cardiopulmonary resuscitation, one required extracorporeal life support, three required intubation, and two received bag-valve-mask ventilation. One patient had recurrence of toxicity after 8 hours after naloxone discontinuation. Seventeen of 18 patients required boluses of naloxone, and four required prolonged naloxone infusions (26-39 hours). All 18 patients tested positive for fentanyl in the serum. Quantitative assays conducted in 13 of the sera revealed fentanyl concentrations of 7.9 to 162 ng/mL (mean = 52.9 ng/mL). Pill analysis revealed fentanyl amounts of 600-6,900 μg/pill. The pills are virtually indistinguishable from authentic hydrocodone/acetaminophen tablets and are similar in weight. To date, our county has reported 56 cases of fentanyl opioid toxicity, with 15 fatalities. In our institution, the outbreak has stressed the capabilities and resources of the emergency department and intensive care units. A serious outbreak of exaggerated opioid toxicity caused by fentanyl-adulterated tablets purchased on the street as hydrocodone/acetaminophen is under way in California. These patients required higher dosing and prolonged infusions of naloxone. Additionally, observation periods off naloxone were extended due to delayed, recurrent toxicity. The outbreak has serious ramifications for public health and safety, law
Hughes, John R.; Glaser, Mitchell
Discusses the use of transdermal nicotine (TN) in smoking cessation and its value as an effective procedure. The article reveals that, compared to a placebo, TN has double the quit rate percentages, and less than 5% of smokers quit TN due to side effects. (GLR)
Batchelder, Rachel J; Calder, Richard J; Thomas, Chris P; Heard, Charles M
The aim of this study was to investigate the feasibility of the transdermal delivery of catechins and caffeine from green tea extract. Drug-in-adhesive patches containing 1.35, 1.03, 0.68, and 0.32 mg cm(-2) green tea extract were formulated and the dissolution of (-)-epigallocatechin gallate (EGCg), (-)-epigallocatechin (EGC) and (-)-epicatechin (EC) from these was determined. Transdermal delivery was determined across full thickness pig ear skin from saturated solutions of green tea extract in pH 5.5 citrate-phosphate buffer, polyethylene glycol 400 and a 50:50 mixture of the citrate phosphate buffer and polyethylene glycol in addition to patches containing 1.35 mg cm(-2) green tea extract. Dissolution experiments indicated first order release which was dose dependent in respect of the loading level, although the amounts permeated were not always proportional to the amounts in the formulation. The highest percentage permeation of EGCg was found to be from the patch formulation. EGCg, EGC and EC were all successfully delivered transdermally from saturated solutions and adhesive patches containing green tea extract in this study. There was some evidence for the dermal metabolism of EGCg, but after 24 h 0.1% permeated from the patches containing 1.35 mg cm(-2) green tea extract. This was equivalent to the percentage absorbed after intragastric administration of green tea extract in rats. In addition, the concentration of EGCg in the Franz cell receptor chamber after 24 h permeation from the 0.9 cm diameter patch containing 1.35 mg cm(-2) was within the range of Cmax plasma levels achieved after oral dosing of 2.2-4.2 gm(-2) green tea extract. Caffeine was also delivered at concentrations above those previously reported.
Shaw, J P; Ferry, D G; Pethica, D; Brenner, D; Tucker, I G
To assess nicotine patch use in smokers who purchased the product as a non-prescription medicine from pharmacies. A questionnaire administered at the time of purchase. Community pharmacies throughout New Zealand. A total of 805 male and female purchasers of nicotine patches aged 18 through 87 years. Patterns of usage including self-reported smoking history, previous quit-smoking attempts, previous and current use of transdermal nicotine and other products, side effects, and concomitant smoking. Most respondents (74%) had attempted to quit smoking previously, many of whom (53%) had used a non-prescription nicotine replacement product. Approximately 60% of purchasers were first-time users. For those continuing a course of treatment, there was no evidence of use for longer than the manufacturer's recommendation (12 weeks). Twenty-eight per cent of respondents reported continuing smoking while using transdermal nicotine, although the number of cigarettes smoked was much less than in the reported smoking history. Side effects were reported by 24% of patch users in the current course, but there was no evidence of significant safety problems. This survey provides preliminary data on the non-prescription usage of transdermal nicotine when purchased through pharmacies.
Penetar, David M; Kouri, Elena M; Gross, Michelle M; McCarthy, Elissa M; Rhee, Christina K; Peters, Erica N; Lukas, Scott E
Despite the fact that tobacco and marihuana are often used together, relatively little is known about the effects of this combination. In order to investigate the effects of the principal psychoactive component in tobacco smoke, nicotine, on marihuana-induced intoxication, we conducted a double blind, cross-over experiment using nicotine transdermal patches. Ten male and 10 female participants received either placebo or a 21 mg transdermal nicotine patch 4 h before smoking one of two marihuana cigarettes (1.99 or 3.51% delta-9-tetrahydrocannabinol (Delta(9) THC) content). Measurements of physiological activity (heart rate, blood pressure, and skin temperature) and subjective effects (self-reports of drug effects on visual analog scales (VAS) and the Addiction Research Center Inventory (ARCI)) were made periodically before and for 3h after smoking. Nicotine pre-treatment enhanced several responses to marihuana, in particular, heart rate, reports of "stimulated" on the visual analog scales, and scores on the Amphetamine scale of the ARCI. Male participants reported a more pronounced effect of marihuana that persisted longer than that of the female participants. Compared to the male participants, female participants experienced an attenuated response to marihuana and were less affected by the drug combination. The results of this study show that nicotine can have an important influence on the subjective and physiological effects of smoked marihuana. These effects have implications for the safety and efficacy of marihuana smokers who are self-medicating with the nicotine transdermal patch to manage their tobacco dependence.
... FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS... § 510.600(c) of this chapter. (c) Conditions of use—(1) Dogs—(i) Amount. 1.2 mg/lb (2.7 mg/kg) applied... control of postoperative pain associated with surgical procedures in dogs. (iii) Limitations. Fentanyl is...
... FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS... § 510.600(c) of this chapter. (c) Conditions of use—(1) Dogs—(i) Amount. 1.2 mg/lb (2.7 mg/kg) applied... control of postoperative pain associated with surgical procedures in dogs. (iii) Limitations. Fentanyl is...
Heroin and fentanyl use have reached epidemic proportions in the United States and are now blamed for the majority of drug-related overdose deaths. Both drugs are produced primarily in South America and Asia and enter the United States illegally. One result of smoking or injecting heroin or fentanyl is the development of a substance use disorder (SUD), which causes changes in brain chemistry and function. These changes result in negative behaviors and an inability to stop use. Yet, treatments are available and recovery is possible. Nurses have the potential to impact the heroin and fentanyl epidemic through developing therapeutic relationships with patients who are at risk or already have a SUD. Strategies for effective communication include maintaining a supportive, nonjudgmental attitude and incorporating motivational interviewing. All patients should be screened for opioid use and referred for treatment if indicated. It is important for nurses to be knowledgeable about heroin and fentanyl and available treatments. [Journal of Psychosocial Nursing and Mental Health Services, 55(6), 16-20.]. Copyright 2017, SLACK Incorporated.
Egras, Amy M; Umland, Elena M
Vasomotor symptoms (VMS) are among the most bothersome complaints of postmenopausal women. To date, the most widely studied and effective treatment for VMS is hormone replacement therapy, consisting of estrogen (in women without a uterus) or estrogen plus progestin (in women with a uterus). Traditionally, oral estrogens have been used for treatment. However, over the years, additional estrogen formulations have been developed including transdermal patches; vaginal rings, creams, and tablets; and injectable preparations. Two newer formulations are transdermal estrogen spray and estradiol topical emulsion. This review evaluates the current literature assessing the use of these two newer formulations for the treatment of VMS associated with menopause.
This Sojourner rover image of the Cabbage Patch shows small rounded objects on the surface that are about 3-4 cm across. Some of these are within excavations, which are about 0.5 cm wide. Several questions arise about the pebbles: Why are they rounded? Where did they come from? What do they mean?Geologists use MULTIPLE WORKING HYPOTHESES when attempting to explain observations. Some hypotheses that could account for the pebbles are: They were rounded during transport by waters of catastrophic floods and deposited on the Ares Vallis floodplain They were rounded by wave action on an ancient Martian beach They were rounded during glacial transport They are glasses that were produced by melting during impact cratering. The glass was first ejected from the crater, then molded into spherical shapes or drops as it traveled through the atmosphere, and finally was deposited at the sites They are spatter from lava flows They are nodules brought up from the deep Martian interior by lava flows or pyroclastic eruptions. They are concretions formed in sedimentary rocks They came from ancient conglomerate rocks. The pebbles were rounded by water action and subsequently lithified into conglomerate rocks. Later, the waters of catastrophic floods transported the conglomerates and deposited them on the Ares floodplain. The pebbles were then freed from the rocks by weathering. A combination of the aboveMars Pathfinder is the second in NASA's Discovery program of low-cost spacecraft with highly focused science goals. The Jet Propulsion Laboratory, Pasadena, CA, developed and manages the Mars Pathfinder mission for NASA's Office of Space Science, Washington, D.C. JPL is a division of the California Institute of Technology (Caltech).
van Seventer, R; Smit, J M; Schipper, R M; Wicks, M A; Zuurmond, W W A
This randomised, multicentre, direct open comparative trial evaluated the efficacy, treatment convenience, tolerability and safety aspects of transdermal therapeutic system (TTS)-fentanyl and sustained-release oral morphine (SRM) in both opioid-naïve patients with moderate-to-severe cancer-related pain and in patients who had already been using opioids for mild-to-moderate pain. The two treatment groups were run in parallel. Special attention was paid to constipation, nausea/vomiting, drowsiness and respiratory depression. The 131 enrolled patients started the 4-week treatment at low doses of opioid (25 microg/h TTS-fentanyl for 3 days or 30 mg SRM every 12 h) and were individually titrated. Tolerability, efficacy and safety were assessed throughout the study period. Frequency of constipation was the primary study variable and accordingly the study was powered for this. Both patients and investigators made a global treatment evaluation. TTS-fentanyl and SRM were shown to be equally effective. Pain control and sleep quality improved with both treatments. None of the patients developed respiratory depression. Statistically significantly more patients in the SRM treatment group discontinued the trial prematurely (59% vs 27%; p < 0.001), particularly due to adverse events (36% vs 4%; p < 0.001). Fewer patients in the TTS-fentanyl than in the SRM treatment group reported constipation during the trial. This finding was statistically significant after 1 week of treatment (27% vs 57%; p = 0.003). The favourable tolerability profile of TTS-fentanyl was also reflected in both the patient and the investigator global evaluation of the treatment. Patient assessment favoured TTS-fentanyl treatment in terms of a significantly lower rate of troublesome side-effects ('quite a bit' to 'very much' troublesome side-effects in 14% vs 36% of patients; p = 0.003) and less interruption of daily activities (absence of any interruption of daily activities in 88% vs 63% of patients; p = 0
Xie, Xi; Pascual, Conrado; Lieu, Christopher; Oh, Seajin; Wang, Ji; Zou, Bende; Xie, Julian; Li, Zhaohui; Xie, James; Yeomans, David C; Wu, Mei X; Xie, Xinmin Simon
Neuropathic pain caused by nerve injury is debilitating and difficult to treat. Current systemic pharmacological therapeutics for neuropathic pain produce limited pain relief and have undesirable side effects, while current local anesthetics tend to nonspecifically block both sensory and motor functions. Calcitonin gene related peptide (CGRP), a neuropeptide released from sensory nerve endings, appears to play a significant role in chronic neuropathic pain. In this study, an analgesic microneedle (AMN) patch was developed using dissolvable microneedles to transdermally deliver selective CGRP antagonist peptide in a painless manner for the treatment of localized neuropathic pain. Local analgesic effects were evaluated in rats by testing behavioral pain sensitivity in response to thermal and mechanical stimuli using neuropathic pain models such as spared-nerve injury and diabetic neuropathy pain, as well as neurogenic inflammatory pain model induced by ultraviolet B (UVB) radiation. Unlike several conventional therapies, the AMN patches produced effective analgesia on neuropathic pain without disturbing the normal nociception and motor function of the rat, resulting from the high specificity of the delivered peptide against CGRP receptors. The AMN patches did not cause skin irritation or systemic side effects. These results demonstrate that dissolvable microneedle patches delivering CGRP antagonist peptide provide an effective, safe, and simple approach to mitigate neuropathic pain with significant advantages over current treatments.
Ogawa, Noriko; Furuishi, Takayuki; Nagase, Hiromasa; Endo, Tomohiro; Takahashi, Chisato; Yamamoto, Hiromitsu; Kawashima, Yoshiaki; Loftsson, Thorsteinn; Kobayashi, Masaru; Ueda, Haruhisa
Water-soluble fentanyl citrate salt has been used in sublingual or buccal formulations for the breakthrough pain treatment. However, fentanyl absorption through the lipid mucosal membrane may be improved by enhancing the non-ionic lipophilic fentanyl base solubility. Therefore, the interaction between cyclodextrins (CDs) and fentanyl base has been evaluated to obtain basic information for its application. Parent CDs (α-, β- and γ-CD) as well as α- and β-CD derivatives were used for solubility studies with fentanyl base. Nuclear magnetic resonance (NMR) studies were applied in a system including β-CD or glucosyl-β-CD (G1-β-CD) with fentanyl base or fentanyl citrate. (1) H- and (13) C-NMR studies and a two-dimensional rotating frame Overhauser effect spectroscopy (ROESY) study were conducted to confirm inclusion complexes formation. Parent CDs displayed BS type phase solubility diagrams; β-CD exhibited a strong interaction with fentanyl base. Hydrophilic β-CD derivatives, such as G1-β-CD, displayed AL type phase diagrams and higher solubilizing effects compared with parent CDs. ROESY study suggested that fentanyl phenyl groups were included in β-CD cavity. This study revealed that hydrophilic β-CD derivatives, such as G1-β-CD, could be useful pharmaceutical additives for oral mucosal formulations because of the improved fentanyl base solubility via inclusion complexation. © 2015 Royal Pharmaceutical Society.
Thompson, Joshua P; Thompson, Dennis F
To provide a systematic review of the current role of nebulized fentanyl in acute pain and potentially other conditions. A MEDLINE literature search inclusive of the dates 1946 to May 2016 was performed using the following search terms: fentanyl and administration, inhaled Excerpta Medica was searched from 1980 to May 2016 using the following search terms: exp fentanyl/inhalation drug administration Additionally, Web of Science was searched using the terms fentanyl and pain inclusive of 1945 to May 2016. We utilized the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines to select English language, human primary literature, review articles, and supporting data assessing the efficacy of nebulized fentanyl in acute pain. Seven clinical trials have demonstrated no difference in efficacy between nebulized fentanyl and intravenous (IV) opioids. Few adverse effects were reported; however, the trials were of short duration. Nebulized fentanyl appeared to be a rapid-acting analgesic that does not require IV access. Evidence suggests that nebulized fentanyl is as effective as IV opioids in the treatment of acute pain, with relatively few adverse effects. However, questions remain about the extemporaneous preparation of fentanyl nebulized solution, the variability in nebulization devices, and ensuring consistent drug delivery to distal airways in the clinical setting. The abuse potential of nebulized fentanyl should also be considered. © The Author(s) 2016.
Mundada, A S; Avari, J G
The objective of the present study was to evaluate a novel film forming biomaterial for its potential application in the preparation of unilaminate transdermal adhesive matrix systems. The biomaterial, Damar Batu (DB), was tried alone and in combination with Eudragit RL100 as a matrixing agent in the preparation of transdermal patches. Developed transdermal patches of Diltiazem hydrochloride (DH) were evaluated for thickness uniformity, weight uniformity, folding endurance and drug content. USP dissolution apparatus V was used for in vitro drug release studies. Modified Franz diffusion cell used for permeation study using excised human cadaver skin. Total 6 formulations were developed and on the basis of in vitro drug release and in vitro skin permeation profile F5 composed of DB: Eudragit RL100 (60:40) and carrying 20 %w/w DH was selected as an optimized formulation for in vivo study. The in vivo study results showed that F5 achieved the Cmax of about 269.76 ± 1.52 ng/mL in 6 h and sustained the release of the drug till 24 h. The skin irritation study results proved that the novel biomaterial is non-sensitizing and non-irritating. Drug-polymer interaction study carried out to check the compatibility of drug and polymer showed the intactness of the drug in the formulation proving the compatibility of the polymer. It can be proposed from the outcome of the present study that by applying suitable adhesive layer and backing membrane, DB: Eudragit RL100 (60:40) transdermal patches can be of potential therapeutic use.
Heard, Charles M; Johnson, Sarah; Moss, Gary; Thomas, Chris P
Extracts of guarana (Paullinia cupana) feature as putatively stimulating ingredients in a number of foods, drinks and dietary/herbal supplements. The objective of this work was to investigate in vitro the transdermal delivery of the major pharmacologically active compounds contained in guarana extract. Saturated solutions of guarana were prepared in polyethylene glycol 400 (PEG400), propylene glycol (PG) and H(2)O at 32 degrees C. Guarana extract was also formulated in Duro-tak 2287 transdermal adhesive in a range of concentrations and the diffusional release was determined in addition to adhesive properties. Transdermal delivery across full thickness pig ear skin was investigated in vitro using Franz-type diffusion cells, with reverse-phase HPLC being used for the quantification of the permeation of theobromine (TB), theophylline (TP), (+)-catechin (C) and caffeine (CF). Based upon a combination of release and adhesive property data a patch containing 5.55 mg guarana extract cm(-2) was deemed optimal. The general trend for the delivery of the 4 analytes was: water >5.55 mg cm(-2) patch approximately PG>PEG400. For CF the greatest steady state flux was obtained from the water vehicle: 19 microg cm(-2)h(-1), with approximately 420 microg cm(-2) permeating after 24h. This was some 6x times more than from the drug-in-adhesive patch and 10x greater than PG, a well-known penetration enhancer, and 50x that of the 'regular' excipient PEG400. A water vehicle also provided the greatest delivery of TB (0.45 microg cm(-2) h(-1)), TP (0.022 microg cm(-2) h(-1)), and C (0.10 microg cm(-2) h(-1)). An inverse relationship was noted between lipophilicity and k(p) in each vehicle. The simultaneous transdermal delivery of the major actives of guarana was established, with permeation rates being highly concentration and vehicle dependent.
Drug Del. Rev. 9:201-237 (1992). SViable skin 3. G. B. Kasting, R. L. Smith, and E. G. Cooper. Effect of lipid V’. (a) solubility and molecular size on...AD Award Number: DAMD17-02-1-0712 TITLE: Skin Bioengineering: Noninvasive Transdermal Monitoring PRINCIPAL INVESTIGATOR: Richard H. Guy, Ph.D...COVERED (Leave blank) January 2005 Final (1 Jan 2003 - 31 Dec 2004) 4. TITLE AND SUBTITLE 5. FUNDING NUMBERS DAMD17-02-1-0712 Skin Bioengineering
Oxybutynin is an efficacious treatment for overactive bladder, but its clinical utility is hampered by relative intolerability due to its side effect profile. Over the last few years, various attempts to enhance the tolerability of oxybutynin by varying the drug delivery mechanism have been introduced and have included extended release, rectal suppository, transdermal patch, and gel formulations. The recent introduction of a transdermal oxybutynin gel in a sachet form has been complemented by the administration of gel in a metered dose pump. This paper reviews the available evidence for transdermal oxybutynin gel and, where it exists, for the pump-based gel. The clinical utility of the pump-based gel is discussed. PMID:24199182
Lewis, Alan S.; Qayyum, Zheala; Koslosky, Kourtney; Picciotto, Marina R.; Volkmar, Fred R.
Aggression remains a major cause of morbidity in patients with autism spectrum disorder (ASD). Current pharmacotherapy for aggression is not always effective and is often associated with morbidity. Nicotinic acetylcholinergic neurotransmission may play a prominent role in ASD pathophysiology based on human and animal studies, and preclinical studies show nicotine administration can reduce aggression-related behaviors. Transdermal nicotine has been used to treat agitation in neuropsychiatric conditions with cholinergic dysfunction. Here we report the use of transdermal nicotine as an adjunctive medication to treat aggression in a hospitalized adolescent with ASD. Nicotine patch was recurrently well tolerated, and reduced the need for emergency medication and restraint. These findings suggest further study of transdermal nicotine for aggression comorbid with ASD is warranted. PMID:25982311
Van Schalkwyk, Gerrit I; Lewis, Alan S; Qayyum, Zheala; Koslosky, Kourtney; Picciotto, Marina R; Volkmar, Fred R
Aggression remains a major cause of morbidity in patients with autism spectrum disorder (ASD). Current pharmacotherapy for aggression is not always effective and is often associated with morbidity. Nicotinic acetylcholinergic neurotransmission may play a prominent role in ASD pathophysiology based on human and animal studies, and preclinical studies show nicotine administration can reduce aggression-related behaviors. Transdermal nicotine has been used to treat agitation in neuropsychiatric conditions with cholinergic dysfunction. Here we report the use of transdermal nicotine as an adjunctive medication to treat aggression in a hospitalized adolescent with ASD. Nicotine patch was recurrently well tolerated, and reduced the need for emergency medication and restraint. These findings suggest further study of transdermal nicotine for aggression comorbid with ASD is warranted.
Sofalvi, Szabolcs; Schueler, Harold E; Lavins, Eric S; Kaspar, Claire K; Brooker, Ian T; Mazzola, Carrie D; Dolinak, David; Gilson, Thomas P; Perch, Steve
In July of 2016, carfentanil (CF) emerged in Northeast Ohio resulting in over 25 deaths within a 30-day period. A total of 125 deaths have occurred in Summit County and Cuyahoga County has reported 40 deaths, relating to the presence of CF either alone, or in combinations with heroin and fentanyl. Prior to this surge in CF cases, positive fentanyl enzyme-linked immunosorbent assay (ELISA) screening results were increasing in number. Many were negative for fentanyl confirmation by gas chromatography-mass spectrometry. Fentanyl analogs such as CF, acetyl fentanyl (AF), 2-furanyl fentanyl (2-Fu-F) and 3-methylfentanyl (3-MF) may be present in these cases. Some fentanyl analogs like CF and 3-MF do not cross-react with the Immunalysis ELISA fentanyl assay. With the emergence of potent synthetic fentanyl analogs, questions arose as to how to interpret their very low concentrations or absence in the blood in relation to cause of death. Driving under the influence of drugs (DUID) blood specimens had also tested positive for CF by reference laboratories. A liquid chromatography-tandem mass spectrometry method was developed to identify and quantify fentanyl, norfentanyl (NF) and four analogs: AF, 2-Fu-F, 3-MF and CF. The method has been utilized to quantify these fentanyl analogs in blood and vitreous humor in authentic antemortem and postmortem cases. Calibration curves were established between 0.10-4.0 ng/mL (NF, AF, 3-MF, 2-Fu-F and CF) and 1.0-40 ng/mL for fentanyl. In total, 98 postmortem cases analyzed produced the following blood concentration ranges: CF (0.11-0.88 ng/mL), 3-MF (0.15-1.7 ng/mL), 2-Fu-F (0.15-0.30 ng/mL), AF (0.14-0.16 ng/mL), fentanyl (1.1-15 ng/mL) and NF (0.10-3.7 ng/mL). Only CF, fentanyl and NF were detected in a statistically significant subset DUID population of 26 cases producing concentration ranges between 0.11 and 0.47 ng/mL, 1.0 and 9.8 ng/mL, and 0.11 and 3.5 ng/mL, respectively. © The Author 2017. Published by Oxford University Press
Ruzycki, Shannon; Yarema, Mark; Dunham, Michael; Sadrzadeh, Hossein; Tremblay, Alain
Increasing rates of opioid abuse, particularly fentanyl, may lead to more presentations of unusual effects of opioid toxicity. Diffuse alveolar hemorrhage is a rare complication of fentanyl overdose. A 45-year-old male presented in hypoxic respiratory failure secondary to diffuse alveolar hemorrhage requiring intubation. Comprehensive drug screening detected fentanyl without exposure to cocaine. Further history upon the patient's recovery revealed exposure to snorted fentanyl powder immediately prior to presentation. Diffuse alveolar hemorrhage is a potential, though rare, presentation of opioid intoxication. Recognition of less common complications of opioid abuse such as diffuse alveolar hemorrhage is important in proper management of overdoses.
Staskin, David R
The transdermal system for delivery of medication to treat overactive bladder may provide an improved efficacy-to-tolerability ratio by regulating serum drug levels; avoiding gastrointestinal and hepatic metabolism, which is important when the metabolite has a lesser therapeutic index than the parent drug; and achieving clinical efficacy with a lower total drug burden. Additional advantages may include increased compliance and obviation of the need for oral drug administration, which is especially beneficial for the patient who is taking multiple oral medications or is caregiver-dependent. An efficient patch system must preserve the physical integrity of the drug layer, provide adequate adhesion, store and release the drug and permeation-enhancing agent in a predictable manner, promote consistent absorption through the skin regardless of location or skin or subcutaneous tissue differences, demonstrate dose proportionality, maintain skin integrity during product use and removal, and be cosmetically acceptable. A novel transdermal delivery system that incorporates an occlusive layer covering an acrylic adhesive containing the active agent oxybutynin and a skin permeation enhancer has been demonstrated in clinical trials to achieve these goals. PMID:16985986
Cohen, Steven P; Chaudhry, Hira
Migraine is a common and debilitating condition affecting approximately nearly one in four women in the USA and Europe. Episodic attacks can be associated with a number of symptoms, with nausea and/or vomiting being among the most frequent and distressing. Sumatriptan is widely used for acute treatment of migraine and is available in several formulations. The efficacy of oral sumatriptan is well-established. However, patients who experience migraine-associated nausea and/or vomiting can have difficulty swallowing tablets and may delay taking anti-migraine medication. In addition, absorption of oral sumatriptan can be reduced by migraine-associated gastroparesis. Non-oral formulations of sumatriptan are recommended for patients with nausea and/or vomiting, but their use may be limited by adverse effects and patient acceptance. A new transdermal formulation of sumatriptan has recently become available in the USA for acute treatment of migraine in adults. In this article, we review the properties of the sumatriptan iontophoretic transdermal patch and discuss the evidence to support its use in clinical practice.
Bakrudeen, Haja Bava; Sudarvizhi, C; Reddy, B S R
Bio-based nanocomposites were prepared using starch nanocrystals obtained by acid hydrolysis of native starches using different acid sources. In recent times, focuses on starch nanocrystals (SNCs) have been increasing in number of research works dedicated to the development of bio-nanocomposites by blending with different biopolymeric matrices. The work mainly deals with the preparation of starch nanocrystals using different native starches by acid hydrolysis using hydrochloric acid and trifluroacetic acid. The as-prepared starch nanocrystals are having high crystallinity and more platelet morphologies, and used as a drug carrying filler material in the hydrogel formulations with the care of different polymer matrices. The condensed work also concentrates on the dispersion of antiviral drug in the hydrogels, which are applied onto biocompatible bio-membrane to be formulating a complete transdermal patch. The acid hydrolysed starch nanocrystals were thoroughly characterized using TEM, SEM, particle size analysis and zeta potential. Their thermal stability and the crystalline properties were also characterized using TG-DSC and XRD respectively. The physiochemical interaction and compatibility between the drug and the SNCs filler in the polymeric hydrogels were evaluated using FT-IR analysis. The formulated hydrogels were subjected to evaluation of in vitro permeation studies using Franz diffusion studies. The in vitro study was indicated substantial guarantee for the fabrication of drug dispersed in polymeric hydrogels using SNCs as filler matrices for a successful transdermal drug delivery. Copyright © 2016 Elsevier B.V. All rights reserved.
Chourasia, Manish K; Kang, Lifeng; Chan, Sui Yung
The potential of ethosomes for delivering ketoprofen via skin was evaluated. The ethosomes were prepared, optimized and characterized. Vesicular shape, size and entrapment efficiency were determined by transmission electron microscopy, dynamic light scattering and minicolumn centrifugation technique, respectively. Vesicle sizes varied from 120.3±6.1 to 410.2±21.8 nm depending on the concentrations of soya phosphatidyl choline (SPC) and ethanol. Entrapment efficiency increased with concentrations of SPC and ethanol. The formulations exhibited entrapment efficiencies of 42-78%. In vitro release through cellophane membrane showed sustained release of drug from ethosomal formulations in contrast to hydroalcoholic drug solution (HA), which released most of the drug within 2-3 h. In vitro drug permeation across human skin revealed improved drug permeation and higher transdermal flux with ethosomal formulations compared to hydroethanolic drug solution. Kinetics of in vitro skin permeation showed zero order drug release from formulations. Based on in vitro transdermal flux, the estimated steady state in vivo plasma concentration from ethosomes attained therapeutic drug levels whereas hydroalcoholic drug solution exhibited sub therapeutic drug concentration with a patch size of 50 cm(2). Skin permeation of ethosomal formulations assessed by confocal microscopy revealed enhanced permeation of Rhodamine 123 loaded formulation in comparison to the hydroalcoholic solution.
Lai, Hou-Chuan; Hu, Mei-Hua; Liaw, Wen-Jinn; Lu, Chueng-He; Huang, Go-Shine
Postanesthetic involuntary movements are triggered by a variety of drugs, including propofol, sevoflurane, anti-emetics, and anti-psychotics. A case of acute involuntary movements in a healthy man after fentanyl exposure is presented. The movements consisted of large-amplitude motions of the upper limbs of the elbow joint for flexion and extension, and shaking of the head from side to side. Copyright © 2013 Elsevier Inc. All rights reserved.
structural features of morphine emerged, as did the relationships between morphine and other alkaloids such as thebaine and codeine . After an arduous...followed by hydrogenolysis and alkylation provided the target molecule , fentanyl (1). However, no yields were given in the patent literature...Robinson, R, "Consititution of Codeine and Thebaine," Mem Proc. Manchester Lit. Phil. Soc., Vol. 69, p. 79 (1925). 4. Gates, M., and Tschudi, G., "The
studies by Janssen and coworkers, 5 carfentanil is one of the most powerful, achiral fentanyls. In addition to high potency, cis-3-methylfentanyl,5...1.0 Suferttanil 1260 4.4 Alfentanil 72 0.25 b Carfentanil 7682 27 Lofentanil 5625 20 (+)-cis-3-Methylfentanyl 5431 19 Ohmefentanyl 63 0 0c 28 c...challenging. The results of metabolic studies of carfentanil are not reported to date. Based on knowledge of the metabolic transformations of these
Development of transdermal therapeutic formulation of CNS5161, a novel NMDA receptor antagonist, by utilizing pressure-sensitive adhesives II: improved transdermal absorption and evaluation of efficacy and safety.
Naruse, Mamoru; Ogawara, Ken-ichi; Kimura, Toshikiro; Konishi, Ryoji; Higaki, Kazutaka
The aim of this study was to prepare a transdermal therapeutic formulation of CNS5161, an NMDA receptor antagonist developed as a drug for neuropathic pain. Since a silicone pressure-sensitive adhesive (PSA) was found to be the best PSA for CNS5161 among six different PSAs examined in our previous study, the effects of the loading concentration of CNS5161 on release and rat skin permeability were investigated using silicone PSAs. The release of CNS5161 was elevated with an increase in the drug concentration from 1% to 14%. The transdermal flux at the steady state reached a plateau at 8% and over, while crystallization of CNS5161 was not observed for any formulation even at high drug concentrations. The drug concentration in rat skin at the steady state was also saturated at 8% and over, which correlated well with the transdermal flux at the steady state. Therefore, skin permeation clearance defined to the skin concentration at the steady state was almost constant at 0.21/h from 2% to 14% of CNS5161, which suggests that drug concentrations in the skin would be a driving force for transport of the drug to the receptor side. Since increasing the concentration of CNS5161 in the PSA patch was not able to elevate the transdermal flux, 12 formulations containing several permeation enhancers were examined to improve the transdermal transport of CNS5161. Among them, the formulation containing propylene glycol, diisopropyl adipate, and polyvinylpyrrolidone significantly increased the transdermal flux by approximately 1.8-fold by improving the diffusivity of CNS5161 in the skin, and also significantly enhanced the analgesic effect of CNS5161. This formulation caused only slight skin irritation, which indicated that it would be a promising transdermal therapeutic system for CNS5161.
Mabandla, Musa V.
The present study investigated the effects of transdermally delivered oleanolic acid (OA) monotherapy and in combination with chloroquine (CHQ) on malaria parasites and glucose homeostasis of P. berghei-infected male Sprague-Dawley rats. Oral glucose test (OGT) responses to OA-pectin patch and CHQ-OA combination matrix patch were monitored in non-infected and infected rats. To evaluate the short-term effects of treatment, percentage parasitaemia, blood glucose, glycogen and plasma insulin were monitored in separate groups of animals treated with either OA-patch monotherapy or CHQ-OA combination pectin patch over a 21-days period. Animals treated with drug-free pectin and CHQ acted as untreated and treated positive controls, respectively. Infected control rats exhibited significantly increased parasitaemia which was accompanied by hypoglycaemia. Both OA monotherapy and CHQ-OA combination therapy reduced and cleared the malaria parasites within a period of 4 and 3 days, respectively. Compared to respective controls groups, OGT responses of animals treated with OA monotherapy or CHQ-OA combination therapy exhibited lower blood glucose levels at all time points. A once-off transdermal application of OA-patch or CHQ-OA combination patch significantly improved blood glucose concentrations inducing any changes in insulin concentration. Transdermal OA used as a monotherapy or in combination with CHQ is able to clear and reduce the malaria parasites within a shorter period of time without eliciting any adverse effects on glucose homeostasis of P. berghei-infected rats. PMID:27907019
Nicoli, S; Penna, E; Padula, C; Colombo, P; Santi, P
Oxybutynin is used extensively in the treatment of patients with overactive bladder. The aim of this work was to realize and test in vitro a new transdermal bioadhesive film containing oxybutynin. Transdermal films were prepared by dissolving in water an adhesive (Plastoid), a film-forming polymer (polyvinyl alcohol), a plasticizer (sorbitol) and the drug. The mixture was then spread on siliconized paper and oven-dried. Permeation experiments were conducted in Franz-type diffusion cells using rabbit ear skin as barrier. The donor compartment contained a water solution, the prepared film (with or without backing) or the commercial patch (Oxytrol). The experiments were performed for 24h. Oxybutynin showed good permeation characteristics across the skin. When the film was applied in occlusive conditions the release profiles were much higher than in non-occlusive conditions, reaching 50% of drug permeated after 24h. Compared to the commercial patch Oxytrol, the film was more efficient suggesting that a smaller area or a lower drug loading could be employed. The results obtained show that the bioadhesive film can be a promising and innovative therapeutic system for the transdermal administration of oxybutynin.
Yu, Weijiang; Jiang, Guohua; Liu, Depeng; Li, Lei; Chen, Hua; Liu, Yongkun; Huang, Qin; Tong, Zaizai; Yao, Juming; Kong, Xiangdong
To reduce the inconvenience and pain of subcutaneous needle injection, the calcium sulfate and gelatin biodegradable composite microneedle patches with high aspect-ratio microneedles (MNs) and a flexible substrate have been developed. The microneedles with an aspect-ratio approximate 6:1 exhibit excellent mechanical property which can achieve 0.4N for each needle. The cross-section views show the inside of microneedles that have abundant pores and channels which offer potential for different drug-release profiles. The preparation procedures, degradable property for the biodegradable composite microneedle patches are described in the paper. Insulin, the drug to control blood glucose levels in diabetic patients, has been embedded into the biodegradable composite MNs. The hypoglycemic effect for transdermal delivery of insulin is studied using diabetic Sprague-Dawley (SD) rats as models in vivo. After transdermal administration to the diabetic rats, the released insulin from biodegradable composite MNs exhibit an obvious and effective hypoglycemic effect for longer time compared with that of subcutaneous injection route. This work suggests that biodegradable composite MNs containing of insulin have a potential application in diabetes treatment via transdermal ingestion.
Mainardi, Federico; Zanchin, Giorgio; Maggioni, Ferdinando
Several cases of symptomatic hemicrania continua (HC) have been reported. A 66-year-old man, suffering from migraine without aura, presented with a four month history of a new headache fulfilling the ICHD 3beta clinical criteria for HC. HC onset was strictly related to the use of transdermal nitroglycerine patch (TNP). In agreement with the cardiologist, TNP was discontinued and the headache promptly disappeared; symptoms reappeared within 6-12 hours after nitroglycerine reintroduction. After permanent discontinuation of TNP, headache disappeared at one year follow-up. To the best of our knowledge, this is the first report of the occurrence of an HC-like headache related to TNP. © 2016 American Headache Society.
Kitaoka, Momoko; Wakabayashi, Rie; Kamiya, Noriho
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
Gómez-Bernal, Silvia; Loureiro, Manuel; Rodríguez-Granados, María Teresa; Toribio, Jaime
Hormonal contraceptives are a known but rarely reported cause of photosensitivity. A 35-year-old female developed several episodes of a prurigionous papulovesicular eruption located on sun-exposed areas that resolved without scarring in days. She had been using a transdermal contraceptive (EVRA: norelgestromin and ethinyloestradiol) for 3 years, and once it was stopped, the patient became asymptomatic. She had another episode after the use of oral contraceptives (YAZ: ethinyloestradiol and drospirenone). The biopsy of the lesions showed a spongiotic dermatitis. Minimal erythema dose was diminished when the patient was using EVRA and YAZ and became normal when they were withdrawn. Phototesting with UVA, photopatch testing and blood porphyrins were normal. Antinuclear antibodies were 1/80 initially and were 1/320 6 months later. Anti-deoxyribonucleic acid antibodies, extractable nuclear antigens, anti Ro and Anti La were negative and no systemic symptoms had developed. When all hormonal contraceptives were stopped, the patient became asymptomatic. We report a case of systemic photosensitivity induced by the contraceptive patch. To the best of our knowledge, no other cases induced by transdermal contraceptives have been reported previously.
Mystakidou, Kyriaki; Tsilika, Eleni; Parpa, Efi; Papageorgiou, Charalambos; Georgaki, Stavroula; Vlahos, Lambros
Few studies have investigated the effect of fentanyl delivered via the transdermal route with regard to the patient's psychological status. Patients who were naive to strong opioids and were attending a palliative care unit for pain relief from advanced cancer participated in this study to determine the effect of transdermal therapeutic system fentanyl (TTS-F) on their psychological condition. Spielberger State-Trait Anxiety Inventory (STAI), Zung Self-Rating Depression Scale (SDS), the Karnofsky Performance Scale (100-0, optimum-death), and a Visual Analogue Scale (VAS) (0: no pain; 10: worst pain) were used to measure the level of pain. Data were collected at baseline (T0), on the 7th day (T1), and on the 14th day (T2) of TTS-F application in order to determine changes in correlation to TTS-F dose. Patients' status improved according to the Zung SDS questionnaire (P < .0005) and with each of its subscales (P < .05). A similar improvement was observed according to the Spielberger STAI questionnaire (P = .002). Moreover, VAS measures demonstrated that patients achieved significant pain relief (P < .0005), while patients' performance status did not alter significantly over the study period. Furthermore, the Zung SDS showed a statistically significant correlation when compared with the Spielberger STAI (P < .01). These data provide some evidence that the psychological status, as measured with respect to depression and anxiety in patients with advanced cancer, is improved in patients receiving TTS-fentanyl. Future research should use a broad range of psychological measurements in order to assist the development of practices, which are aimed at the improvement of quality of life in these patients.
Ameri, Mahmoud; Kadkhodayan, Miryam; Nguyen, Joe; Bravo, Joseph A; Su, Rebeca; Chan, Kenneth; Samiee, Ahmad; Daddona, Peter E
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.
Ameri, Mahmoud; Kadkhodayan, Miryam; Nguyen, Joe; Bravo, Joseph A.; Su, Rebeca; Chan, Kenneth; Samiee, Ahmad; Daddona, Peter E.
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
Dale, Lowell C; Schroeder, Darrell R; Wolter, Troy D; Croghan, Ivana T; Hurt, Richard D; Offord, Kenneth P
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
Winblad, B; Grossberg, G; Frölich, L; Farlow, M; Zechner, S; Nagel, J; Lane, R
The rivastigmine patch is the first transdermal treatment for Alzheimer disease (AD). By providing continuous delivery of drug into the bloodstream over 24 hours, transdermal delivery may offer benefits superior to those of oral administration. This study compared the efficacy, safety and tolerability of rivastigmine patches with capsules and placebo. IDEAL (Investigation of transDermal Exelon in ALzheimer's disease) was a 24-week, double-blind, double-dummy, placebo- and active-controlled study. Patients with AD were randomized to placebo or one of three active treatment target dose groups: 10-cm(2) rivastigmine patch (delivering 9.5 mg/24 hours); 20-cm(2) rivastigmine patch (17.4 mg/24 hours); or 6-mg BID rivastigmine capsules. Primary efficacy measures were the Alzheimer's Disease Assessment Scale-Cognitive subscale and Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change. Secondary outcome measures assessed a range of domains, including behavior, cognitive performance, attention, executive functions, and activities of daily living. A total of 1,195 AD patients participated. All rivastigmine treatment groups showed significant improvement relative to placebo. The 10-cm(2) patch showed similar efficacy to capsules, with approximately two-thirds fewer reports of nausea (7.2% vs 23.1%) and vomiting (6.2% vs 17.0%), incidences statistically not significantly different from placebo (5.0% and 3.3% for nausea and vomiting, respectively). The 20-cm(2) patch showed earlier improvement and numerically superior cognitive scores vs the 10-cm(2) patch with similar tolerability to capsules. Local skin tolerability was good. The transdermal patch with rivastigmine may offer additional therapeutic benefits and may prove to be the best delivery system for this drug to treat AD.
Fagerström, K O; Schneider, N G; Lunell, E
Nicotine gum and transdermal nicotine have been shown to relieve withdrawal and double success rates over placebo in trials of smoking cessation. This study tested whether combining the two methods would relieve withdrawal more effectively compared to either treatment alone. Twenty-eight smokers served as their own controls in each of four conditions: active gum + active patch (double active), active gum + placebo patch (gum only active), placebo gum + active patch (patch active) and placebo gum + placebo patch (double placebo). This "double placebo" design controls sensory, psychological and ritual variables associated with each drug form. Withdrawal symptoms were rated four times daily for 3 days in each condition. Total baseline (smoking) withdrawal scores using visual analogue scales (VAS) averaged 101.1. During cessation, total withdrawal increased to 187.0 for the double placebo condition, 142.2 for the active gum/placebo patch treatment and 128.3 for the active patch/placebo gum treatment. The double active condition equalled smoking with score 99.2. All pairwise comparisons were significant (P < 0.001) except between the two single active conditions and between smoking versus the double active condition. Significant time-of-day effects by treatment on withdrawal were observed for the double placebo condition (P < 0.05) with less withdrawal in the morning. The findings suggest: 1) combining nicotine gum with transdermal nicotine may be superior to either treatment alone, 2) more symptoms may be nicotine specific (relieved by replacement) than previously thought.
Gulati, Gaurav Kumar; Chen, Tao; Hinds, Bruce Jackson
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.
Pergolizzi, Joseph V; Philip, Beverly K; Leslie, John B; Taylor, Robert; Raffa, Robert B
Transdermal scopolamine, a patch system that delivers 1.5 mg of scopolamine gradually over 72 hours following an initial bolus, was approved in the United States in 2001 for the prevention of postoperative nausea and vomiting (PONV) in adults. Scopolamine (hyoscine) is a selective competitive anatagonist of muscarinic cholinergic receptors. Low serum concentrations of scopolamine produce an antiemetic effect. Transdermal scopolamine is effective in preventing PONV versus placebo [relative risk (RR)=0.77, 95% confidence interval (CI), 0.61-0.98, P = 0.03] and a significantly reduced risk for postoperative nausea (RR=0.59, 95% CI, 0.48-0.73, P < 0.001), postoperative vomiting (RR=0.68, 95% CI, 0.61-0.76, P < 0.001), and PONV (RR 0.73, 95% CI, 0.60-0.88, P = 001) in the first 24 hours after the start of anesthesia.
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
Kelley, M.; Elko, S.
Authenticating and upgrading system software plays a critical role in information security, yet practical tools for assessing and installing software are lacking in today's marketplace. The SafePatch tool provides the mechanism of performing automated analysis, notification, distribution, and installation of security patches and related software to network-based computer systems in a vendor-independent fashion. SafePatch assists in the authentication of software by comparing the system's objects with the patch's objects. SafePatch will monitor vendor's sites to determine when new patches are released and will upgrade system software on target systems automatically. This paper describes the design of SafePatch, motivations behind the project and the advantages of SafePatch over existing tools.
Chamberlain, Neil F. (Inventor); Hodges, Richard E. (Inventor); Zawadzki, Mark S. (Inventor)
Disclosed herein is a patch antenna comprises a planar conductive patch attached to a ground plane by a support member, and a probe connector in electrical communication with the conductive patch arranged to conduct electromagnetic energy to or from the conductive patch, wherein the conductive patch is disposed essentially parallel to the ground plane and is separated from the ground plane by a spacing distance; wherein the support member comprises a plurality of sides disposed about a central axis oriented perpendicular to the conductive patch and the ground plane; wherein the conductive patch is solely supported above the ground plane by the support member; and wherein the support member provides electrical communication between the planer conductive patch and the ground plane.
Goggin, Melissa M; Nguyen, An; Janis, Gregory C
The illicit drug market has seen an increase in designer opioids, including fentanyl and methadone analogs, and other structurally unrelated opioid agonists. The designer opioid, furanyl fentanyl, is one of many fentanyl analogs clandestinely synthesized for recreational use and contributing to the fentanyl and opioid crisis. A method has been developed and validated for the analysis of furanyl fentanyl and furanyl norfentanyl in urine specimens from pain management programs. Approximately 10% of samples from a set of 500 presumptive heroin-positive urine specimens were found to contain furanyl fentanyl, with an average concentration of 33.8 ng/mL, and ranging from 0.26 to 390 ng/mL. Little to no furanyl norfentanyl was observed; therefore, the furanyl fentanyl specimens were further analyzed by untargeted high-resolution mass spectrometry to identify other metabolites. Multiple metabolites, including a dihydrodiol metabolite, 4-anilino-N-phenethyl-piperidine (4-ANPP) and a sulfate metabolite were identified. The aim of the presented study was to identify the major metabolite(s) of furanyl fentanyl and estimate their concentrations for the purpose of toxicological monitoring. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: firstname.lastname@example.org.
Djafarzadeh, Siamak; Vuda, Madhusudanarao; Jeger, Victor; Takala, Jukka; Jakob, Stephan M
Remifentanil interferes with hepatic mitochondrial function. The aim of the present study was to evaluate whether hepatic mitochondrial function is affected by fentanyl, a more widely used opioid than remifentanil. Human hepatoma HepG2 cells were exposed to fentanyl or pretreated with naloxone (an opioid receptor antagonist) or 5-hydroxydecanoate (5-HD, an inhibitor of mitochondrial adenosine triphosphate (ATP)-sensitive potassium [mitoKATP] channels), followed by incubation with fentanyl. Mitochondrial function and metabolism were then analyzed. Fentanyl marginally reduced maximal mitochondrial complex-specific respiration rates using exogenous substrates (decrease in medians: 11%-18%; P = 0.003-0.001) but did not affect basal cellular respiration rates (P = 0.834). The effect on stimulated respiration was prevented by preincubation with naloxone or 5-HD. Fentanyl reduced cellular ATP content in a dose-dependent manner (P < 0.001), an effect that was not significantly prevented by 5-HD and not explained by increased total ATPase concentration. However, in vitro ATPase activity of recombinant human permeability glycoprotein (an ATP-dependent drug efflux transporter) was significantly stimulated by fentanyl (P = 0.004). Our data suggest that fentanyl reduces stimulated mitochondrial respiration of cultured human hepatocytes by a mechanism that is blocked by a mitoKATP channel antagonist. Increased energy requirements for fentanyl efflux transport may offer an explanation for the substantial decrease in cellular ATP concentration.
Pacifici, Gian Maria
Fentanyl is a synthetic opioid that is very important in anesthetic practice because of its relatively short time to peak analgesic effect and the rapid termination of action after small bolus doses. The objective of this survey is to review the clinical pharmacology of fentanyl in preterm infants. The bibliographic search was performed using PubMed and EMBASE databases as search engines. In addition, the books Neofax: A manual of drugs used in neonatal care and Neonatal formulary were consulted. Fentanyl is N-dealkylated by CYP3A4 into the inactive norfentanyl. Fentanyl may be administered as bolus doses or as a continuous infusion. In neonates, there is a remarkable interindividual variability in the kinetic parameters. In neonates, fentanyl half-life ranges from 317 minutes to 1266 minutes and in adults it is 222 minutes. Respiratory depression occurs when fentanyl doses are >5 μg/kg. Chest wall rigidity may occur in neonates and occasionally is associated with laryngospasm. Tolerance to fentanyl may develop after prolonged use of this drug. Significant withdrawal symptoms have been reported in infants treated with continuous infusion for 5 days or longer. Fentanyl is an extremely potent analgesic and is the opioid analgesic most frequently used in the neonatal intensive care unit.
Morissette, Sandra Baker; Palfai, Tibor P; Gulliver, Suzy Bird; Spiegel, David A; Barlow, David H
In a 2 (patch) x 2 (smoking) x 2 (anxiety) mixed design, 52 undergraduate smokers randomly received a nicotine (21 mg) or placebo patch. After a 4-hr nicotine absorption/deprivation period, participants imagined several scenarios varying in cue content: (a) anxiety plus smoking, (b) anxiety, (c) smoking, and (d) neutral. Although smoking urge increased in both the nicotine and placebo conditions after the absorption/deprivation period, those who received the placebo reported significantly greater urge. During the cue reactivity trials, a significant Patch x Smoking x Anxiety interaction effect was observed for urge. However, participants who received nicotine still experienced moderate urges, indicating that nicotine did not attenuate cue-elicited urge. Transdermal nicotine did not diminish anxiety during the absorption/deprivation period or in response to the cues. Copyright 2005 APA, all rights reserved.
Karas-Trzeciak, Magdalena; Grabowski, Tomasz; Woloszczuk-Gebicka, Bogumila; Borucka, Beata
The aim of the study was to evaluate pharmacokinetics of fentanyl administered as continuous epidural infusion with 0.2% ropivacaine for postoperative pain relief in infants and toddlers, and older children undergoing major abdominal and urological procedures. Thirteen infants and toddlers (median age 14 [range 3-36] months, 11 [5-17] kg, Group I) and 11 children (68 [45-131] months, 21 [16-52] kg, Group II) participated in the study. Epidural catheter was placed under general anesthesia in the L1-L2, L2-L3, or L3-L4 epidural space and threaded up to 4 cm into the epidural space. Bolus dose of 0.2% ropivacaine, 0.5 ml·kg(-1) and fentanyl, 2 μg·kg(-1) was given, then followed by continuous infusion of 0.2% ropivacaine, 0.15 ml·kg(-1) ·h(-1) with fentanyl 1.12 μg·kg(-1) ·h(-1) . In the postoperative period, fentanyl dose was reduced to 0.375 μg·kg(-1) ·h(-1) . With this dosing regimen, fentanyl concentration in plasma was within the range of analgesic concentrations, and did not exceed 1.0 ng·ml(-1) . After discontinuation of epidural infusion, pharmacokinetics of fentanyl was complicated by a slight increase in plasma concentration during the elimination phase. Both elimination half-life of fentanyl (t1/2, MRT ) and mean residence time (MRT) were much longer than those observed after single IV bolus dose, and longer in Group I than in Group II (t1/2 MRT 15.9 [3.6-31.5] h vs 8.0 [7.1-13.3] h, P < 0.05, MRTstop-last 22.9 [5.1-45.5] h vs 11.5 [10.2-19.1] h, P < 0.05). Therefore, monitoring of vital signs seems warranted for several hours after the termination of the epidural infusion because risk of respiratory depression may persist, especially in the younger age group. © 2015 John Wiley & Sons Ltd.
... Loss Surgery? A Week of Healthy Breakfasts Shyness Birth Control Patch KidsHealth > For Teens > Birth Control Patch Print A A A What's in this ... Much Does It Cost? What Is It? The birth control patch is a thin, beige, 1¾-inch (4½- ...
... Loss Surgery? A Week of Healthy Breakfasts Shyness Birth Control Patch KidsHealth > For Teens > Birth Control Patch A A A What's in this article? ... Much Does It Cost? What Is It? The birth control patch is a thin, beige, 1¾-inch (4½- ...
Ziesenitz, Victoria C; Vaughns, Janelle D; Koch, Gilbert; Mikus, Gerd; van den Anker, Johannes N
Fentanyl and its derivatives sufentanil, alfentanil, and remifentanil are potent opioids. A comprehensive review of the use of fentanyl and its derivatives in the pediatric population was performed using the National Library of Medicine PubMed. Studies were included if they contained original pharmacokinetic parameters or models using established routes of administration in patients younger than 18 years of age. Of 372 retrieved articles, 44 eligible pharmacokinetic studies contained data of 821 patients younger than 18 years of age, including more than 46 preterm infants, 64 full-term neonates, 115 infants/toddlers, 188 children, and 28 adolescents. Underlying diagnoses included congenital heart and pulmonary disease and abdominal disorders. Routes of drug administration were intravenous, epidural, oral-transmucosal, intranasal, and transdermal. Despite extensive use in daily clinical practice, few studies have been performed. Preterm and term infants have lower clearance and protein binding. Pharmacokinetics was not altered by chronic renal or hepatic disease. Analyses of the pooled individual patients' data revealed that clearance maturation relating to body weight could be best described by the Hill function for sufentanil (R (2) = 0.71, B max 876 mL/min, K 50 16.3 kg) and alfentanil (R (2) = 0.70, B max (fixed) 420 mL/min, K 50 28 kg). The allometric exponent for estimation of clearance of sufentanil was 0.99 and 0.75 for alfentanil clearance. Maturation of remifentanil clearance was described by linear regression to bodyweight (R (2) = 0.69). The allometric exponent for estimation of remifentanil clearance was 0.76. For fentanyl, linear regression showed only a weak correlation between clearance and bodyweight in preterm and term neonates (R (2) = 0.22) owing to a lack of data in older age groups. A large heterogeneity regarding study design, clinical setting, drug administration, laboratory assays, and pharmacokinetic estimation was observed
Ripolin, Anastasia; Quinn, James; Larrañeta, Eneko; Vicente-Perez, Eva Maria; Barry, Johanne; Donnelly, Ryan F
We describe, for the first time, the design, production and evaluation of large microneedle patches. Such systems, based on 16 individual microneedle arrays (needle height 600μm), were prepared from aqueous blends of 15% w/w Gantrez(®) S97 and 7.5% w/w poly(ethyleneglycol) 10,000Da. Ester-based crosslinking was confirmed by FTIR and mechanical strength was good. Insertion depths in a validated skin model were approximately 500μm. Ten human volunteers successfully self-inserted the microneedles of these larger patches in their skin, following appropriate instruction, as confirmed by transepidermal water loss measurements. The mean insertion depth ranged between 300 and 450μm over the area of the large patches. That this was not significantly different to a single unit MN patch self-applied by the same volunteers is encouraging. Microneedle patch sizes much larger than the 1-2cm(2) will be required if this technology is to be successfully translated to clinic for delivery of drug substances. The work described here suggests that use of such larger patches by patients can be successful, potentially opening up the possibility for a significant expansion of the size of the market for transdermal drug delivery.
Choi, Leena; Ferrell, Benjamin A; Vasilevskis, Eduard E; Pandharipande, Pratik P; Heltsley, Rebecca; Ely, E Wesley; Stein, C Michael; Girard, Timothy D
Objective To characterize fentanyl population pharmacokinetics in patients with critical illness and identify patient characteristics associated with altered fentanyl concentrations. Design Prospective cohort study. Setting Medical and surgical ICUs in a large tertiary care hospital in the United States. Patients Patients with acute respiratory failure and/or shock who received fentanyl during the first five days of their ICU stay. Measurements and Main Results We collected clinical and hourly drug administration data and measured fentanyl concentrations in plasma collected once daily for up to five days after enrollment. Among 337 patients, the mean duration of infusion was 58 hours at a median rate of 100 µg/hr. Using a nonlinear mixed-effects model implemented by NONMEM, we found fentanyl pharmacokinetics were best described by a two-compartment model in which weight, severe liver disease, and congestive heart failure most affected fentanyl concentrations. For a patient population with a mean weight of 92 kg and no history of severe liver disease or congestive heart failure, the final model, which performed well in repeated 10-fold cross-validation, estimated total clearance (CL), intercompartmental clearance (Q), and volumes of distribution for the central (V1) and peripheral compartments (V2) to be 35 (95% confidence interval: 32 to 39) L/hr, 55 (42 to 68) L/hr, 203 (140 to 266) L, and 523 (428 to 618) L, respectively. Severity of illness was marginally associated with fentanyl pharmacokinetics but did not improve the model fit after liver and heart disease were included. Conclusions In this study, fentanyl pharmacokinetics during critical illness were strongly influenced by severe liver disease, congestive heart failure, and weight, factors that should be considered when dosing fentanyl in the ICU. Future studies are needed to determine if data-driven fentanyl dosing algorithms can improve outcomes for ICU patients. PMID:26491862
Maimon, Benjamin E.; Zorzos, Anthony N.; Bendell, Rhys; Harding, Alexander; Fahmi, Mina; Srinivasan, Shriya; Calvaresi, Peter; Herr, Hugh M.
Objective: A fundamental limitation in both the scientific utility and clinical translation of peripheral nerve optogenetic technologies is the optical inaccessibility of the target nerve due to the significant scattering and absorption of light in biological tissues. To date, illuminating deep nerve targets has required implantable optical sources, including fiber-optic and LED-based systems, both of which have significant drawbacks. Approach: Here we report an alternative approach involving transdermal illumination. Utilizing an intramuscular injection of ultra-high concentration AAV6-hSyn-ChR2-EYFP in rats. Main results: We demonstrate transdermal stimulation of motor nerves at 4.4 mm and 1.9 mm depth with an incident laser power of 160 mW and 10 mW, respectively. Furthermore, we employ this technique to accurately control ankle position by modulating laser power or position on the skin surface. Significance: These results have the potential to enable future scientific optogenetic studies of pathologies implicated in the peripheral nervous system for awake, freely-moving animals, as well as a basis for future clinical studies.
Lee, Dayong; Chronister, Chris W; Broussard, Wilson A; Utley-Bobak, Suzanne R; Schultz, Daniel L; Vega, Russell S; Goldberger, Bruce A
Fentanyl induces pharmacological effects and abuse liability comparable to other prescription opioids and heroin. A surge in fentanyl-related fatalities has been periodically reported throughout the USA. The University of Florida Forensic Toxicology Laboratory observed a significant increase in fentanyl-related deaths starting in mid-2014. The present report evaluated toxicological findings, demographics of the decedents and circumstances of death in the postmortem cases that were submitted to the laboratory for toxicological analysis from July 2014 to January 2015 and that were tested for fentanyl in biological specimens. The cases originated from 6 of the 24 Florida Medical Examiner Districts, with the majority from District 12 (Desoto, Manatee and Sarasota counties). The specimens were analyzed for fentanyl by gas chromatography-mass spectrometry; the limit of detection (LOD) was 0.62 ng/mL and the limit of quantification (LOQ) was 2.5 ng/mL. During the 7-month period, the laboratory tested 143 postmortem cases for fentanyl and 50% had quantifiable fentanyl in postmortem blood. Fentanyl concentrations ranged from 2.5 to 68 ng/mL (n = 66; median: 9.8 ng/mL); six cases were positive for fentanyl >LOD but
Garnock-Jones, Karly P
Fentanyl buccal soluble film (Onsolis(®), Breakyl(®), Painkyl™) comprises two layers: a mucoadhesive layer containing the active drug, and an inactive layer with the aim of preventing the diffusion of fentanyl into the oral cavity. It is approved in several countries worldwide, including the USA and those of the EU, for the management of breakthrough cancer pain in opioid-tolerant, adult patients with cancer. This article reviews the pharmacological properties of fentanyl buccal soluble film and its clinical efficacy and tolerability in these patients. Fentanyl buccal soluble film provides an additional option for transmucosal delivery of fentanyl, with approximately half of the dose undergoing an initial, rapid absorption via the buccal mucosa (accounting for its high bioavailability). In clinical trials, fentanyl buccal soluble film was associated with significant improvements in pain intensity scores versus placebo and was generally well tolerated. The most common adverse events were typical opioid-associated adverse events, such as nausea and vomiting. Fentanyl buccal soluble film is a useful option for the treatment of breakthrough cancer pain in opioid-tolerant patients.
FAROOQUI, Mariya; ERICSON, Marna E; GUPTA, Kalpna
Background Topically applied opioids promote angiogenesis and healing of ischemic wounds in rats. We examined if topical fentanyl stimulates wound healing in diabetic rats by stimulating growth-promoting signaling, angiogenesis, lymphangiogenesis and nerve regeneration. Methods We used Zucker diabetic fatty rats that develop obesity and diabetes on a high fat diet due to a mutation in the Leptin receptor. Fentanyl blended with hydrocream was applied topically on ischemic wounds twice daily, and wound closure was analyzed regularly. Wound histology was analyzed by hematoxylin and eosin staining. Angiogenesis, lymphangiogenesis, nerve fibers and phospho-PDGFR-β were visualized by CD31-, lymphatic vessel endothelium-1, protein gene product 9.5- and anti-phospho PDGFR-β-immunoreactivity, respectively. Nitric oxide synthase (NOS) and PDGFR-β signaling were analyzed using Western immunoblotting. Results Fentanyl significantly promoted wound closure as compared to PBS. Histology scores were significantly higher in fentanyl-treated wounds, indicative of increased granulation tissue formation, reduced edema and inflammation, and increased matrix deposition. Fentanyl treatment resulted in increased wound angiogenesis, lymphatic vasculature, nerve fibers, nitric oxide, NOS and PDGFR-β signaling as compared to PBS. Phospho PDGFR-β co-localized with CD31 co-staining for vasculature. Conclusions Topically applied fentanyl promotes closure of ischemic wounds in diabetic rats. Increased angiogenesis, lymphangiogenesis, peripheral nerve regeneration, NO and PDGFR-β signaling are associated with fentanyl-induced tissue remodeling and wound healing. PMID:25266258
Tønnesen, P; Nørregaard, J; Simonsen, K; Säwe, U
The use of nicotine chewing gum combined with psychological support improves the success rate in stopping smoking. We studied the safety and efficacy of a transdermal nicotine patch in stopping smoking. We conducted a double-blind randomized study comparing the effect of a 16-hour nicotine patch (15 +/- 3.5 mg of nicotine in 16 hours) with those of a placebo patch. Of the 289 smokers (207 women and 82 men) enrolled in the study, 145 were treated with nicotine patches and 144 with placebo patches for 16 weeks. The rates of sustained abstinence were significantly better with active treatment than with the placebo: 53, 41, 24 and 17% of those in the nicotine-patch group were abstinent after 6, 12, 26, and 52 weeks, respectively, as compared with 17, 10, 5 and 4% of those in the placebo-patch group (p less than 0.0001). Only two subjects with the nicotine patch and one with the placebo patch withdrew from the study because of side effects. The nicotine skin patch proved to be safe and effective, as demonstrated by a higher rate of abstinence than with the placebo.
Taylor, Donald R
Breakthrough cancer pain (BTCP) is defined as a transient exacerbation of pain that arises in patients with otherwise controlled persistent pain. BTCP typically has a rapid onset and relatively short duration, but it causes a significant amount of physical and psychological distress for patients. Several rapid-onset fentanyl formulations have been introduced in the USA to replace traditional oral opioids for the treatment of BTCP: a transmucosal lozenge, a sublingual orally disintegrating tablet, a buccal tablet, a buccal soluble film, a pectin nasal spray and, the newest formulation to enter the market, a sublingual spray. This article reviews the six rapid-onset formulations of fentanyl approved in the USA for the management of BTCP with emphasis on describing the published literature on fentanyl sublingual spray. The different fentanyl formulations vary in pharmacokinetic properties and ease of use, but all have a rapid onset and a relatively short duration of analgesia. Fentanyl sublingual spray has demonstrated absorption within 5 minutes of administration, with fentanyl plasma concentrations increasing over the first 30 minutes and remaining elevated for 60-90 minutes in pharmacokinetic studies in healthy subjects. Fentanyl sublingual spray shows linear dose proportionality, and changes in the temperature or acidity of the oral cavity do not alter its pharmacokinetic properties. In patients with BTCP, statistically significant pain relief is measurable at 5 minutes after administration of fentanyl sublingual spray, when compared with placebo, with significant pain relief lasting at least 60 minutes after administration. Adverse events are typical of opioid treatment and are considered mild to moderate in intensity. In summary, fentanyl sublingual spray provides rapid onset of analgesia and is a tolerable and effective treatment for BTCP.
McPherson, Christopher; Haslam, Matthew; Pineda, Roberta; Rogers, Cynthia; Neil, Jeffrey J.; Inder, Terrie E.
Background Fentanyl is commonly utilized in preterm infants. Relatively little is known regarding the neurodevelopmental outcomes of preterm infants exposed to fentanyl. Objective To investigate the association between cumulative fentanyl dose and brain injury and diameters in a cohort of preterm infants Methods Data on demographics, perinatal course, and neonatal course, including total fentanyl exposure prior to term equivalent age, were retrospectively evaluated for 103 infants born at ≤ 30 weeks gestational age who underwent magnetic resonance imaging at term equivalent age (mean gestational age 26.9 ± 1.8 weeks). Magnetic resonance images were evaluated for brain injury and regional brain diameters. Developmental testing was conducted at term equivalent and 2 years of age. Results Seventy-eight infants (76%) received fentanyl (median cumulative dose 3 μg/kg, interquartile range 1 – 441 μg/kg). Cumulative fentanyl dose in the first week of life correlated with the incidence of cerebellar hemorrhage after correction for covariates (OR 2.1, 95% confidence interval 1.1 – 4.1). Cumulative fentanyl dose before term equivalent age correlated with reductions in transverse cerebellar diameter after correction for covariates including the presence of cerebellar hemorrhage (r = 0.461, p = 0.002). No correlation was detected between cumulative fentanyl dose and development at 2 years of age. Conclusions Higher cumulative fentanyl dose in preterm infants correlated with a higher incidence of cerebellar injury and lower cerebellar diameter at term equivalent age. Our findings must be taken with caution, but emphasize the need for future prospective trials examining the risks and benefits of commonly utilized analgesic agents in preterm infants. PMID:26369570
Park, Donghee; Park, Hyunjin; Seo, Jongbum; Lee, Seunghun
Transdermal drug delivery (TDD) has several significant advantages compared to oral drug delivery, including elimination of pain and sustained drug release. However, the use of TDD is limited by low skin permeability due to the stratum corneum (SC), the outermost layer of the skin. Sonophoresis is a technique that temporarily increases skin permeability such that various medications can be delivered noninvasively. For the past several decades, various studies of sonophoresis in TDD have been performed focusing on parameter optimization, delivery mechanism, transport pathway, or delivery of several drug categories including hydrophilic and high molecular weight compounds. Based on these various studies, several possible mechanisms of sonophoresis have been suggested. For example, cavitation is believed to be the predominant mechanism responsible for drug delivery in sonophoresis. This review presents details of various studies on sonophoresis including the latest trends, delivery of various therapeutic drugs, sonophoresis pathways and mechanisms, and outlook of future studies.
Kwiatkowski, Krzysztof C. (Inventor); Hayes, Ryan T. (Inventor); Magnuson, James W. (Inventor); Giletto, Anthony (Inventor)
A device for the transdermal delivery of a therapeutic agent to a biological subject that includes a first electrode comprising a first array of electrically conductive microprojections for providing electrical communication through a skin portion of the subject to a second electrode comprising a second array of electrically conductive microprojections. Additionally, a reservoir for holding the therapeutic agent surrounding the first electrode and a pulse generator for providing an exponential decay pulse between the first and second electrodes may be provided. A method includes the steps of piercing a stratum corneum layer of skin with two arrays of conductive microprojections, encapsulating the therapeutic agent into biocompatible charged carriers, surrounding the conductive microprojections with the therapeutic agent, generating an exponential decay pulse between the two arrays of conductive microprojections to create a non-uniform electrical field and electrokinetically driving the therapeutic agent through the stratum corneum layer of skin.
Transdermal drug delivery offers a non-invasive route of drug administration, although its applications are limited by low skin permeability. Various enhancers including iontophoresis, chemicals, ultrasound, and electroporation have been shown to enhance transdermal drug transport. Although all these methods have been individually shown to enhance transdermal drug transport, their combinations have often been found to enhance transdermal transport more effectively than each of them alone. This paper summarizes literature studies on these combinations with respect to their efficacy and mechanisms.
Darwish, Mona; Kirby, Mary; Robertson, Philmore; Hellriegel, Edward; Jiang, John G
The fentanyl buccal tablet (FBT) is designed to enhance the rate and extent of fentanyl absorption through the buccal mucosa. To evaluate the bioequivalence of microg-equivalent doses of FBT administered as single and multiple tablets and assess differences in the arterial and venous pharmacokinetics of FBT in healthy volunteers. Twenty-seven healthy adults, aged 19-45 years, participated in the randomised, open-label, three-period, crossover study. In the first two periods, FBT was administered as four 100 microg tablets simultaneously or one FBT 400 microg to assess bioequivalence. Venous blood samples were obtained over a 72-hour period to measure plasma fentanyl concentrations. In the third period, arterial and venous blood samples were obtained simultaneously from before administration of one FBT 400 microg through 4 hours after administration to evaluate the impact of arterial versus venous sampling on the pharmacokinetic profile. As subjects were not opioid tolerant, naltrexone was administered to block opioid receptor-mediated effects of fentanyl. Adverse events were recorded throughout. Maximum plasma concentration (C(max)) and area under the plasma concentration-time curve from time zero to infinity (AUC(infinity)) on average were approximately 12% and 13% higher, respectively, for FBT administered as four 100 microg tablets simultaneously compared with one FBT 400 microg. Maximum plasma concentrations in the arterial circulation were approximately 60% higher and occurred 15 minutes earlier than those measured from the venous circulation. No serious adverse events were reported during the study. Despite small differences in C(max) and AUC(infinity) (on average 12% and 13%, respectively), FBT administered as four 100 microg tablets simultaneously compared with one 400 microg tablet did not meet the criteria for bioequivalence. An increased surface area exposure with four tablets compared with one tablet may account for the slightly higher maximum
Sachdeva, Vishal; Zhou, Yingcong; Banga, Ajay K
The objective of this study was to investigate the use of iontophoresis and/or microneedles to enhance transdermal delivery of leuprolide acetate in vivo in hairless rats. Microporation was achieved using 500 μm long maltose microneedles and pore formation was confirmed using dye binding studies, histology studies, calcein imaging studies, pore permeability index calculation and trans-epidermal water loss measurement. Iontophoresis was performed using liquid reservoir patch with inbuilt silver wire electrode and a current density of 0.1 mA/cm2 was applied for 4 hours. Delivery studies were performed using microneedles and iontophoresis alone and in combination. Passive studies involving delivery through intact skin and injections of drug solution administered subcutaneously served as controls. Blood samples were collected at predetermined time points and plasma samples were analyzed for drug using ELISA. Significantly higher drug levels were detected at the end of 6 hours treatment by microneedles alone treatment (0.98 ± 0.08 ng/ml) as compared to passive (0.36 ± 0.22 ng/ml) delivery (p < 0.05). Further, three times more drug was found to be present systemically with iontophoresis alone (3.47 ± 0.03 ng/ml) or by combination (3.54 ± 0.08 ng/ml) treatments as compared to microneedles alone treatment (p < 0.05) at the end of treatment duration. When compared to iontophoresis alone treatment, combination treatment resulted in faster drug delivery due to propulsion of the drug through the preformed micropores. In conclusion, the use of microneedles and/or iontophoresis seems promising for the transdermal delivery of peptide like leuprolide acetate.
Pergolizzi, Joseph V; Scholten, Willem; Smith, Kevin J; Leighton-Scott, James; Willis, Jenna C; Henningfield, Jack E
Pain is a global epidemic, exacerbated by barriers to access of opioid analgesics. Regulations about opioids attempt to protect public health from the risks of harmful use of opioids, diversion, and dependence. Transdermal buprenorphine is an effective opioid analgesic agent with unique properties that may make it particularly well suited for more widespread use. It is a versatile analgesic product with demonstrated safety and effectiveness in cancer and noncancer pain populations. Its pharmacological properties make it a first-line opioid analgesic for geriatric patients and patients with renal dysfunction; no dosing adjustments need to be made. The 7-day transdermal delivery system is convenient for patients and promotes compliance. A low dose of buprenorphine can provide effective and well-tolerated pain relief. Although buprenorphine has been associated with certain opioid-related adverse effects, such as dizziness and nausea, it is associated with a lower rate of constipation than many other opioid analgesics. The potential for nonmedical use of buprenorphine is relatively low compared with other opioid agents. Buprenorphine has a relatively low likeability for nonmedical use and the transdermal matrix patch renders the substance particularly difficult to extract for illicit purposes. Copyright © 2015. Published by Elsevier B.V.
Harris, Debra S; Everhart, Thomas; Jacob, Peyton; Lin, Emil; Mendelson, John E; Jones, Reese T
Background The selective MAO-B inhibitor selegiline has been evaluated in clinical trials as a potential medication for the treatment of cocaine dependence. This study evaluated the safety of and pharmacologic interactions between 7 days of transdermal selegiline dosed with patches (Selegiline Transdermal System, STS) that deliver 6 mg/24 hours and 2.5 mg/kg of cocaine administered over 4 hours. Methods Twelve nondependent cocaine-experienced subjects received deuterium-labeled cocaine-d5 intravenously (IV) 0.5 mg/kg over 10 minutes followed by 2 mg/kg over 4 hours before and after one week of transdermal selegiline 6 mg/24 hours. Plasma and urine were collected for analysis of selegiline, cocaine, catecholamine and metabolite concentrations. Pharmacodynamic measures were obtained. Results Selegiline did not change cocaine pharmacokinetic parameters. Selegiline administration increased phenylethylamine (PEA) urinary excretion and decreased urinary MHPG-sulfate concentration after cocaine when compared to cocaine alone. No serious adverse effects occurred with the combination of selegiline and cocaine, and cocaine-induced physiological effects were unchanged after selegiline. Only 1 peak subjective cocaine effects rating changed, and only a few subjective ratings decreased across time after selegiline. Conclusion No pharmacological interaction occurred between selegiline and a substantial dose of intravenous cocaine, suggesting the combination will be safe in pharmacotherapy trials. Selegiline produced few changes in subjective response to the cocaine challenge perhaps because of some psychoactive neurotransmitters changing in opposite directions. PMID:19646280
Katsumi, Hidemasa; Quan, Ying-Shu; Kamiyama, Fumio; Kusamori, Kosuke; Sakane, Toshiyasu; Yamamoto, Akira
Transdermal delivery of peptide and protein drugs may be limited by the stratum corneum, which is a protective barrier against the entry of microorganisms and water. Many approaches have been utilized to promote peptide and protein drugs delivery across the stratum corneum, including chemical enhancer modification and physical disruption of barrier function. However, it has been difficult to achieve therapeutic levels of peptide and protein drugs via this route without any skin irritation. Recently, attention has been paid to the possibility of using microneedle arrays in delivering peptide and protein drugs into the skin. As a novel and minimally invasive approach, microneedle arrays are capable of creating superficial pathways across the skin for peptide and protein drugs to achieve enhanced transdermal drug delivery. This method combines the efficacy of conventional injection needles with the convenience of transdermal patches, while minimizing the disadvantages of these administration methods. Therefore, microneedle arrays are a very useful alternative method for delivering peptide and protein drugs from the skin into the systemic circulation without any serious damage to skin. In this review, recent challenges in the developments of microneedle arrays for the delivery of peptide and protein drugs are summarized. Then, future developments of microneedle arrays for the delivery of peptide and protein drugs are also discussed in order to improve their therapeutic efficacy and safety.
Strasinger, Caroline; Paudel, Kalpana S; Wu, Ji; Hammell, Dana; Pinninti, Raghotham R; Hinds, Bruce J; Stinchcomb, Audra
Oral dosage forms and traditional transdermal patches are inadequate for complex clonidine therapy dosing schemes, because of the variable dose/flux requirement for the treatment of opioid withdrawal symptoms. The purpose of this study was to evaluate the in vitro transdermal flux changes of clonidine in response to alterations in carbon nanotube (CNT) delivery rates by applying various electrical bias. Additional skin diffusion studies were carried out to demonstrate the therapeutic feasibility of the system. This study demonstrated that application of a small electrical bias (-600 mV) to the CNT membrane on the skin resulted in a 4.7-fold increase in clonidine flux as compared with no bias (0 mV) application. The high and low clonidine flux values were very close to the desired variable flux of clonidine for the treatment of opioid withdrawal symptoms. Therapeutic feasibility studies demonstrated that CNT membrane served as the rate-limiting step to clonidine diffusion and lag and transition times were suitable for the clonidine therapy. Skin elimination studies revealed that clonidine depletion from the skin would not negatively affect clonidine therapy. Overall, this study showed that clonidine administration difficulties associated with the treatment of opiate withdrawal symptoms can be reduced with the programmable CNT membrane transdermal system.
Ruby, P K; Pathak, Shriram M; Aggarwal, Deepika
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.
Bond, A C; Thompson, M A
Anaesthesia with a combination of diazepam and pentazocine is compared with the well established technique of neuroleptanaesthesia using droperidol and fentanyl. The former compared favourably, producing similar cardiovascular stability, rapid recovery of conciousness and postoperative analgesia.
Davar, Robab; Janati, Sima; Mohseni, Fereshteh; Khabazkhoob, Mehdi; Asgari, Soheila
Background: The purpose of this study was to determine the optimal endometrial preparation protocol by comparing the clinical outcome of two methods of endometrial preparation in frozen-thawed embryo transfer (FET) cycles, including that is, oral estradiol and 17ß-estradiol transdermal patch. Methods: In this randomized controlled trial, women underwent either conventional IVF or intracytoplasmic sperm injection (ICSI) who had at least two top-quality embryos appropriate for cryopreservation and frozen embryos from previous cycles. In the study group (n=45), 17-B estradiol transdermal patches 100 μg were applied from the second day of the cycle and continued every other day. Then, each patch was removed after four days. In the control group (n=45), oral estradiol valerate 6 mg was started at the same time and continued daily. Results: There was a significant difference in estradiol level on the day of progesterone administration and the day of embryo transfer between the two groups (p= 0.001 in both), but no significant difference was observed between them in biochemical and clinical pregnancy rates (32.6% vs. 33.3%, p=1.000 and 30.2% vs. 33.3%, p=0.810, respectively). Conclusion: It is suggested that estradiol transdermal patches be used instead of oral estradiol in FET cycles. Due to the reduced costs, drug dose, and emotional stress as well as the simplicity of the protocol for patients. PMID:27141464
Griswold, Matthew K; Chai, Peter R; Krotulski, Alex J; Friscia, Melissa; Chapman, Brittany; Boyer, Edward W; Logan, Barry K; Babu, Kavita M
To compare user self-identification of nonpharmaceutical fentanyl exposure with confirmatory urine drug testing in emergency department (ED) patients presenting after heroin overdose. This was a cross-sectional study of adult ED patients who presented after a heroin overdose requiring naloxone administration. Participants provided verbal consent after which they were asked a series of questions regarding their knowledge, attitudes and beliefs toward heroin and nonpharmaceutical fentanyl. Participants also provided urine samples, which were analyzed using liquid chromatography coupled to quadrupole time-of-flight mass spectrometry to identify the presence of fentanyl, heroin metabolites, other clandestine opioids, common pharmaceuticals and drugs of abuse. Thirty participants were enrolled in the study period. Ten participants (33%) had never required naloxone for an overdose in the past, 20 participants (67%) reported recent abstinence, and 12 participants (40%) reported concomitant cocaine use. Naloxone was detected in all urine drug screens. Heroin or its metabolites were detected in almost all samples (93.3%), as were fentanyl (96.7%) and its metabolite, norfentanyl (93.3%). Acetylfentanyl was identified in nine samples (30%) while U-47700 was present in two samples (6.7%). Sixteen participants self-identified fentanyl in their heroin (sensitivity 55%); participants were inconsistent in their qualitative ability to identify fentanyl in heroin. Heroin users presenting to the ED after heroin overdose requiring naloxone are unable to accurately identify the presence of nonpharmaceutical fentanyl in heroin. Additionally, cutting edge drug testing methodologies identified fentanyl exposures in 96.7% of our patients, as well as unexpected clandestine opioids (like acetylfentanyl and U-47700).
Somerville, Nicholas J; O'Donnell, Julie; Gladden, R Matthew; Zibbell, Jon E; Green, Traci C; Younkin, Morgan; Ruiz, Sarah; Babakhanlou-Chase, Hermik; Chan, Miranda; Callis, Barry P; Kuramoto-Crawford, Janet; Nields, Henry M; Walley, Alexander Y
Opioid overdose deaths in Massachusetts increased 150% from 2012 to 2015 (1). The proportion of opioid overdose deaths in the state involving fentanyl, a synthetic, short-acting opioid with 50-100 times the potency of morphine, increased from 32% during 2013-2014 to 74% in the first half of 2016 (1-3). In April 2015, the Drug Enforcement Agency (DEA) and CDC reported an increase in law enforcement fentanyl seizures in Massachusetts, much of which was believed to be illicitly manufactured fentanyl (IMF) (4). To guide overdose prevention and response activities, in April 2016, the Massachusetts Department of Public Health and the Office of the Chief Medical Examiner collaborated with CDC to investigate the characteristics of fentanyl overdose in three Massachusetts counties with high opioid overdose death rates. In these counties, medical examiner charts of opioid overdose decedents who died during October 1, 2014-March 31, 2015 were reviewed, and during April 2016, interviews were conducted with persons who used illicit opioids and witnessed or experienced an opioid overdose. Approximately two thirds of opioid overdose decedents tested positive for fentanyl on postmortem toxicology. Evidence for rapid progression of fentanyl overdose was common among both fatal and nonfatal overdoses. A majority of interview respondents reported successfully using multiple doses of naloxone, the antidote to opioid overdose, to reverse suspected fentanyl overdoses. Expanding and enhancing existing opioid overdose education and prevention programs to include fentanyl-specific messaging and practices could help public health authorities mitigate adverse effects associated with overdoses, especially in communities affected by IMF.
Friesgaard, K D; Nikolajsen, L; Giebner, M; Rasmussen, C-H; Riddervold, I S; Kirkegaard, H; Christensen, E F
Management of pain in the pre-hospital setting is often inadequate. In 2011, ambulance personnel were authorized to administer intravenous fentanyl in the Central Denmark Region. The aim of this study was to evaluate the efficacy and safety of intravenous fentanyl administered by ambulance personnel. Pre-hospital medical charts from 2348 adults treated with intravenous fentanyl by ambulance personnel during a 6-month period were reviewed. The primary outcome was the change in pain intensity on a numeric rating scale (NRS) from before fentanyl treatment to hospital arrival. Secondary outcomes included the number of patients with reduction in pain intensity during transport (NRS ≥ 2), the number of patients with NRS > 3 at hospital arrival, and potential fentanyl-related side effects. Fentanyl reduced pain from before treatment (8, IQR 7-9) to hospital arrival (4, IQR 3-6) (NRS reduction: 3, IQR 2-5; P = 0.001), 79.3% of all patients had a reduction in > 2 on the NRS during transport, and 58.4% of patients experienced pain at hospital arrival (NRS > 3). Twenty-one patients (0.9%) had oxygen saturation < 90%. A decrease in Glasgow Coma Scale was seen in 31 patients (1.3%) and hypotension observed in 71 patients (3.0%). Intravenous fentanyl caused clinically meaningful pain reduction in most patients and was safe in the hands of ambulance personnel. Many patients had moderate to severe pain at hospital arrival. As the protocol allowed higher doses of fentanyl, feedback on effect and safety should be part of continuous education of ambulance personnel. © 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.
Katoh, T; Uchiyama, T; Ikeda, K
This study was designed to determine if fentanyl altered MAC-awake (the end-tidal concentration of sevoflurane associated with eye opening to verbal command) in 30 healthy, ASA I patients. During anaesthesia, no other anaesthetics or drugs were given with the exception of sevoflurane. After surgery, end-tidal anaesthetic concentration was maintained constant for at least 15 min. If patients failed to respond to command, the end-tidal concentration was decreased and again maintained constant for 15 min. The anaesthetic concentration midway between the value permitting the response and that just preventing the response was recorded as MAC-awake. Fentanyl was administered at predicted plasma concentrations of 1 and 2 ng mg-1 using a computer-controlled continuous infusion and plasma concentrations of fentanyl were measured at the time of MAC-awake measurements. MAC-awake of the control group in which fentanyl was not administered was mean 0.67 (SD 0.12)% or 0.36 (0.03) MAC, being significantly higher than that of the fentanyl 2-ng ml-1 group (0.57 (0.09)% or 0.30 (0.04) MAC). In the fentanyl 1-ng ml-1 group, MAC-awake (0.65 (0.10)% or 0.34 (0.05) MAC) did not differ from that in the control group. Logistic regression analysis showed that increasing plasma concentration of fentanyl and increasing age significantly reduced the MAC-awake of sevoflurane. Because the reduction was very small relative to the overall scatter of the MAC-awake, a low plasma concentration of fentanyl did not significantly reduce the MAC-awake of sevoflurane.
Blesa, Rafael; Ballard, Clive; Orgogozo, Jean-Marc; Lane, Roger; Thomas, Simu K
Alzheimer disease (AD) has a significant impact on caregivers. Administering and managing medications is one of their many daily tasks. More effective modes of drug administration may benefit patient and caregiver, and may improve compliance. A prospective outcome of the IDEAL (Investigation of TransDermal Exelon in ALzheimer's disease) trial was to evaluate caregiver preference for rivastigmine patches compared with capsules. The 24-week, randomized, double-blind, double-dummy, placebo- and active-controlled IDEAL trial investigated once-daily rivastigmine patches vs twice-daily capsules in moderate AD patients. Caregivers rated patch adhesion throughout. The AD Caregiver Preference Questionnaire (ADCPQ) assessed patch vs capsule from caregivers' perspective, based on expectations, preferences, and satisfaction with treatment. A total of 1,059 caregivers completed the ADCPQ while their respective patients were on study drug. More than 70% of caregivers preferred the patch to capsules overall. The patch was preferred to capsules with respect to ease of use (p < 0.0001) and ease of following the schedule (p < 0.0001). Caregivers indicated greater satisfaction overall (p < 0.0001) and less interference with daily life (p < 0.01) with the patch vs capsules. The preference substudy of the IDEAL trial demonstrated that caregivers of AD patients preferred patches to capsules for drug delivery. Preference for the patch may indicate reduced caregiver stress, substantiated by greater satisfaction and less interference with daily life. These benefits may lead to improved compliance.
Hofmann, Birte; Reinecke, Isabel; Schuett, Barbara; Merz, Martin; Zurth, Christian
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
Marwah, Harneet; Garg, Tarun; Goyal, Amit K; Rath, Goutam
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.
Gröber, Uwe; Werner, Tanja; Vormann, Jürgen; Kisters, Klaus
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.
Ringer, S K; Spielmann, N; Weiss, M; Mauch, J Y
Intravenous fentanyl (10 mcg/kg) or saline (control) was randomly administered to 10 healthy sevoflurane-mono-anaesthetized piglets. Trembling was assessed by two blinded observers using a visual analogue scale (VAS) and a simple ordinal scale at baseline and 5 min (T5) after drug administration. If no trembling was observed at that time point, the opposite treatment was administered and piglets were re-evaluated after another 5 min (T10). Four out of five piglets showed trembling after fentanyl (T5), while none given saline showed any trembling. With fentanyl the VAS scores were significantly higher at T5 compared either with baseline or with the control treatment. Control animals received fentanyl after the 5 min evaluation and all piglets showed clear trembling afterwards. The median time after fentanyl administration until first muscle tremors was 51 (20-840) s. In summary, nine out of 10 sevoflurane-anaesthetized piglets showed muscle tremors after intravenous fentanyl. Tremors subsided over time and no specific treatment was necessary.
Wang, Sai-Ying; Mei, Yang; Sheng, Hui; Li, Yang; Han, Rui; Quan, Cheng-Xuan; Hu, Zhong-Hua; Ouyang, Wen; Liu, Zhao-Qian
Objective To explore the feasibility and dosage of tramadol combined with fentanyl in awake endotracheal intubation. Methods Using Dixon’s up-and-down sequential design, the study enrolled patients from each of the 20-49, 50-60 and 70-and-above age groups scheduled for elective surgery under general anesthesia. The feasibility and dosage of tramadol combined with fentanyl in awake endotracheal intubation, guided by fiberoptic bronchoscopy, were verified. Results After intravenous injection with fentanyl 2.2 μg/kg and tramadol 2.0 mg/kg in the 20-49 age group, fentanyl 1.6 μg/kg and tramadol 1.9 mg/kg in the 50-69 age group and fentanyl 1 μg/kg and tramadol 1.8 mg/kg in those at the age of 70 or above, the patients achieved conscious sedation without obvious respiratory depression. Meanwhile, under these dosages, the patients could easily tolerate the thyrocricocentesis airway surface anesthesia and fiberoptic bronchoscope guided tracheal intubation. Postoperative follow-up showed that most patients had memory of the intubation process but without significant discomfort. No awake endotracheal intubation-related side effect was noted. Conclusions Fiberoptic bronchoscope guided nasotracheal intubation can be successfully completed with background administration of fentanyl and tramadol. However, the specific dosages need to be tailored in different age of patients. PMID:23825758
Sucato, Gina S; Bhatt, Suraj K; Murray, Pamela J; Ott, Mary A
To examine the factors related to adolescents' decisions to use the transdermal contraceptive patch (patch) so as to develop a model for understanding how adolescents decide to use new contraceptive methods. We conducted in-depth semi-structured interviews with 18 young women aged 15-21 years who had experience using the patch. Data were analyzed using a two-stage method informed by grounded theory. We constructed a two-level model, encompassing individual, social, and environmental factors, to explain adolescents' decisions to use a new method of hormonal contraception. Social and environmental influences on the decision-making process included media, social network experiences and opinions, healthcare providers, and partner relationships. These in turn affected the following individual factors in the decision to use the patch: individual characteristics, method knowledge and beliefs, method support, and past contraceptive experience. The newness of the patch permeated all levels of the decision-making process. This model provides a framework for understanding the use of new contraceptive methods and can inform clinical strategies for contraceptive counseling with adolescents. Copyright © 2011 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.
Seo, Sang Won; Suh, Mee Kyung; Chin, Juhee; Na, Duk L
Mental confusion or delirium can occur after application of scopolamine patch. However, predisposing factors for scopolamine-induced delirium are not known. It is expected that undetected incipient dementia or mild cognitive impairment (MCI) may be prone to develop mental confusion after applying the scopolamine patch. For the past 5 years, we found seven elderly women who had experienced transdermal scopolamine-induced mental confusion. They underwent neuropsychological tests after recovery from mental confusion (mean duration from onset to the test: 66 days). The results showed that all the patients were impaired in at least one of cognitive domains, fulfilling the criteria of MCI. These findings suggest that scopolamine patch-induced mental confusion should be included in the differential diagnoses of mental confusion in elderly, especially in travel situation, and that older people with undetected MCI are prone to develop scopolamine patch-induced mental confusion.
Griessinger, Norbert; Sittl, Reinhard; Likar, Rudolf
The objective of this post-marketing surveillance study was to collect effectiveness and safety data on the labelled use of buprenorphine transdermal patches (Transtec*) under routine clinical conditions. For this open, observational study, patients with moderate to severe cancer or non-cancer pain requiring treatment with an opioid analgesic were recruited at hospitals, outpatient clinics and general practitioners' practices in Germany. Buprenorphine transdermal patches (35 microg/h, 52.5 microg/h or 70 microg/h) were prescribed at physicians' discretion in accordance with the product's Summary of Product Characteristics (SmPC). Patients assessed their pain relief as 'very good', 'good', 'satisfactory', 'poor' or 'no effect'. Investigators were instructed to report all adverse events throughout the observation period. On completion, effectiveness and tolerability were evaluated for the overall study population, cancer and non-cancer patients, and patients < 70 years and > or = 70 years. Other analyses assessed pain relief with respect to previous opioid treatment and increased patch strength, and in patients who remained on their original dose. The total observation time was 9 months, and the average individual documented treatment time was 60.8 days. A total of 13,179 patients were evaluated; 3690 (28%) with cancer pain and 9489 (72%) with non-cancer pain. The most frequent diagnoses in non-cancer patients were musculoskeletal disorders (77%) and neuropathy (23%). In the great majority of cases (78%), treatment was started with the 35 microg/h patch. The initial dose needed to be increased subsequently only in about 18% of subjects. Buprenorphine transdermal patches provided effective, sustained and dose-dependent analgesia in patients with cancer and non-cancer pain, irrespective of the patients' age or pain syndromes. Whereas good or very good pain relief was documented only for 6% of the patients with the initial assessment, this percentage increased to 71% at
Thorngkham, Pornwalai; Paradee, Nophawan; Niamlang, Sumonman; Sirivat, Anuvat
Transdermal drug delivery is an alternative route to transport the drug into the blood system. This method has been continuously developed to overcome limitations and is now suitable for a wide variety of drug molecules. In this work, the influences of electric field and conductive polymer were investigated for developing a unique drug delivery system from double-centrifuged natural rubber (DCNR) matrix. Indomethacin (IN) was loaded into polycarbazole (PCz) as a conductive polymer drug host to promote the efficient transportation of the drug. The IN-loaded PCz was blended with DCNR to form a transdermal patch. The permeation of IN through the PCz/NR film and pig skin was carrried out by a modified Franz diffusion cell. The IN diffused from DCNR film by the diffusion controlled combined with erosion mechanism depending on the pore formation period. The drug permeation increased with decreasing cross-link ratio because of more accessible pathways for the drug permeation. Moreover, an electric field and the inclusion of PCz as the drug carrier dramatically improved the diffusion of the drug from the membrane by through the electrorepulsive force and electro-reduced PCz expansion. Thus, the PCz/DCNR films are shown here as a potential transdermal patch under applied electric field.
Lobo, Shabbir; Sachdeva, Sameer; Goswami, Tarun
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.
Yu, C; Li, S; Deng, F; Yao, Y; Qian, L
Dexmedetomidine is an α2-adrenergic receptor agonist that causes minimal respiratory depression compared with alternative drugs. This study investigated whether combined dexmedetomidine/fentanyl offered better sedation and analgesia than midazolam/fentanyl in dental surgery. Sixty patients scheduled for unilateral impacted tooth extraction were randomly assigned to receive either dexmedetomidine and fentanyl (D/F) or midazolam and fentanyl (M/F). Recorded variables were patient preoperative anxiety scores, vital signs, visual analogue scale (VAS) pain scores, Observer's Assessment of Alertness/Sedation Scale (OAAS) scores after drug administration, surgeon and patient degree of satisfaction, and the duration of analgesia after surgery. The OAAS scores were significantly lower for patients administered D/F compared to those who received M/F. The duration of analgesia after the surgical procedure was significantly longer in patients who received D/F (5.3 h) than in those who received M/F (4.1 h; P=0.017). The number of surgeons satisfied with the level of sedation/analgesia provided by D/F was significantly higher than for M/F (P=0.001). Therefore, dexmedetomidine/fentanyl appears to provide better sedation, stable haemodynamics, surgeon satisfaction, and postoperative analgesia than midazolam/fentanyl during office-based unilateral impacted tooth extraction.
Thromboembolic complications are the most common preventable cause of mortality and morbidity in trauma patients. Thrombosis is also the common cause of ischemic heart disease (acute coronary syndrome), stroke, and venous thromboembolism. Heparin, as a potent anticoagulant, has been used in clinical practice for more than five decades and remains the major medicine for the prevention and treatment of venous thromboembolism. However it binds to the endothelium and has a high affinity for plasma proteins resulting in a short half-life and unpredictable bioavailability. Transdermal drug delivery can address the problems of short half-life and unpredictable bioavailability. Other advantages of transdermal drug delivery include convenience, improved patient compliance, prompt termination of dosing and avoidance of the first-pass effect. This review focuses on different approaches used for transdermal delivery of heparin.
Wong, Tak-Wah; Ko, Shu-Fen; Hui, Sek-Wen
The application of electroporation to enhance transdermal delivery has opened up a new possibility to introduce larger molecules such as peptide hormones and vaccines as well as minigenes and RNAi etc. through the transdermal route. Many devices have been developed to deliver the pulse electric field needed to permeate the skin. These devices include both non-puncturing surface electrodes as well as puncturing electrodes of different geometrical arrangements. The latter type uses electroporation only to increase uptake of molecules injected through the puncturing electrode or syringe. Different electroporation protocols have been developed to maximize transport, uptake and minimizing pain. Synergistic effect of chemical enhancers and physical (sonic, vibrational and thermal) treatments are used to enhance the transport. This article reviews the patents pertaining to the instrumentation as well as application protocols of transdermal delivery, uptake enhancement and interstitial fluid sampling by electroporation.
Andrews, Samantha; Lee, Jeong Woo; Choi, Seong-O
Purpose Transdermal insulin delivery is an attractive needle-free alternative to subcutaneous injection conventionally used to treat diabetes. However, skin’s barrier properties prevent insulin permeation at useful levels. Methods We investigated whether microdermabrasion can selectively remove skin’s surface layers to increase skin permeability as a method to administer insulin to diabetic rats. We further assessed the relative roles of stratum corneum and viable epidermis as barriers to insulin delivery. Results Pretreatment of skin with microdermabrasion to selectively remove stratum corneum did not have a significant effect on insulin delivery or reduction in blood glucose level (BGL). Removal of full epidermis by microdermabrasion significantly reduced BGL, similar to the positive control involving subcutaneous injection of 0.1U insulin. Significant pharmacokinetic differences between microdermabrasion and subcutaneous injection were faster time to peak insulin concentration after injection and larger peak insulin concentration and area-under-the-curve after microdermabrasion. Conclusions Microdermabrasion can increase skin permeability to insulin at levels sufficient to reduce BGL. Viable epidermis is a barrier to insulin delivery such that removal of full epidermis enables significantly more insulin delivery than removal of stratum corneum alone. PMID:21499837
Lim, Chris H L; Turner, Angus; Lim, Blanche X
Published audits have demonstrated that corneal abrasions are a common presenting eye complaint. Eye patches are often recommended for treating corneal abrasions despite the lack of evidence for their use. This systematic review was conducted to determine the effects of the eye patch when used to treat corneal abrasions. The objective of this review was to assess the effects of patching for corneal abrasion on healing and pain relief. We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (2016, Issue 4), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to May 2016), EMBASE (January 1980 to May 2016), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to May 2016), System for Information on Grey Literature in Europe (OpenGrey) (January 1995 to May 2016), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 9 May 2016. We also searched the reference lists of included studies, unpublished 'grey' literature and conference proceedings and contacted pharmaceutical companies for details of unpublished trials. We included randomised and quasi-randomised controlled trials that compared patching the eye with no patching to treat simple corneal abrasions. Two authors independently assessed the risk of bias and extracted data. Investigators were contacted for further information regarding the quality of trials. The primary outcome was healing at 24, 48 and 72 hours while secondary outcomes included measures of pain, quality of life and adverse effects. We graded the certainty of the evidence using GRADE. We included 12 trials which
Poltavski, D V; Petros, T
Previous research investigating cognitive effects of nicotine has produced mixed findings partly due to the use of abstaining smokers and cigarettes as a delivery system. The present study examined effects of nicotine delivered via a transdermal patch on prose memory and sustained attention in male smokers (n=25) and nonsmokers (n=22), who were randomly assigned to either a placebo or a nicotine condition. All groups were matched on their verbal ability and gross personality characteristics (state/trait anxiety levels, extroversion-introversion, and impulsivity level). In the nicotine condition, smokers were treated with a 21-mg transdermal patch, while nonsmokers received a 7-mg nicotine patch. Six hours following patch application, their performance was assessed on a computerized prose memory task and the Rapid Visual Information Processing task (RVIP) in a counterbalanced order and double-blind fashion. The results demonstrated that smokers in the placebo group recalled a significantly greater number of propositions than their counterparts in the nicotine group. Nonsmokers in the nicotine condition also remembered significantly more of the prose material than smokers in the same condition and showed a trend towards better recall of propositions of medium importance in the nicotine condition in comparison to the nonsmokers in the placebo group. No between-group differences were found on the RVIP task. A significant effect of time was found for systolic blood pressure and heart rate. The results cannot be interpreted using the arousal theory of nicotine effects on attention and are explained on the basis of a dose-dependent nicotinic action possibly recruiting cholinergic cortical projections.
Scott, Jessica A; Banga, Ajay K
Active transdermal technology, commonly associated with drug delivery, has been used in recent years by the cosmetic industry for the aesthetic restoration of skin and delivery of cosmetic agents. In this article, we provide an overview of the skin's structure, various skin types, skin's self-repair mechanisms that are stimulated from the usage of cosmetic devices and discuss cosmetic applications. Summaries of the most common active transdermal technologies such as microneedles, iontophoresis, sonophoresis, lasers and microdermabrasion will be provided, in relation to the marketed cosmetic devices available that incorporate these technologies. Lastly, we cover combinations of active technologies that allow for more enhanced cosmetic results, and the current limitations of cosmetic devices.
Moll, Xavier; Fresno, Laura; García, Félix; Prandi, David; Andaluz, Anna
The clinical efficacy of a 70 microg/h transdermal buprenorphine patch and of 20 microg/kg of buprenorphine administered subcutaneously (SC) for the relief of post-operative pain was determined in 24 healthy female dogs undergoing elective ovariohysterectomy (OHE). Dogs were randomly assigned to three groups: (1) a control group that received no analgesics, (2) a BSC group that received buprenorphine SC (20 microg/kg), and (3) a BP group that received buprenorphine by a 70 microg/h transdermal patch. Dogs were scored for signs of pain at 0, 2, 4, 6, 8, 10, 14, 20, 26, 32 and 38 h after extubation using the Numerical Rating Scale (NRS) and a modified University of Melbourne Pain Scale (UMPS). Mean NRS and UMPS scores for dogs in the BSC group (2.56 ± 0.23 and 3.05 ± 0.27, respectively) and the BP group (2.02 ± 0.24 and 2.67 ± 0.23, respectively) were significantly lower (P<0.05) compared with dogs in the control group (5.42 ± 0.38 and 7.89 ± 0.44, respectively), whereas differences between the two buprenorphine treatment groups were not significant. The results indicated that the analgesia produced by the 70 microg/h patch was similar to that induced by SC administration of 20 microg/kg of buprenorphine in dogs undergoing OHE, suggesting that the transdermal buprenorphine patch may be a useful alternative for pain management in dogs. 2009 Elsevier Ltd. All rights reserved.
Schnoll, Robert A; Patterson, Freda; Wileyto, E Paul; Tyndale, Rachel F; Benowitz, Neal; Lerman, Caryn
Transdermal nicotine is widely used for smoking cessation, but only approximately 20% of smokers quit successfully with this medication. Interindividual variability in nicotine metabolism rate may influence treatment response. This study sought to validate, and extend in a larger sample, our previous finding that the ratio of plasma nicotine metabolites 3'-hydroxycotinine (3-HC)/cotinine, a measure of nicotine metabolism rate, predicts response to nicotine patch. A sample of 568 smokers was enrolled in a study that provided counseling and 8-weeks of 21 mg nicotine patch. Pretreatment 3-HC/cotinine ratio was examined as a predictor of 7-day point prevalence abstinence, verified with breath carbon monoxide (CO), 8 weeks after the quit date. Controlling for sex, race, age, and nicotine dependence, smokers in the upper 3 quartiles of 3-HC/cotinine ratio (faster metabolizers) were approximately 50% less likely to be abstinent vs. smokers in the first quartile (slow metabolizers; 28% vs. 42%; OR=.54 [95% CI:.36-.82], p=.003). Among abstainers, plasma nicotine levels (assessed 1 week after treatment began) decreased linearly across the 3-HC/cotinine ratio (beta=-3.38, t=-3.09, p<.05). These data support the value of the 3-HC/cotinine ratio as a biomarker to predict success with transdermal nicotine for smoking cessation.
Elshoff, Jan-Peer; Cawello, Willi; Andreas, Jens-Otto; Mathy, Francois-Xavier; Braun, Marina
This narrative review reports on the pharmacological and pharmacokinetic properties of rotigotine, a non-ergolinic D₃/D₂/D₁ dopamine receptor agonist approved for the treatment of early- and advanced-stage Parkinson's disease (PD) and moderate to severe restless legs syndrome (RLS). Rotigotine is formulated as a transdermal patch providing continuous drug delivery over 24 h, with a plasma concentration profile similar to that of administration via continuous intravenous infusion. Absolute bioavailability after 24 h transdermal delivery is 37 % of the applied rotigotine dose. Following a single administration of rotigotine transdermal system (24-h patch-on period), most of the absorbed drug is eliminated in urine and feces as sulphated and glucuronidated conjugates within 24 h of patch removal. The drug shows a high apparent volume of distribution (>2500 L) and a total body clearance of 300-600 L/h. Rotigotine transdermal system provides dose-proportional pharmacokinetics up to supratherapeutic dose rates of 24 mg/24 h, with steady-state plasma drug concentrations attained within 1-2 days of daily dosing. The pharmacokinetics of rotigotine transdermal patch are similar in healthy subjects, patients with early- or advanced-stage PD, and patients with RLS when comparing dose-normalized area under the plasma concentration-time curve (AUC) and maximum plasma drug concentration (Cmax), as well as half-life and other pharmacokinetic parameters. Also, it is not influenced in a relevant manner by age, sex, ethnicity, advanced renal insufficiency, or moderate hepatic impairment. No clinically relevant drug-drug interactions were observed following co-administration of rotigotine with levodopa/carbidopa, domperidone, or the CYP450 inhibitors cimetidine or omeprazole. Also, pharmacodynamics and pharmacokinetics of an oral hormonal contraceptive were not influenced by rotigotine co-administration. Rotigotine was generally well tolerated, with an adverse event profile
Liaw, J; Lin, Y
The primary objective of this study was to investigate the feasibility of PEO-PPO-PEO copolymer gel as a release vehicle for percutaneous administration of fentanyl in vitro and in vivo. A cellulose membrane and nude mouse skin with series concentrations of PEO-PPO-PEO block copolymers were used to examine the sustained-release pattern and permeation of fentanyl. The in vivo percutaneous absorption was examined using rabbits to evaluate the preliminary pharmacokinetics of fentanyl with 46% PEO-PPO-PEO copolymer formulation patches. The micelle formation ability of this block copolymer and the penetration ability of PEO-PPO-PEO copolymer over time were also studied by pyrene fluorescence probe methods and the dynamic light scattering test. At a concentration of 46% at 37 degrees C, PEO-PPO-PEO copolymers formed a gel and showed a pseudo-zero-order sustained-release profile. With increasing concentration of copolymer in the cellulose membrane transport, the apparent release flux of fentanyl (200 microgram/ml) decreased to 1. 09+/-0.19 microgram cm(-2) h(-1). Assessment of the effect of the copolymer on nude mouse skin also showed a decrease in the apparent permeability coefficient [(P(H(2)O))=2.24+/-0.47x10(-6) cm s(-1) vs. (P(46% block copolymer))=0.93+/-0.23x10(-7) cm s(-1)]. The preliminary pharmacokinetics of the fentanyl patch was shown to be in steady state within 24 h, and this was maintained for at least 72 h with an elimination half-life (t(1/2)) of 10.5+/-3.4 h. A fluorescence experiment showed polymeric micelle formation of PEO-PPO-PEO copolymers at 0.1% (w/w) within 50 nm micelle size and the PEO-PPO-PEO copolymers were able to penetrate nude mouse skin within 24 h. Thus, it appears that fentanyl preparations based on PEO-PPO-PEO copolymer gel might be practical for percutaneous delivery.
Koren, G; Crean, P; Klein, J; Goresky, G; Villamater, J; MacLeod, S M
Immediately following the connection of pediatric patients to cardiopulmonary bypass we have consistently observed a steep decrease in fentanyl plasma concentration (74 +/- 8.7%) (mean +/- SD), much greater than would have been expected from hemodilution alone (50.6% +/- 12.0%) (p less than 0.0001). Priming of the pump with 20 ng/ml of fentanyl before connection to the patients did not prevent this phenomenon. In order to study the possibility that fentanyl is sequestered by the bypass, levels of the primed drug in the bypass were assessed before connecting the pump to the children and a steep fall from 20 ng/ml to zero was shown before initiation of bypass. Pharmacokinetic assessment of fentanyl in a closed pump circuit showed that levels of 120 ng/ml fall to 2 ng/ml within 3 min and remain stable at the lower concentration for at least 30 min. Further studies have identified the membrane oxygenator as the major site of fentanyl sequestration. Concentrations across the membrane fall from 120 ng/ml to 10 ng/ml. The attached siliconized tubing is associated with a minor binding effect sufficient to reduce concentrations from 110 to 84 ng/ml. The pvc tubing, aluminium heat exchanger and plastic reservoir had no binding effect on fentanyl. The possibility that a decrease in fentanyl protein binding caused the fall in serum concentration was checked in 5 patients undergoing open heart surgery. After initiation of the cardiopulmonary bypass, there was a significant decrease in albumin serum concentrations from 32.0 +/- 2.3 mM to 15.0 +/- 1.6 mM (p less than 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)
Minghetti, P; Cilurzo, F; Montanari, L
Adhesion is an essential property of the dermal and transdermal therapeutic systems (TS). It is influenced by the composition and the thickness of the matrix and also by the characteristics of the backing layer. Our aim was to evaluate the usefulness of the "thumb tack test," the "tack rolling ball test," and the "peel adhesion 180 degrees test" in the development studies and quality control of TS. These tests were performed on two series of placebo patches in which the backing layer was made of artificial silk (series 1) and polyurethane film (series 2). The patches of both series were prepared using five different mixtures of a hydrophilic adhesive copolymer and a hydrophobic nonadhesive copolymer as matrices. Plastoid E 35 L, a copolymer of dimethylaminoethyl methacrylate and neutral methacrylic esters, was used as the adhesive polymer. Eudragit NE 40 D, a copolymer of ethylacrylate and methylmethacrylate, was used as the nonadhesive copolymer. In the standard procedure for the peel adhesion 180 degrees test, used in the tape industries, the adherent is made of stainless steel. Because the latter has a high surface energy, it was not suitable for the analysis of the patches with a polyurethane backing layer. Therefore, the critical surface tension of five alternative materials (rubber, polysiloxane, polyethylene, nylon, polyvinyl chloride) was evaluated. Polyethylene was selected for the modified peel adhesion 180 degrees test, and better results were obtained in terms of feasibility of the test and ability to discriminate between the different patches prepared.
Madhaiyan, Kalaipriya; Sridhar, Radhakrishnan; Sundarrajan, Subramanian; Venugopal, Jayarama Reddy; Ramakrishna, Seeram
Biocompatible PCL polymer nanofiber mediated sustained release of hydrophilic drug and applicability as transdermal delivery system is attempted. This new attempt to investigate water soluble vitamin delivery with hydrophobic polymer nanofiber sustained the release of the vitamin and the method is suited for the transdermal patch applications. The drug loaded fibers were characterized with SEM for morphology, porometer for pore size measurements, mechanical strength calculation and FT-IR for drug load characterization. The contact angle measurement showed surface wettability and controlled release of drug was quantified with UV absorption measurements. To further enhance the release of vitamin, the polymer fiber was plasma treated at different time intervals and made hydrophilic gradually. Since the increased surface area and drug encapsulation in nano-reservoirs can able to release drug in small quantities and in a sustained manner we attempted the release of the energy supplement with nanofibrous delivery mode. Copyright © 2013 Elsevier B.V. All rights reserved.
Yun, Jumi; Lee, Dae Hoon; Im, Ji Sun; Kim, Hyung-Il
Transdermal drug delivery system (TDDS) was prepared with temperature-responsive hydrogel. The graphite was oxidized and incorporated into hydrogel matrix to improve the thermal response of hydrogel. The micro heater was fabricated to control the temperature precisely by adopting a joule heating method. The drug in hydrogel was delivered through a hairless mouse skin by controlling temperature. The efficiency of drug delivery was improved obviously by incorporation of graphite oxide due to the excellent thermal conductivity and the increased interfacial affinity between graphite oxide and hydrogel matrix. The fabricated micro heater was effective in controlling the temperature over lower critical solution temperature of hydrogel precisely with a small voltage less than 1 V. The cell viability test on graphite oxide composite hydrogel showed enough safety for using as a transdermal drug delivery patch. The performance of TDDS could be improved noticeably based on temperature-responsive hydrogel, thermally conductive graphite oxide, and efficient micro heater.
Distinct bright patches are visible on Ariel, the brightest of Uranus five largest satellites. NASA Voyager 2 obtained this image Jan. 22, 1986, from a distance of 2.52 million kilometers 1.56 million miles.
The Gemini 6 patch is hexagonal in shape, reflecting the mission number; and the spacecraft trajectory also traces out the number "6". The Gemini 6 spacecraft is shown superimposed on the "twin stars" Castor and Pollux, for "Gemini".
Schmidt, Jack; Lilianstrom, Al; Romero, Andy; Dawson, Troy; Sieh, Connie; /Fermilab
FNAL has over 5000 PCs running either Linux or Windows software. Protecting these systems efficiently against the latest vulnerabilities that arise has prompted FNAL to take a more central approach to patching systems. Due to different levels of existing support infrastructures, the patching solution for linux systems differs from that of windows systems. In either case, systems are checked for vulnerabilities by Computer Security using the Nessus tool.
Peterson, Alexis B; Gladden, R Matthew; Delcher, Chris; Spies, Erica; Garcia-Williams, Amanda; Wang, Yanning; Halpin, John; Zibbell, Jon; McCarty, Carolyn Lullo; DeFiore-Hyrmer, Jolene; DiOrio, Mary; Goldberger, Bruce A
In March and October 2015, the Drug Enforcement Administration (DEA) and CDC issued nationwide alerts identifying fentanyl, particularly illicitly manufactured fentanyl (IMF), as a threat to public health and safety (1,2). IMF is pharmacologically similar to pharmaceutical fentanyl (PF), but is unlawfully produced in clandestine laboratories, obtained via illicit drug markets, and includes fentanyl analogs. Fentanyl is a synthetic opioid 50-100 times more potent than morphine and approved for the management of surgical/postoperative pain, severe chronic pain, and breakthrough cancer pain.* DEA's National Forensic Laboratory Information System (NFLIS) collects drug identification results from drug cases analyzed by federal, state, and local forensic laboratories throughout the United States.(†) In 2014, 80% of fentanyl submissions (i.e., drug products obtained by law enforcement that tested positive for fentanyl) in NFLIS were identified from 10 states, including Florida and Ohio (2), and seven of these 10 states reported sharp increases in fentanyl-related overdose deaths (fentanyl deaths) (3). This report presents findings of increased fentanyl deaths during 2013-2015 from investigations conducted by the University of Florida and the Ohio Department of Public Health, in collaboration with CDC. Analyses examined the association between trends in fentanyl-related law enforcement submissions and fentanyl deaths and describes groups at risk for fentanyl death using medical examiner and coroner reports. The marked increases in fentanyl death in Florida and Ohio during 2013-2015 were closely associated with parallel increases in fentanyl submissions, with the largest impact on persons who use heroin, consistent with reports that IMF is commonly mixed with or sold as heroin (1,4). In Ohio, circumstances associated with fentanyl deaths included a current diagnosed mental health disorder(§) and recent release from an institution such as a jail, rehabilitation facility
Hans, Guy; Robert, Dominique
This paper reviews the current clinical data for the role of transdermal buprenorphine (BUP TDS) in the treatment of diverse acute and chronic pain syndromes. Literature searches were carried out using PubMed (1988 to June 2009). The published findings seem to support hypotheses regarding the rather unique analgesic mechanisms of buprenorphine as compared with pure μ-opioids like morphine and fentanyl. However, the exact mechanism of this analgesic efficacy still remains largely unknown despite recent advances in preclinical pharmacological studies. Such assessments have demonstrated the sustained antihyperalgesic effect of buprenorphine in diverse animal pain models. These findings are supported in a growing number of clinical studies of oral, intrathecal, intravenous, and Bup TDS. This review paper focuses almost entirely on the clinical experience concerning the transdermal administration of buprenorphine, although preclinical aspects are also addressed in order to provide a complete picture of the unique pharmacological properties of this analgesic drug. Mounting evidence indicates the appropriateness of Bup TDS in the treatment of diverse acute and chronic pain syndromes which have been less or not responsive to other opioids. Additionally, BUP TDS seems to hold great promise for other difficult-to-treat (pain) conditions, such as patients in the intensive care setting. However, its use is somewhat tempered by the occurrence of local skin reactions which have been shown to be often therapy resistant. Further studies are certainly warranted to identify even more precisely the clinical syndromes that are most sensitive to buprenorphine treatment, and to compare buprenorphine to other opioids in head-to-head trials of acute and chronic pain conditions. PMID:21197300
Sako, Saori; Tokunaga, Shoji; Tsukamoto, Masanori; Yoshino, Jun; Fujimura, Naoyuki; Yokoyama, Takeshi
Fentanyl is a strong µ-opioid analgesic which attenuates the stimulation of surgical invasion and tracheal intubation. However, intravenous fentanyl often induces coughing [fentanyl-induced coughing (FIC)] during induction of anesthesia. We found that the swallowing action, when requested at induction of anesthesia, attenuated FIC. In the current study, we investigated the relationship between the occurrence of FIC and the swallowing action. The study included American Society of Anesthesiologists physical status I or II patients, aged 20-64 years, who were undergoing elective surgery. They were divided into two groups-one group was urged to perform the swallowing action immediately before intravenous fentanyl (S group), and the other group performed no swallowing action (non-S group). The patients first received intravenous fentanyl and were observed for 90 s. Each patient's background, dose of fentanyl and occurrence of coughing were investigated from their records and a motion picture recording. The incidence of FIC was evaluated by chi-squared test, and severity was tested by Wilcoxon rank-sum test. P < 0.05 was considered statistically significant. The incidence of FIC in the S group and non-S group was 14.0 and 40.4%, respectively. The risk of FIC was reduced in the S group by 75%; risk ratio (95% confidence interval) was 0.35 (0.20, 0.60). The number of coughs in the S group were less than in the non-S group (P < 0.001). The swallowing action immediately before intravenous fentanyl may be a simple and clinically feasible method for preventing FIC effectively. Clinical trial number: UMIN000012086 ( https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=Rn000014126&language=J ).
Levy, Julia G.; Chowdhary, R. K.; Ratkay, Leslie G.; Waterfield, Douglas; Obochi, Modestus; Leong, Simon; Hunt, David W. C.; Chan, Agnes H.
The photosensitizer benzoporphyrin derivative monoacid ring A (VerteporfinR or BPD) has maximum absorption characteristics (690 nm) and biodistribution characteristics which permit activation of the drug in capillaries of the skin without causing skin photosensitivity (transdermal PDT). This permits targeting of cells in the circulation for selective ablation. Since BPD has been shown to accumulate preferentially in activated lymphocytes and monocytes, studies have been undertaken to determine the effect of transdermal PDT on murine models for rheumatoid arthritis (the MRL/lpr adjuvant enhanced model) and multiple sclerosis (the experimental allergic encephalomyelitis (EAE) model in PL mice). Localized transdermal PDT with BPD was found to be completely successful in preventing the development of adjuvant enhanced arthritis in the MRL/lpr mouse as well as improving the underlying arthritic condition of these animals. In the EAE model, in which an adoptive transfer system was used, it was found that transdermal PDT of recipients was effective in preventing EAE if treatments were implemented up to 24 hours after cell transfer but was not effective if given later, indicating the requirement for circulating T cells for effective treatment.
Gil, Yotam; Rotter, Nadav; Arnon, Shlomi
There is an increasing demand for transdermal high-data-rate communication for use with in-body devices, such as pacemakers, smart prostheses, neural signals processors at the brain interface, and cameras acting as artificial eyes as well as for collecting signals generated within the human body. Prominent requirements of these communication systems include (1) wireless modality, (2) noise immunity and (3) ultra-low-power consumption for the in-body device. Today, the common wireless methods for transdermal communication are based on communication at radio frequencies, electrical induction, or acoustic waves. In this paper, we will explore another alternative to these methods--optical wireless communication (OWC)--for which modulated light carries the information. The main advantages of OWC in transdermal communication, by comparison to the other methods, are the high data rates and immunity to external interference availed, which combine to make it a promising technology for next-generation systems. In this paper, we present a mathematical model and experimental results of measurements from direct link and retroreflection link configurations with Gallus gallus domesticus derma as the transdermal channel. The main conclusion from this work is that an OWC link is an attractive communication solution in medical applications. For a modulating retroreflective link to become a competitive solution in comparison with a direct link, low-energy-consumption modulating retroreflectors should be developed.
Smith, Nadine Barrie
The use of needles for multiple injection of drugs, such as insulin for diabetes, can be painful. As a result, prescribed drug noncompliance can result in severe medical complications. Several noninvasive methods exist for transdermal drug delivery. These include chemical mediation using liposomes and chemical enhancers or physical mechanisms such as microneedles, iontophoresis, electroporation, and ultrasound. Ultrasound enhanced transdermal drug delivery offers advantages over traditional drug delivery methods which are often invasive and painful. A broad review of the transdermal ultrasound drug delivery literature has shown that this technology offers promising potential for noninvasive drug administration. From a clinical perspective, few drugs, proteins or peptides have been successfully administered transdermally because of the low skin permeability to these relatively large molecules, although much work is underway to resolve this problem. The proposed mechanism of ultrasound has been suggested to be the result of cavitation, which is discussed along with the bioeffects from therapeutic ultrasound. For low frequencies, potential transducers which can be used for drug delivery are discussed, along with cautions regarding ultrasound safety versus efficacy. PMID:18203426
Zheng, Jun; Han, Wen; Han, Xiao-Dong; Ma, Xiao-Yuan; Zhang, Pengbo
This study aims to evaluate the effect of naloxone on intravenous fentanyl patient-controlled analgesia after laparoscopic cholecystectomy under total intravenous anesthesia.A total of 90 patients, who underwent intravenous fentanyl patient-controlled analgesia after laparoscopic cholecystectomy under total intravenous anesthesia, were included into this study. All patients were randomly divided into 3 groups (each group, n=30): naloxone group (naloxone+fentanyl), tropisetron group (tropisetron+fentanyl), and fentanyl group (fentanyl). Patients in each group were given a corresponding dose of naloxone. Postoperative analgesia effect and the incidence of side effects such as nausea and vomiting were observed.Small doses of naloxone or tropisetron combined with fentanyl used for intravenous patient-controlled analgesia can significantly reduce the incidence of nausea and vomiting. Six hours after surgery, visual analogue scale (VAS) scores were significantly lower in patients that underwent intravenous patient-controlled analgesia using low-dose naloxone combined with fentanyl compared with patients who received fentanyl alone; however, the postoperative analgesic effect of tropisetron was not observed. Compared with the combination of tropisetron and fentanyl, low-dose naloxone combined with fentanyl can obviously reduce the incidence of nausea and vomiting in patients who underwent intravenous patient-controlled analgesia after laparoscopic cholecystectomy, and enhance the analgesic effect of fentanyl 6 hours after surgery.Low-dose naloxone can reduce the incidence of nausea and vomiting in patients who underwent laparoscopic cholecystectomy under total intravenous anesthesia, and exhibits a certain synergic analgesic effect.
Zheng, Jun; Han, Wen; Han, Xiao-Dong; Ma, Xiao-Yuan; Zhang, Pengbo
Abstract This study aims to evaluate the effect of naloxone on intravenous fentanyl patient-controlled analgesia after laparoscopic cholecystectomy under total intravenous anesthesia. A total of 90 patients, who underwent intravenous fentanyl patient-controlled analgesia after laparoscopic cholecystectomy under total intravenous anesthesia, were included into this study. All patients were randomly divided into 3 groups (each group, n=30): naloxone group (naloxone+fentanyl), tropisetron group (tropisetron+fentanyl), and fentanyl group (fentanyl). Patients in each group were given a corresponding dose of naloxone. Postoperative analgesia effect and the incidence of side effects such as nausea and vomiting were observed. Small doses of naloxone or tropisetron combined with fentanyl used for intravenous patient-controlled analgesia can significantly reduce the incidence of nausea and vomiting. Six hours after surgery, visual analogue scale (VAS) scores were significantly lower in patients that underwent intravenous patient-controlled analgesia using low-dose naloxone combined with fentanyl compared with patients who received fentanyl alone; however, the postoperative analgesic effect of tropisetron was not observed. Compared with the combination of tropisetron and fentanyl, low-dose naloxone combined with fentanyl can obviously reduce the incidence of nausea and vomiting in patients who underwent intravenous patient-controlled analgesia after laparoscopic cholecystectomy, and enhance the analgesic effect of fentanyl 6 hours after surgery. Low-dose naloxone can reduce the incidence of nausea and vomiting in patients who underwent laparoscopic cholecystectomy under total intravenous anesthesia, and exhibits a certain synergic analgesic effect. PMID:27902584
Darwish, Mona; Kirby, Mary; Robertson, Philmore; Hellriegel, Edward; Jiang, John G
This study evaluated the single-dose and steady-state pharmacokinetics of fentanyl buccal tablet 400 microg in healthy adult volunteers. After receiving naltrexone 50 mg to block opioid receptor-mediated effects of fentanyl, subjects received fentanyl buccal tablet 400 microg on day 1, then every 6 hours from day 4 to day 9 (21 doses). Naltrexone 50 mg was administered every 12 hours throughout the study. Plasma fentanyl concentrations were determined for 72 hours after administration of fentanyl buccal tablet 400 microg on day 1 and the last dose of fentanyl buccal tablet 400 microg on day 9. Following single- and multiple-dose administration of fentanyl buccal tablet, the median time to maximum concentration (tmax) was 52.2 and 49.8 minutes, respectively. Peak plasma concentration of fentanyl (Cmax) was 0.88 ng/mL for the single-dose regimen and 1.77 ng/mL for the multiple-dose regimen. Steady state was reached within 5 days, consistent with the observed median half-life of approximately 22 hours following multiple doses. Observed accumulation of fentanyl after multiple doses of fentanyl buccal tablet was slightly greater than would be expected based on the single-dose data. This was attributed to the redistribution of fentanyl from a deep tissue compartment into the plasma. This study indicates that fentanyl buccal tablet has predictable pharmacokinetics following multiple-dose administration.
Davila, G Willy
Overactive bladder is a dreadful syndrome that affects a considerable number of patients. Antimuscarinics are the mainstay of pharmacotherapy for this condition. Transdermal (TD) oxybutynin (OXY) bypasses the first-pass metabolism and reduces the formation of N-desethyloxybutynin, a compound believed to be associated with anticholinergic side effects. The 3.9 mg matrix TD system is applied twice weekly and transports OXY directly into the systemic circulation. The patch can be applied to abdomen, buttock, and hip, and provides continuous OXY delivery that minimizes peak and trough fluctuations in plasma levels. In clinical trials, TD and oral OXY produced a significant reduction in incontinence episodes, with no difference between oral and TD treatments. In addition, TDOXY was similar to tolterodine, and it produced a significant improvement in the number of urinary incontinence episodes, complete continence, and urodynamic and quality of life parameters compared with placebo. The incidence of anticholinergic adverse events with TDOXY was similar to placebo. Most common adverse events were mild–moderate skin reactions. Treatment satisfaction survey suggested patients’ preference to use the TD system in the future. Counseling on healthy skin care and appropriate product use can enhance patients’ knowledge about TDOXY for overactive bladder treatment. PMID:18044106
Raja, Waseem K.; MacCorkle, Scott; Diwan, Izzuddin M.; Abdurrob, Abdurrahman; Lu, Jessica; Omenetto, Fiorenzo G.; Kaplan, David L.
Microneedles are a relatively simple, minimally invasive and painless approach to deliver drugs across the skin. However, there remain limitations with this approach because of the materials most commonly utilized for such systems. Silk protein, with tunable and biocompatibility properties, is a useful biomaterial to overcome the current limitations with microneedles. Silk devices preserve drug activity, offer superior mechanical properties and biocompatibility, can be tuned for biodegradability, and can be processed under aqueous, benign conditions. In the present work, we report the fabrication of dense microneedle arrays from silk with different drug release kinetics. The mechanical properties of the microneedle patches are tuned by post-fabrication treatments or by loading the needles with silk microparticles to increase capacity and mechanical strength. Drug release is further enhanced by the encapsulation of the drugs in the silk matrix and coating with a thin dissolvable drug layer. The microneedles are used on human cadaver skin and drugs were delivered successfully. The various attributes demonstrated suggest that silk-based microneedle devices can provide significant benefit as a platform material for transdermal drug delivery. PMID:23653252
Cristancho, Mario A; Thase, Michael E
Although safer and easier to use antidepressants (ie.,SSRIs/SNRIs) have largely displaced MAOIs, these medications still have a role in difficult to treat conditions. Efforts to improve MAOIs benefit-risk profile resulted on the reversible MAOI and in the first antidepressant patch (selegiline transdermal delivery system-STS). The later had been available in the US since 2006. Thus a review on its safety profile and comparative efficacy is timely. This review provides an overview of STS's clinical pharmacology and summarizes what has been learned across nearly a decade of experience. Product labels and the search engine PubMed were used to obtain relevant information. STS remains a unique treatment option. It is the only FDA-approved antidepressant for patients with significant problems ingesting, tolerating, or absorbing oral medications. It remains the only MAOI that can be initiated without dietary restrictions at a therapeutic dose and has a low incidence of side effects when compared to other MAOIs. STS also provides an interesting option for depressed patients suffering from Parkinson's disease. However these advantages are counterweighted by drawbacks including the need for wash-out periods and the lack of convincing data illustrating its utility for treatment of more severe, treatment refractory depression.
Solak, Okan; Oz, Gürhan; Kokulu, Serdar; Solak, Ozlem; Doğan, Gökçen; Esme, Hıdır; Ocalan, Kubilay; Baki, Elif Doğan
The most commonly observed pathology in chest traumas is rib fracture, and the most important clinical symptom is severe pain. To investigate the effectiveness of intramuscular opioid (IMO), intravenous patient-controlled analgesia (IVPCA) and the Fentanyl transdermal therapeutic system (TTS) in the management of rib fracture pain. Prospective randomized clinical trial. In our prospective and randomised study, we included 45 patients with a diagnosis of multiple rib fractures. There were three groups and intercostal nerve blockage (ICB) in the first day and oral paracetamol for five days was administered to each group as standard. In Group IMO (n=15), 4×40 mg pethidine HCl was administered to the patients, while in Group IVPCA (n=15) this was 5 μg/mL continuous intravenous fentanyl and was 50 μg fentanyl TTS in Group TTS (n=15). The demographics, injury data and vital signs of the patients were recorded. Pain was scored using Visual Analogue Scale (VAS). The pain during lying down (VASl) and mobilisation (VASm) was detected. There were no differences between the three groups regarding age, sex, the trauma pattern, the number and distribution of costal fracture localisations, the presence of additional pathology, complications, thoracal catheter and the duration of thoracal catheter. No significant difference between the groups regarding systolic and diastolic arterial tension, number of breaths and beats in a minute was observed (p>0.05). We observed an improvement in the mean VAS score after treatment in all three groups. The mean VASl score significantly decreased after treatment in each group (p<0.05). The mean VASl and VASm scores measured on the 1(st), 2(nd), 3(rd), 4(th) and 5(th) days were found to be higher in Group IMO than in Groups IVPCA and TTS; however, these differences were not statistically significant (p>0.05). In the analgesia of patients with multiple rib fractures, TTS administration with ICB showed similar effectiveness with IVPCA
Poklis, Justin; Poklis, Alphonse; Wolf, Carl; Mainland, Mary; Hair, Laura; Devers, Kelly; Chrostowski, Leszek; Arbefeville, Elise; Merves, Michele; Pearson, Julia
In the last two years, an epidemic of fatal narcotic overdose cases has occurred in the Tampa area of Florida. Fourteen of these deaths involved fentanyl and/or the new designer drug, acetyl fentanyl. Victim demographics, case histories, toxicology findings and causes and manners of death, as well as, disposition of fentanyl derivatives and their nor-metabolites in postmortem heart blood, peripheral blood, bile, brain, liver, urine and vitreous humor are presented. In the cases involving only acetyl fentanyl (without fentanyl, n=4), the average peripheral blood acetyl fentanyl concentration was 0.467 mg/L (range 0.31 to .60 mg/L) and average acetyl norfentanyl concentration was 0.053 mg/L (range 0.002 to 0.086 mg/L). In the cases involving fentanyl (without acetyl fentanyl, n=7), the average peripheral blood fentanyl concentration was 0.012 mg/L (range 0.004 to 0.027 mg/L) and average norfentanyl blood concentration was 0.001 mg/L (range 0.0002 to 0.003 mg/L). In the cases involving both acetyl fentanyl and fentanyl (n=3), the average peripheral blood acetyl fentanyl concentration was 0.008 mg/L (range 0.006 to 0.012 mg/L), the average peripheral blood acetyl norfentanyl concentration was 0.001 mg/L (range 0.001 to 0.002 mg/L), the average peripheral blood fentanyl concentration was 0.018 mg/L (range 0.015 to 0.021 mg/L) and the average peripheral blood norfentanyl concentration was 0.002 mg/L (range 0.001 mg/L to 0.003 mg/L). Based on the toxicology results, it is evident that when fentanyl and/or acetyl fentanyl were present, they contributed to the cause of death. A novel ultrahigh performance liquid chromatography (UPLC) tandem mass spectrometry (MS/MS) method to identify and quantify acetyl fentanyl, acetyl norfentanyl, fentanyl and norfentanyl in postmortem fluids and tissues is also presented. PMID:26583960
Poklis, Justin; Poklis, Alphonse; Wolf, Carl; Mainland, Mary; Hair, Laura; Devers, Kelly; Chrostowski, Leszek; Arbefeville, Elise; Merves, Michele; Pearson, Julia
In the last two years, an epidemic of fatal narcotic overdose cases has occurred in the Tampa area of Florida. Fourteen of these deaths involved fentanyl and/or the new designer drug, acetyl fentanyl. Victim demographics, case histories, toxicology findings and causes and manners of death, as well as, disposition of fentanyl derivatives and their nor-metabolites in postmortem heart blood, peripheral blood, bile, brain, liver, urine and vitreous humor are presented. In the cases involving only acetyl fentanyl (without fentanyl, n=4), the average peripheral blood acetyl fentanyl concentration was 0.467 mg/L (range 0.31 to 0.60 mg/L) and average acetyl norfentanyl concentration was 0.053 mg/L (range 0.002 to 0.086 mg/L). In the cases involving fentanyl (without acetyl fentanyl, n=7), the average peripheral blood fentanyl concentration was 0.012 mg/L (range 0.004 to 0.027 mg/L) and average norfentanyl blood concentration was 0.001 mg/L (range 0.0002 to 0.003 mg/L). In the cases involving both acetyl fentanyl and fentanyl (n=3), the average peripheral blood acetyl fentanyl concentration was 0.008 mg/L (range 0.006 to 0.012 mg/L), the average peripheral blood acetyl norfentanyl concentration was 0.001 mg/L (range 0.001 to 0.002 mg/L), the average peripheral blood fentanyl concentration was 0.018 mg/L (range 0.015 to 0.021mg/L) and the average peripheral blood norfentanyl concentration was 0.002 mg/L (range 0.001 mg/L to 0.003 mg/L). Based on the toxicology results, it is evident that when fentanyl and/or acetyl fentanyl were present, they contributed to the cause of death. A novel ultrahigh performance liquid chromatography (UPLC) tandem mass spectrometry (MS/MS) method to identify and quantify acetyl fentanyl, acetyl norfentanyl, fentanyl and norfentanyl in postmortem fluids and tissues is also presented.
Paudel, Kalpana S; Milewski, Mikolaj; Swadley, Courtney L; Brogden, Nicole K; Ghosh, Priyanka; Stinchcomb, Audra L
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
Imamoglu, Melih; Aygun, Ali; Bekar, Omer; Erdem, Erkan; Cicek, Mustafa; Tatli, Ozgur; Karaca, Yunus; Sahin, Aynur; Turkmen, Suha; Turedi, Suleyman
To assess the effectiveness of nebulized fentanyl used for analgesia in renal colic. This research was planned as a randomized, blinded study in which prospectively collected data were analyzed retrospectively to compare nebulized and intravenous (iv) fentanyl therapies. Patients with renal colic with 'moderate' or worse pain on a four-point verbal pain score (VPS) or with pain of 20mm or above on a 100-mm visual analogue score (VAS) at time of presentation were randomized into iv fentanyl (n=62) or nebulized fentanyl (n=53) study groups. Decreases in VAS and VPS scores at 15 and 30min compared to baseline, rescue analgesia requirements and side-effects between the groups were compared. Both iv fentanyl and nebulized fentanyl provided effective analgesia in renal colic patients at the end of 30min. However, iv fentanyl provided more rapid and more effective analgesia than nebulized fentanyl. Patients receiving iv fentanyl had lower rescue analgesia requirements than those receiving nebulized fentanyl (37.1% vs 54.7%), although the difference was not statistically significant (p=0.058). In addition, side-effects were more common in the iv fentanyl group compared to the nebulized fentanyl group (22.1% vs 9.4%), although the difference was also not significant (p=0.058). Nebulized fentanyl provides effective analgesia in patients with renal colic. However, iv fentanyl exhibits more rapid and more powerful analgesic effects than nebulized fentanyl. Nonetheless, due to its ease of use and few potential risks and side-effects the nebulized form can be used as an alternative in renal colic. Copyright © 2017 Elsevier Inc. All rights reserved.
... been determined by DEA's Office of Forensic Sciences that ANPP can also be produced through synthetic... fentanyl, rather than from fentanyl diverted from legal pharmaceutical manufacturers. Forensic testing of.... The forensic data suggests that most of these fentanyl-related deaths are from fentanyl illicitly...
Lee, Jaewon; Yoon, Joon Shik; Lee, Jae Hyup; Chung, So-Hak; Lee, Kyu-Yeol; Kim, Young Yul; Kim, Jong Moon; Kong, Min Ho; Kang, Ung Gu
Background Opioids are recently recommended for those who do not gain adequate pain relief from the use of acetaminophen or nonsteroidal anti-inflammatory drugs. Medical opioids are administered in various routes, and transdermal opioid products that can make up for the weaknesses of the oral or intravenous products have been developed. This study is to evaluate the clinical usefulness of fentanyl matrix in terms of the long-term improvement in pain and physical and mental functions. Methods This was a multicenter, open, prospective, observational study that was conducted in 54 institutions in Korea. Patients with non-cancerous chronic pain completed questionnaires, and investigators also completed questionnaires. A total of 1,355 subjects participated in this study, and 639 subjects completed the study. Subjects received transdermal fentanyl matrix (12 µg/hr, 25 µg/hr, or 50 µg/hr depending on the patient's response and demand). Subjects visited at 29 ± 7 days, 85 ± 14 days, and 169 ± 14 days after administration, respectively, to receive drug titration and fill out the questionnaires. The results were analyzed using the intention-to-treat (ITT) analysis, full analysis set (FAS), and per-protocol (PP) analysis. The FAS analysis included only 451 participants; the PP analysis, 160 participants; and the ITT analysis, 1,355 participants. Results The intensity of pain measured by the Numeric Rating Scale decreased from 7.07 ± 1.78 to 4.93 ± 2.42. The physical assessment score and mental assessment score of the Short-Form Health Survey 12 improved from 28.94 ± 7.23 to 35.90 ± 10.25 and from 35.80 ± 11.76 to 42.52 ± 10.58, respectively. These differences were significant, and all the other indicators also showed improvement. Adverse events with an incidence of ≥ 1% were nausea, dizziness, vomiting, and pruritus. Conclusions The long-term administration of fentanyl matrix in patients with non-cancerous pain can reduce the intensity of pain and significantly
Lishko, Polina; Clapham, David E.; Navarro, Betsy; Kirichok, Yuriy
Sperm intracellular pH and calcium concentration ([Ca2+]i) are two central factors that control sperm activity within the female reproductive tract. As such, the ion channels of the sperm plasma membrane that alter intracellular sperm [Ca2+] and pH play important roles in sperm physiology and the process of fertilization. Indeed, sperm ion channels regulate sperm motility, control sperm chemotaxis toward the egg in some species, and may trigger the acrosome reaction. Until recently, our understanding of these important molecules was rudimentary due to the inability to patch-clamp spermatozoa and directly record the activity of these ion channels under voltage clamp. Recently, we overcame this technical barrier and developed a method for reproducible application of the patch-clamp technique to mouse and human spermatozoa. This chapter covers important aspects of application of the patch-clamp technique to spermatozoa, such as selection of the electrophysiological equipment, isolation of spermatozoa for patch-clamp experiments, formation of the gigaohm seal with spermatozoa, and transition into the whole-cell mode of recording. We also discuss potential pitfalls in application of the patch-clamp technique to flagellar ion channels. PMID:23522465
Williamsen, Joel E. (Inventor); Weddendorf, Bruce C. (Inventor)
A rigid patch body for placing over a damaged portion (hole) of an external wall of a pressurized vessel, such as a space vehicle or a habitat, is discussed. The rigid patch body allows an astronaut to make temporary repairs to the pressurized vessel from the exterior of the vessel, which enables more permanent repairs to be made from the interior of the vessel. The pressure wall patch of the present invention includes a floor surrounded by four side members. Each side member includes a threaded screw for anchoring the patch body to the external wall of the pressurized vessel and a recess in its lower surface for supporting an inflatable bladder for surrounding the damaged portion (hole) of the external wall to seal the area surrounding the damaged portion. This allows the vessel to be repressurized. The floor of the rigid patch body supports a source of gas that is connected to the gas supply valve and a gas supply gauge in communication with the gas supply valve and the inflatable bladder.
Valdez, Carlos A.; Leif, Roald N.; Mayer, Brian P.
The alternate and optimized syntheses of the parent opioid fentanyl and its analogs are described. The routes presented exhibit high-yielding transformations leading to these powerful analgesics after optimization studies were carried out for each synthetic step. The general three-step strategy produced a panel of four fentanyls in excellent yields (73–78%) along with their more commonly encountered hydrochloride and citric acid salts. The following strategy offers the opportunity for the gram-scale, efficient production of this interesting class of opioid alkaloids. PMID:25233364
Bick, Matthew J; Greisen, Per J; Morey, Kevin J; Antunes, Mauricio S; La, David; Sankaran, Banumathi; Reymond, Luc; Johnsson, Kai; Medford, June I; Baker, David
We describe the computational design of proteins that bind the potent analgesic fentanyl. Our approach employs a fast docking algorithm to find shape complementary ligand placement in protein scaffolds, followed by design of the surrounding residues to optimize binding affinity. Co-crystal structures of the highest affinity binder reveal a highly preorganized binding site, and an overall architecture and ligand placement in close agreement with the design model. We use the designs to generate plant sensors for fentanyl by coupling ligand binding to design stability. The method should be generally useful for detecting toxic hydrophobic compounds in the environment.
Levin, Tomer T; Bakr, Mohamed Hussien; Nikolova, Tanya
Fentanyl and diltiazem are frequently used medications. Diltiazem inhibits cytochrome P450 3A4 isoenzymes. This can suppress fentanyl metabolism. We present a case of delirium after coadministration of fentanyl and diltiazem. Cautious use is warranted while concomitantly administering fentanyl and diltiazem as this can potentiate fentanyl toxicity. Other 3A4 inhibitors include ketoconazole, erythromycin, nefazodone, ritonavir, delavirdine, aprepitant and imatinib. Psychosomatic medicine psychiatrists, pain and palliative care physicians and cardiologists in particular should be aware of this interaction. Copyright © 2010 Elsevier Inc. All rights reserved.
The objectives of this work were to construct, install, and operate a patch testing unit on a hot gas stream at a coal-fired fluidized-bed boiler. A 2,000-hour patch test was conducted on ceramic disks of materials used in the fabrication of ceramic candles and ceramic cross-flow filters. The primary issues addressed in these tests were the long-term physical, thermal, and chemical stability of the ceramic materials; long-term pressure drop and filtration characteristics of the ceramic filters; potential for irreversible blinding of filter elements; and long-term performance and reliability of auxiliary hardware, such as the tube sheet and pulse-cleaning systems. Results on three samples, or patches, 10 cm in diameter are given.
Grossberg, George T; Schmitt, Frederick A; Meng, Xiangyi; Tekin, Sibel; Olin, Jason
Alzheimer's disease (AD) patients treated with rivastigmine transdermal patch have shown statistically significant differences versus placebo on the AD Assessment scale-cognitive subscale (ADAS-cog). In this retrospective analysis of a double-blind, placebo- and active-controlled, 24-week clinical trial, the specific effects of rivastigmine patch on individual ADAS-cog items and cognitive domains (memory, language, and praxis) were explored. The mean baseline to week 24 changes were calculated for each ADAS-cog item and domain in this exploratory, hypothesis-generating analysis. Patients on 9.5 mg/24 h rivastigmine patch, 17.4 mg/24 h rivastigmine patch, and 3 to 12 mg/d rivastigmine capsules showed improvements over placebo on the memory and praxis ADAS-cog subscales. The rivastigmine patch groups also showed improvements on the language subscale. Significant differences versus placebo were seen on several individual item scores in the rivastigmine-treated groups. Rivastigmine patch was associated with improvements on the memory, praxis, and language domains of cognition in patients with mild-to-moderate AD.
Layek, Amitava; Maitra, Souvik; Gozi, Nitish K; Bhattacharjee, Sulagna; Pal, Sugata; Sen, Suvadeep; Hazra, Avijit
Background and Aims: We aimed to evaluate and compare the block characteristics and duration of analgesia of intrathecal isobaric ropivacaine-fentanyl and bupivacaine-fentanyl combination in adult patients undergoing lower limb orthopedic surgery. Material and Methods: Seventy-four American Society of Anesthesiologists’ I and II adult patients undergoing lower limb orthopedic surgery under subarachnoid block were randomized to receive either 3 ml 0.5% isobaric ropivacaine and 25 mcg fentanyl (Group R) or 3 ml 0.5% isobaric bupivacaine and 25 mcg fentanyl (Group B). The hemodynamic profiles, maximum upper level of sensory block height, time to reach peak block height, two dermatome regression time, and duration of motor block were recorded. Results: There was no statistically significant difference regarding the hemodynamic parameters between the groups. The median (range) peak sensory block height was T7 (T4-T9) in Group R and T7 (T4-T10) in Group B. Time to reach peak block height (13.2 ± 2.3 min in Group R vs. 13.7 ± 2.2 min in Group B; P = 0.385) was similar between the groups. Two dermatome regression time in sensory block (median 120 min vs. 85 min; P < 0.001) and duration of motor block (median 245 min vs. 150 min; P < 0.001) was significantly higher in Group B. The duration of analgesia (median 360 min vs. 245 min; P < 0.001) was significantly higher in the bupivacaine group. Conclusion: Intrathecal isobaric bupivacaine-fentanyl combination produces a significantly longer duration of analgesia, sensory block and motor block than isobaric ropivacaine-fentanyl combination. As ropivacaine has a shorter duration of sensory and motor block, it may be preferred in day care surgery. PMID:26702216
Venkatesh, G.; Fallen, E. L.; Kamath, M. V.; Connolly, S.; Yusuf, S.
OBJECTIVE: To test the hypothesis that short term application of transdermal scopolamine increases heart rate variability (HRV) and restores sympathovagal balance in patients with stable congestive heart failure (CHF). DESIGN: A double blind placebo controlled crossover study. SETTING: Tertiary referral centre. PATIENTS: Twelve patients (mean age 66 (10)) with New York Heart Association class II-IV CHF. All patients had coronary artery disease (mean left ventricular ejection fraction 26.7 (8.9) %). INTERVENTION: Patients were randomly assigned to receive either a placebo skin patch or a transdermal scopolamine patch (Transderm, 0.05 mg/h). Patches remained in place for 48 hours with a 24 hour washout period before crossover. OUTCOME MEASURES: HRV was derived from (a) 24 hour time domain indices (mean RR interval, standard deviation of interbeat interval, and the baseline width of the frequency distribution of RR intervals) and (b) short data set (2.2 mm) power spectral measurements using autoregressive modelling. Autospectral measures were performed in both resting supine and standing (orthostatic) states. The 24 hour Holter record was obtained during the second day of patch application. RESULTS: There was a small but significant (P < 0.05) increase in all time domain HRV variables with scopolamine. There was a paradoxical fall in low frequency (LF) spectral power induced by orthostasis during baseline (-30%) and placebo (-34%) states. Conversely, scopolamine was associated with a 14% increase in LF power during orthostatic stress. Scopolamine thus significantly reduced the orthostatic fall in LF (P < 0.01) compared with either baseline or placebo values. No difference in circadian rhythm was seen between the scopolamine and placebo treatment periods. However, the abrupt fall in the high frequency (vagal) power during the early morning sleep-wake hours was reduced by scopolamine. Scopolamine was also associated with a significant rightward shift in the resting LF
Chen, Quan; Shang, You; Xu, Yong; Li, Ping; Li, Ping; Liu, Guo-Li
To explore analgesic effects of fentanyl and butorphanol on incisional pain in rats and to investigate the pharmacological mechanism of combination. Seventy rats were randomly divided into control group (group N, n = 10), fentanyl group (group F, n = 30), and butorphanol group (group B, n = 30), to determine median effective dose (ED50) in fentanyl and butorphanol. Another 50 rats were treated with both fentanyl and butorphanol (joint group) to quantitatively detect response rate of joint application. Ninety rats were randomly divided into 1/4 ED50 fentanyl (group 1, n = 30), 1/2 ED50 fentanyl (group 2, n = 30), and 3/4 ED50 fentanyl (group 3, n = 30), to detect the correlation between combined pharmacological effects of 2 drugs and their dose proportionality. Statistical analysis was performed using SPSS 17.0. Probit analysis revealed that ED50 of fentanyl was 4.1 μg/kg, whereas ED50 of butorphanol was 295 μg/kg. The qualitative response rate of combination (Po) was 0.84, and expected qualitative response rate (Pe) was 0.75, with no statistical significance (P = 0.3). Furthermore, probit analysis showed that 155 μg/kg butorphanol with 1/4 ED50 fentanyl could reach experimental ED50 of combination of 2 drugs; 115 μg/kg butorphanol with 1/2 ED50 fentanyl could reach experimental combination ED50; and 88 μg/kg butorphanol with 3/4 ED50 fentanyl could reach experimental combination ED50. Both fentanyl and butorphanol showed good analgesic effect on incisional pain in rats, but fentanyl was superior to butorphanol. The pharmacological mechanism of combination with ED50 of fentanyl and butorphanol showed independent joint action, and the combination efficacy was related to the dosage. Copyright © 2016 Elsevier Inc. All rights reserved.
Opioids and the management of chronic severe pain in the elderly: consensus statement of an International Expert Panel with focus on the six clinically most often used World Health Organization Step III opioids (buprenorphine, fentanyl, hydromorphone, methadone, morphine, oxycodone).
Pergolizzi, Joseph; Böger, Rainer H; Budd, Keith; Dahan, Albert; Erdine, Serdar; Hans, Guy; Kress, Hans-Georg; Langford, Richard; Likar, Rudolf; Raffa, Robert B; Sacerdote, Paola
SUMMARY OF CONSENSUS: 1. The use of opioids in cancer pain: The criteria for selecting analgesics for pain treatment in the elderly include, but are not limited to, overall efficacy, overall side-effect profile, onset of action, drug interactions, abuse potential, and practical issues, such as cost and availability of the drug, as well as the severity and type of pain (nociceptive, acute/chronic, etc.). At any given time, the order of choice in the decision-making process can change. This consensus is based on evidence-based literature (extended data are not included and chronic, extended-release opioids are not covered). There are various driving factors relating to prescribing medication, including availability of the compound and cost, which may, at times, be the main driving factor. The transdermal formulation of buprenorphine is available in most European countries, particularly those with high opioid usage, with the exception of France; however, the availability of the sublingual formulation of buprenorphine in Europe is limited, as it is marketed in only a few countries, including Germany and Belgium. The opioid patch is experimental at present in U.S.A. and the sublingual formulation has dispensing restrictions, therefore, its use is limited. It is evident that the population pyramid is upturned. Globally, there is going to be an older population that needs to be cared for in the future. This older population has expectations in life, in that a retiree is no longer an individual who decreases their lifestyle activities. The "baby-boomers" in their 60s and 70s are "baby zoomers"; they want to have a functional active lifestyle. They are willing to make trade-offs regarding treatment choices and understand that they may experience pain, providing that can have increased quality of life and functionality. Therefore, comorbidities--including cancer and noncancer pain, osteoarthritis, rheumatoid arthritis, and postherpetic neuralgia--and patient functional
Xu, Zongben; Sun, Jian
This paper introduces a novel examplar-based inpainting algorithm through investigating the sparsity of natural image patches. Two novel concepts of sparsity at the patch level are proposed for modeling the patch priority and patch representation, which are two crucial steps for patch propagation in the examplar-based inpainting approach. First, patch structure sparsity is designed to measure the confidence of a patch located at the image structure (e.g., the edge or corner) by the sparseness of its nonzero similarities to the neighboring patches. The patch with larger structure sparsity will be assigned higher priority for further inpainting. Second, it is assumed that the patch to be filled can be represented by the sparse linear combination of candidate patches under the local patch consistency constraint in a framework of sparse representation. Compared with the traditional examplar-based inpainting approach, structure sparsity enables better discrimination of structure and texture, and the patch sparse representation forces the newly inpainted regions to be sharp and consistent with the surrounding textures. Experiments on synthetic and natural images show the advantages of the proposed approach.
Suedee, Roongnapa; Bodhibukkana, Chatchada; Tangthong, Naruedom; Amnuaikit, Chomchan; Kaewnopparat, Sanae; Srichana, Teerapol
The aims of this study were to develop a transdermal patch for selective controlled delivery of the active S-enantiomer from racemic propranolol, and to evaluate its performance in vivo using Wistar rats. A molecularly imprinted polymer (MIP) thin-layer composited cellulose membrane with selectivity for S-propranolol was employed as the enantioselective-controlled release system. The effect of gel reservoir (poloxamer and chitosan) on enantioselective delivery was investigated. The chitosan gel allowed excellent selectivity for delivery of the S-propranolol enantiomer, whilst the more rheologically structured poloxamer gel formulation provided no selective release of S-propranolol. The chitosan gel exhibited high flux and had the ability to enantioselective deliver S-propranolol across excised rat skin. The results from confocal laser scanning microscopy study, carried out with the R- and S-propranolol enantiomers labeled with a 1-pyrenebutyric acid probe as fluorescent markers, suggested that the MIP composite membrane selectively regulated the release of the recognised S-enantiomer via a facilitated transport pathway through complex formation with the selective receptor sites, while the release of the R-enantiomer was via a non-selective route. The reservoir patch for enantiomer-controlled delivery of propranolol was therefore fabricated by incorporating the chitosan gel formulation containing racemic propranolol hydrochloride into the MIP composite membrane laminated backing. These patch devices were shown to exhibit the significant stereoselectivity uptake of propranolol when attached to the skin, using pharmacokinetic studies in rats. S-Propranolol enantiomer plasma concentration profiles for the transdermal patch in the in vivo study were comparable to data for the gel formulations that were applied directly to skin, and containing a single S-enantiomer of propranolol. The results demonstrate that the transdermal patch based on the MIP composite membrane
Alvarez-Figueroa, María Javiera; González-Aramundiz, José Vicente
The in vitro iontophoretic transdermal delivery of chlorpromazine (CPZ) across pig skin was investigated. Anodal iontophoresis considerably increased CPZ skin penetration and accumulation compared with the passive controls. The effect of CPZ concentration in the donor solution was studied (1.4-8.2 mM). A higher penetration was observed with an increase of the concentration. In addition, the effect of NaCl concentration was also studied (154-200 mM). As expected, CPZ iontophoretic transport decreased with NaCl content. Finally, the influence of the current density (0.20-0.50 mA/cm(2)) was investigated. The iontophoretic transport of CPZ tends to increase with current density, although this effect was not statistically significant between 0.35 and 0.5 mA/cm(2). On the whole, this work shows that iontophoresis may be used to improve the transdermal delivery of CPZ for the treatment of chronic psychosis.
Gardner, Michael A; Sampsel, Sheena; Jenkins, Werner W; Owens, Janel E
Fentanyl is a synthetic narcotic anesthetic ∼80-100 times more potent than morphine. Owing to the potential for its abuse, the drug may be included in a forensic toxicology work-up, which requires fast, precise and accurate measurements. Here, the stability of fentanyl was assessed when stored at three different temperatures (-20, 4 and 25°C) in synthetic urine. Stability at those three temperatures was demonstrated over 12 weeks upon analysis by gas chromatography-mass spectrometry with a deuterated internal standard (fentanyl-D5) utilizing three different extraction techniques: liquid-liquid extraction (LLE), solid-phase extraction and dispersed liquid-liquid microextraction (DLLME). The DLLME method was then optimized before use in the analysis of fentanyl in urine samples obtained from autopsy cases at the El Paso County Coroner's Office. Accuracy of the DLLME method was assessed by completing spike and recovery studies at three different fortification levels (10, 100 and 250 ng/mL) with excellent recovery (89.9-102.6%). The excellent comparability between DLLME and LLE is demonstrated (Bland-Altman difference plot with a mean difference of 4.9 ng/mL) and the use of this methodology in the analysis of forensically relevant samples is discussed.
Becker, Willem M; Mama, Khursheed R; Rao, Sangeeta; Palmer, Ross H; Egger, Erick L
To describe the prevalence of dysphoria after intraoperative administration of fentanyl by infusion and identify other risk factors influencing this in dogs undergoing stifle surgery. Prospective, randomized clinical study. Dogs (n = 92) that had tibial plateau leveling osteotomy (TPLO) or tibial tuberosity advancement (TTA). Dogs were anesthetized using a standardized anesthetic protocol, and randomly assigned to receive a loading dose followed by 1 of 3 infusions of fentanyl perioperatively: 2 μg/kg/h, 10 μg/kg/h, or 20 μg/kg/h. Dog characteristics and all additional medications were recorded and included as part of the statistical analysis. Dog behavior was scored before anesthesia and during recovery using a scale of 1-4 (Appendices A and B). If no improvement in behavior was seen in 3-5 minutes postextubation, dogs with a score of 3 or 4 during recovery were administered fentanyl (2 μg/kg intravenously [IV]) in the event that the behaviors associated with the higher scores were related to pain. If they did not respond favorably to the administration of additional fentanyl and wound palpation did not elicit a response, but the untoward behaviors continued, dogs were administered either a tranquilizer, sedative, or opioid antagonist, and were considered dysphoric. Of 92 dogs, 22 (23.9%) were considered dysphoric using aforementioned criteria. About one-fourth of dogs enrolled in this study were dysphoric based on study criteria. © Copyright 2012 by The American College of Veterinary Surgeons.
Mather, Laurence E; Woodhouse, Annie; Ward, M Elizabeth; Farr, Stephen J; Rubsamen, Reid A; Eltherington, Lorne G
Aims Pulmonary drug delivery is a promising noninvasive method of systemic administration. Our aim was to determine whether a novel breath-actuated, microprocessor-controlled metered dose oral inhaler (SmartMist™, Aradigm Corporation) could deliver fentanyl in a way suitable for control of severe pain. Methods Aersolised pulmonary fentanyl base 100–300 μg was administered to healthy volunteers using SmartMist™ and the resultant plasma concentration-time data were compared with those from the same doses administered by intravenous (i.v.) injection in the same subjects. Results Plasma concentrations from SmartMist™ were similar to those from i.v. injection. Time-averaged bioavailability based upon nominal doses averaged 100%, and was >50% within 5 min of delivery. Fentanyl systemic pharmacokinetics were similar to those previously reported with no trends to dose-dependence from either route. Side-effects (e.g. sedation, lightheadedness) were the same from both routes. Conclusions Fentanyl delivery using SmartMist™ can provide analgetically relevant plasma drug concentrations. This, combined with its ease of noninvasive use and transportability, suggests a strong potential for field and domicilliary use, and for patient controlled analgesia without the need for i.v. cannulae. PMID:9690947
to this discovery, considerable attention was directed toward molecules that preserved those critical structural features of the morphine molecule ...chemical synthesis to discover molecules of such potency that they could be administered at concentrations high enough for effective binding to the g...projects based on presumed biotransformation routes for fentanyl derviatives. Colapret and coworkers 3 3 synthesized a number of molecules having the
Alves, Heber Nuno Castro; da Silva, Aura Luísa Maia; Olsson, Ingrid Anna S; Orden, José Manuel Gonzalo; Antunes, Luis Marques
A safe and reliable method for anesthetizing rats has long been a leading concern of biomedical researchers. We recently found that the intraperitoneal administration of propofol combined with medetomidine and fentanyl is safe for mouse anesthesia. Here we studied whether the same combination could be used for general anesthesia in rats. We used male Wistar rats to test 10 combinations of propofol, medetomidine, and fentanyl administered intraperitoneally and reversed with intraperitoneal atipamezole 30 min after induction. The depth of anesthesia, induction time, loss of pedal withdrawal reflex, pulse rate, and respiratory rate were evaluated, along with the duration and quality of induction, surgical anesthesia, and recovery. The combination of propofol and medetomidine provided a predictable induction and sufficient hypnosis and muscle relaxation, but surgical anesthesia (loss of pedal withdrawal reflex) was difficult to achieve with this protocol. The addition of fentanyl increased analgesia, making it possible to achieve surgical anesthesia. In conclusion, combination of propofol (100 mg/kg), medetomidine (0.1 mg/kg), and fentanyl (0.1 mg/kg) is a safe and practical technique for intraperitoneal anesthesia in rats, providing a surgical window of 25 min and restraint for 30 min, with rapid recovery after administration of atipamezole. PMID:20819392
Krishnaiah, Y S R; Bhaskar, P
The purpose of the present study was to design a membrane-moderated transdermal therapeutic system (TTS) of nimodipine using 2%w/w hydroxypropyl methylcellulose (HPMC) gel as a reservoir system containing menthol as penetration enhancer and 60%v/v ethanol-water as solvent system. The flux of nimodipine was markedly increased from 35.51 microg/cm2/h to 167.53+/-3.69 microg/cm2/h with the addition of 8%w/w menthol to HPMC drug reservoir. There was an increase in the flux of nimodipine through ethylene vinyl acetate (EVA) copolymer membrane with an increase in vinyl acetate content (9 to 28%w/w) of the copolymer. The permeability flux of nimodipine from the chosen EVA 2825 (with 28%w/w vinyl acetate content) was 152.05+/-2.68 microg/cm2/h, and this flux decreased to 132.69+/-1.45 microg/cm2/h on application of a water-based acrylic adhesive (TACKWHITE A 4MED) coat. However, the transdermal flux of nimodipine across EVA 2825 membrane coated with TACKWHITE A 4MED/ rat skin composite was found to be 116.05+/-2.39 microg/cm2/h, which is about 1.4 times greater than the required flux. Thus a new transdermal therapeutic system for nimodipine was designed using EVA 2825 membrane coated with a pressure-sensitive adhesive TACKWHITE 4A MED, and 2%w/w HPMC gel as reservoir containing 8%w/w of menthol as a penetration enhancer. The in vivo evaluation of nimodipine TTS patch was carried out to find the ability of the fabricated menthol-based TTS patch in providing the predetermined plasma concentration of the drug in human volunteers. The results showed that the menthol-based TTS patch of nimodipine provided steady plasma concentration of the drug with minimal fluctuations with improved bioavailability in comparison with the immediate release tablet dosage form.
Swanson, Dina M; Hair, Laura S; Strauch Rivers, Selly R; Smyth, Brianna C; Brogan, Sara C; Ventoso, Alexis D; Vaccaro, Samantha L; Pearson, Julia M
Carfentanil is a fentanyl analog frequently used in large animal veterinary medicine. Recently, carfentanil has been discovered in postmortem and antemortem cases throughout the United States in the heroin supply either alone or mixed with heroin and/or other fentanyl analogs. The potency of carfentanil is ~10,000 times greater than morphine and 100 times greater than fentanyl. In two recent cases, carfentanil was identified and ruled to be the cause of death, either alone or in combination with other drugs. Case 1 involved a known heroin user. He was discovered slumped over in a running van blocking the bays of a carwash. Two syringes, a spoon with cotton and residue and a yellow baggie of powder were found in the van. Case 2 involved a man living in a tent in a park with his mother. He was last heard from by a sister via phone who stated he sounded very intoxicated and by his mother who noted him to be "itching all over" and upset over his girlfriend. When the mother returned from work, she discovered him unresponsive with a small baggie of brown powder next to him. Routine drug and volatile screening tests were performed on heart blood using headspace gas chromatography, immunoassay and gas chromatography mass spectrometry methods. Results from initial testing on both cases did not have any significant toxicological findings. However, due to the history, scene photos, toxicological findings in blood and urine and analysis of the drug paraphernalia on one of the cases which identified carfentanil and furanyl fentanyl, fentanyl analogues were suspected. Heart blood was sent to a reference laboratory for carfentanil and furanyl fentanyl analysis. Case 1 had a carfentanil concentration of 1.3 ng/mL and a furanyl fentanyl concentration of 0.34 ng/mL. Case 2 had a carfentanil concentration of 0.12 ng/mL. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: email@example.com.
Krivan, V; Vrkoc, I
In this paper we study optimal animal movement in heterogeneous environments consisting of several food patches in which animals trade-off energy gain versus predation risk. We derive a myopic optimization rule describing optimal animal movements by fitness maximization assuming an animal state is described by a single quantity (such as weight, size, or energy reserves). This rule predicts a critical state at which an animal should switch from a more dangerous and more profitable patch to a less dangerous and less profitable patch. Qualitatively, there are two types of behavior: either the animal switches from one patch to another and stays in the new patch for some time before it switches again, or the animal switches between two patches instantaneously. The former case happens if animal state growth is positive in all patches, while the latter case happens if animal state growth is negative in one patch. In particular, this happens if one patch is a refuge. We consider in detail two special cases. The first one assumes a linear animal state growth while the second assumes a saturating animal state growth described by the von Bertalanffy curve. For the first model the proportion of time spent in the more profitable and more risky patch increases with profitability of this patch when state growth is positive in both patches. On contrary, if state growth is negative in the less profitable and safer patch, animals spend proportionally less time in the more profitable and more risky patch as its profitability increases. As a function of the predation risk in the more profitable p