Patch Dose Research Articles

Evaluation of physical variables, thermal nociceptive threshold testing and pharmacokinetics during placement of transdermal buprenorphine matrix-type patch in healthy adult horses.

Matrix type transdermal buprenorphine patches have not been investigated in horses and may provide an effective means of providing continuous pain control for extended period and eliminating venous catheterization. Assessment of the physiological variables (heart rate, respiratory rate, body temperature) and thermal nociceptive threshold testing, and describing the pharmacokinetic profile of transdermal buprenorphine matrix-type patch (20 μg h-1 and 40 μg h-1 dosing) in healthy adult horses. Randomised experimental study with a Latin-square design. Six adult healthy horses received each of the three treatments with a minimum 10 day washout period. BUP0 horses did not receive a patch (control). BUP20 horses received one patch (20 μg h-1) applied on the ventral aspect of the tail base resulting in a dose of 0.03-0.04 μg kg-1 h-1. BUP40 horses received two patches placed alongside each other (40 μg h-1) on the tail base resulting in a dose of 0.07-0.09 μg kg-1 h-1. Whole blood samples (for determination of buprenorphine concentration), physiological variables and thermal threshold testing were performed before (0 h) and at 2, 4, 8, 12, 16, 24, 32, 40, 48, 56, 64, 72, and 96 h after patch application. The patches were removed 72 h following placement and were analyzed for residual buprenorphine content. Between the three groups, there was no change in physiological variables across timepoints as compared to baseline (p > 0.1). With the higher dose, there was a significant increase in thermal thresholds from baseline values from 2 h until 48 h and these values were significantly higher than the group receiving the lower patch dose for multiple timepoints up to 40 h. 40 μg h-1 patch led to consistent measurable plasma concentrations starting at 2 h up to 96 h, with the mean plasma concentrations of > 0.1 ng/ml from 4 h to 40 h. 20 μg h-1 and 40 μg h-1 patch doses were well tolerated by all horses. At higher dose, plasma buprenorphine concentrations were more consistently measurable and blunted thermal thresholds for 48 h vs. 32 h with 20 μg h-1 dosing as compared to control.

Outcomes and GP perceptions of reviewing patients at risk of harm from opioids

Abstract Introduction The Clinical Commissioning Group (CCG) Medicines Optimisation workplan for 2021-22 had a focus on reducing harm from opioids.1,2 In particular, asking GP practices to identify and review two cohorts of patients: those on a combination of oxycodone and amitriptyline or similar high-risk combinations, and those over the age of 65 prescribed fentanyl transdermal patches. Practices were then expected to consider actions on how to reduce the risk for patients and also to provide feedback to the CCG on how the reviews had progressed. Aim We aimed to understand the outcomes, challenges and learning points experienced by practices in reviewing these patients. Methods Sixty practices were invited to participate. A feedback form was received from each practice that completed either or both reviews (covering anonymised outcomes of each review, challenges encountered, and practice-level learning points / changes made). Quantitative data were collated for each action, and feedback comments were categorised into broad groups. No patient details were collected. As this project was a service evaluation, ethical approval was not required. Results Forty-three practices completed the review of the combination of oxycodone and amitriptyline, though 5 of these had no patients to review. Overall, 185 patients were identified. Of these, 21 (11%) patients had the combination prescribing ceased, 22 (12%) were commenced on a reduction plan, and another 46 (25%) have been made aware of the risk and to report respiratory symptoms. Forty-three practices completed the fentanyl review, though one of these had no patients to review. Overall, 272 patients over 65 years were identified with 64 (24%) invited for a review with their GP or other allied health professional, 39 (14%) patients were put on a fentanyl patch dose reduction plan, and 14 (5%) had prescribing ceased. Practices reported various difficulties encountered with these reviews, including patient engagement in making changes to their pain medication which patients are reluctant to reduce; counselling and raising awareness of long-term effects of opioids to help gain patient understanding; how to manage complex patients who had been stable on their regimen over many years; and that it was time consuming to regularly check in with the patient and plan reduction regimens. Changes made by practices included recording risks discussed with patient in their medical record for easier future review; ensuring regular reviews, including by practice-based pharmacists, of patients prescribed opioids; trying to make time to see patients face to face; raising awareness of the risks of prescribing amitriptyline alongside oxycodone e.g. serotonin syndrome; and recognising that a collaborative process and patient engagement is necessary. Discussion/Conclusion The actions undertaken by practices link into national recommendations,1 with some GP feedback similar to the challenges and opportunities to improve patient safety on opioid use as reported elsewhere.3 Even with this small targeted patient cohort, this work demonstrates difficulties encountered by GPs in refraining from opioid prescribing. Other limitations of this small-scale review include lack of certainty whether reductions in opioid prescribing were always clinically appropriate, and reliance on practice feedback.

Systemically Acting Diclofenac Sodium Patch for Control of Low Back Pain: A Randomized, Double-Blind, Placebo-Controlled Study in Japan.

Nonsteroidal antiinflammatory drugs (NSAIDs) are commonly used for pain disorders such as low back pain and exist in multiple formulations; however, no systemically acting transdermal formulations are available for low back pain. Transdermal formulations can be safely administered even to patients with trouble swallowing or at risk of aspiration, and without regard to the effect of food on drug absorption. Unlike locally acting formulations, systemically acting transdermal formulations need not be applied at the target site, so dosing is simple and the burden is not on one area of the skin. A patch with the systemically acting NSAID diclofenac sodium is approved in Japan for treatment of cancer-related pain, and we hypothesized that it would be useful for controlling low back pain. This randomized, double-blind, placebo-controlled study aimed to evaluate the efficacy and safety of diclofenac sodium patch in Japanese patients with low back pain. Eligible patients were randomized to receive diclofenac sodium patch 75mg or 150mg or placebo once daily for 2weeks. The primary endpoint was pain intensity assessed on a visual analog scale (VAS). Primary analysis of the primary endpoint showed that both doses of the diclofenac sodium patch (150mg and 75mg) were superior to placebo in terms of absolute change from baseline in mean 3-day VAS score after 2weeks' treatment; the mean difference between the active and placebo treatments in this variable was -5.67 [95% confidence interval (CI) -9.34 to -2.00] mm in the 150mg group and -5.68 (95% CI -9.34 to -2.01) mm in the 75mg group. Most adverse events were mild. No serious adverse events occurred. In Japanese patients, diclofenac sodium patch is effective for the relief of low back pain and is well tolerated. JPRN number, JPRN-JapicCTI-205134.

Prediction of Corresponding Dose of Transdermal Blonanserin to Oral Dose Based on Dopamine D2 Receptor Occupancy: Unique Characteristics of Blonanserin Transdermal Patch.

Background/PurposeBlonanserin is an atypical antipsychotic, a potent selective antagonist of dopamine D2 receptor (D2), prescribed as oral formulations in patients with schizophrenia. Blonanserin transdermal patch was developed to provide a new treatment option, but the corresponding dose to oral blonanserin was not clear. The aims of this study were to clarify the pharmacokinetic (PK)-pharmacodynamic characteristics of blonanserin after transdermal patch application and to evaluate the corresponding dose to oral formulation based on striatal D2 occupancy.MethodsThe relationship between D2 occupancy and plasma blonanserin concentration was analyzed using an Emax model based on data from positron emission tomography study with oral and transdermal blonanserin. D2 occupancy was simulated using Emax models based on the observed plasma concentrations and the simulated plasma concentrations obtained from population PK model.ResultsPlasma blonanserin concentration levels after repeated patch applications were nearly stable throughout the day and no effect of sex, advanced age, or application site was detected. The concentration at half maximal D2 occupancy during transdermal patch applications, 0.857 ng/mL, was higher than that after oral doses, 0.112 ng/mL, suggesting metabolite contribution after oral doses. The median predicted D2 occupancy during blonanserin patch applications at doses of 40 and 80 mg/d was 48.7% and 62.5%, respectively, and the distribution of D2 occupancy at these doses could cover most of that at oral doses of 8 to 24 mg/d.ConclusionsPredicted D2 occupancy suggested that a 40- to 80-mg/d blonanserin transdermal patch dose corresponds to an 8- to 24-mg/d oral dose for the treatment of schizophrenia.

Electrically controlled nicotine delivery through Carbon nanotube membranes via electrochemical oxidation and nanofluidically enhanced electroosmotic flow.

A promising tool for nicotine addiction treatment is a programmable nicotine delivery device coupled to smart phone-assisted behavioral therapies. Key metrics for such a device are delivery of adjustable nicotine doses tailored to individual needs, compact size and power efficiency. Reported here is a detailed optimization of carbon nanotube (CNT) membrane fabrication based on electrochemical oxidation, to improve its electrically driven performance for nicotine fluxes and switching ON (-1.5V)-OFF (0V) flux ratio. ON- state nicotine flux of ~ 6 µmoles/cm2/h at -1.5V applied bias was achieved allowing ~ 6-folds decrease in the size of device (4 cm2) to attain flux equivalent to high dose nicotine gum (1.1 µmoles/cm2/h). Application of + 1.5V bias in OFF state reduced diffusional background flux, giving an ON (-1.5V)/OFF (+ 1.5V) flux ratio of 68 that enabled device to deliver between the highest nicotine gum (1.1 µmoles/cm2/h) and lowest nicotine patch (0.08 µmoles/cm2/h) doses, as well as taper off nicotine doses for long term addiction treatment. The nicotine transport mechanism was studied as a function of pH and applied bias, using neutral tracer molecule, showing a mechanism of both electroosmosis and electrophoresis in the atomically smooth nanofluidic pores of CNTs. Optimal power consumption/flux efficiency of 111(µW/cm2)/µmoles/cm2/h was achieved allowing watch-battery lifetimes of 7-62days for conventional treatment dosing regimens. Bluetooth-enabled, remotely controlled CNT membrane system has potential for treatments of nicotine, opioid and alcohol addictions that needs dose adjustment with precise temporal control.

Achieving Physiologic 17-ẞ-Estradiol Levels in Transgender Females on Estradiol Transdermal Patches and Optimal Dosing

Purpose: Gender dysphoria is defined as a significant incongruence between an individual’s experienced gender and the gender assigned at birth, leading to persistent distress. Hormone therapy and gender affirmation surgery improve gender dysphoria by mitigating or completely removing undesirable primary/secondary sexual characteristics which would better align with one’s physical and psychological features. Maintaining cross-sex hormone levels in the physiologic range for the preferred gender is the basis of transgender hormonal therapy. For trans females (MTF), estradiol is most commonly administered orally, and studies have shown this route is often successful in achieving therapeutic hormone levels. However, there is wide individual variability in the dose response to oral estradiol, and approximately 25% of patients will not reach therapeutic goal on maximum oral estradiol. Furthermore, high dose oral estrogen has been associated with increased thrombotic risk, especially in older individuals. The efficacy or optimal dose of adding or switching to the transdermal route is not known. We investigated the efficacy of estradiol transdermal patches and the optimal dose to reach therapeutic goal. Methods: A chart review was conducted of all MTF patients who were treated with estradiol transdermal patches in our transgender clinic from 2006 through 2020. We looked at the success of achieving physiologic serum 17-β-estradiol levels (with and without antiandrogens spironolactone and finasteride) on various doses of estradiol transdermal patches. Target serum level for estradiol >100 pg/mL is recommended (but may be lower in certain clinical circumstances). Results: 371 MTF patients were identified, 41 received an estradiol transdermal patch. Of these 41 patients, 16 of them were placed on a transdermal patch due to failure to achieve target 17-β-estradiol levels on maximal oral therapy. We found that 9 of these 16 patients achieved goal estrogen levels, as well as one patient very near goal. Of the 7 who did not reach goal, only 2 were on patch doses >60 mcg/day. The majority who reached goal serum estradiol levels were taking a dose of 100 mcg/daily. When considering all MTF patients on the highest dose (100 mcg) of transdermal estrogen, 11 of 18 attained goal level, as well as one just under goal. Of the 41 MTF patients taking a transdermal patch, only 6 of them had serum estrogen levels lowered from being at goal on oral therapy. Thirteen patients had their estrogen levels improve to reach goal when placed on patch (4 as add-on therapy). Conclusions: Our study supports the findings that using an estradiol transdermal patch can help MTF patients achieve goal 17-β-estradiol levels. This delivery method can be useful for patients unable to reach goal on oral agents and for patients at higher thrombotic risk. The highest dose patch available is often needed to achieve therapeutic goal.

Personalized dosing of nicotine replacement therapy versus standard dosing for the treatment of individuals with tobacco dependence: study protocol for a randomized placebo-controlled trial

BackgroundMedications for smoking cessation are currently only effective in helping a minority of smokers quit. Drug development is slow and expensive; as such, there is much interest in optimizing the effectiveness of existing treatments and medications. Current standard doses of nicotine replacement therapy are not effective for many smokers, and in many cases, the amount of nicotine provided is much less than when a smoker is smoking their usual number of cigarettes. The proposed study will test if titrating the dose of the nicotine patch (up to 84 mg) will improve quitting success compared to those receiving a 21-mg nicotine patch with increasing doses of placebo patch.MethodsThis is a multicenter, pragmatic, two-arm, placebo-controlled, block randomized controlled trial. We will recruit participants who smoke at least 10 cigarettes daily and are interested in making a quit attempt. After 2 weeks of usual treatment with a 21-mg patch, participants who fail to quit smoking (target n = 400) will be randomized to receive escalating doses of a nicotine patch vs matching placebo patches for an additional 10 weeks or up to a maximum dose of 84 mg per day. Those who stop smoking during the first 2 weeks of usual treatment will continue with 21 mg patch treatment for 10 weeks and will form an additional comparison arm. In addition to the medication, participants will receive brief behavioral counseling at each study visit. The primary outcome will be biochemically confirmed continuous abstinence from smoking during the last 4 weeks of treatment (weeks 9 to 12).DiscussionResearch evidence supporting the effectiveness of personalized doses of nicotine replacement therapy could change current practice in a variety of healthcare settings. Given the evidence that quitting smoking at any age diminishes the risk of tobacco-related morbidity and mortality, even small increases in absolute quit rates can have a substantial population-level impact on reducing smoking-related disease, mortality rates, and associated healthcare costs.Trial registrationClinicalTrials.gov, NCT03000387. Registered on 22 December 2016.

Different doses, durations and modes of delivery of nicotine replacement therapy for smoking cessation.

Different doses, durations and modes of delivery of nicotine replacement therapy for smoking cessation.

Progressive nicotine patch dosing prior to quitting smoking: feasibility, safety and effects during the pre-quit and post-quit periods.

Nicotine replacement therapy (NRT) may be more effective in aiding smoking cessation if higher doses of nicotine from it can be tolerated. We examined the responses to, and 4-week abstinence rates observed, when titrating the dose of transdermal nicotine patch up to 84mg/day over 4weeks prior to a target quit date and titrating down again over 4weeks afterwards. Clinical cohort study. Tobacco dependence clinic, Mar del Plata, Argentina. Fifty smokers seeking help with stopping smoking. Participants started on one 21-mg/24-hour patch 4weeks prior to their target quit day (TQD). The dose was increased weekly by adding a 21-mg patch unless participants reported adverse effects and/or did not wish to increase the dose. The dose was reduced by 21mg/day each week from 1week post-TQD, until it reverted to the standard dose (21mg/day) at 4weeks post-TQD. Participants received weekly behavioural support and could also use oral NRT from the TQD. Participants were advised to smoke ad libitum during the pre-quit period. Proportion of participants progressing through each stage of dosing, adherence, adverse effects, changes in cigarette consumption, smoke intake and enjoyment of smoking during the pre-quit period; withdrawal symptoms; carbon monoxide-validated abstinence during 4 weeks post-TQD. Of the 50 participants, 72.0% (n=36) progressed to the 84-mg nicotine dose and 94.0% (n=47) completed the trial. Adverse effects consisted primarily of nausea and were mild and well tolerated. Cigarette consumption, smoke intake and enjoyment of smoking declined significantly during the pre-quit period. Forty-one (82%) participants achieved 4weeks validated abstinence. Abstainers experienced no detectable cigarette withdrawal symptoms. Most smokers seeking help with stopping appear to be able to tolerate doses of transdermal nicotine patch up to 84mg/day during a 4-week pre-quit up-titration period with minimal side effects.

A preclinical evaluation of a programmable CNT membrane device for transdermal nicotine delivery in hairless Guinea pigs

Nicotine replacement therapy in the form of transdermal nicotine patches and nicotine gums combined with behavioral counseling still has a low smoking cessation rate of 25%. A promising approach to smoking cessation is to remotely program variable transdermal nicotine delivery rates, with inputs from counselor and patient through a smartphone counseling application. A switchable carbon nanotube (CNT) membrane device has been developed for transdermal nicotine delivery that can be programmed to deliver variable doses matching those of nicotine patches (7, 14 and 21 mg/24 h) and nicotine gums (2 mg /4 mg). The performance of switchable devices was evaluated in vitro on flow-cell geometry and in vivo on the skin of hairless guinea pig (HGP). In vitro, CNT membrane devices successfully switched between therapeutically useful nicotine fluxes of 1.3–1.8 μmoles/cm2/h (ON, −1.5 V) and 0.17–0.23 μmoles/cm2/h (OFF, 0 V), corresponded to the higher doses of gum and nicotine patch fluxes. In vivo, a microdialysis membrane probe was implanted in skin of HGP to directly detect nicotine fluxes through the skin barriers into dialysate with high temporal resolution. The CNT membrane device on HGP skin resulted in an ON/OFF nicotine flux ratio 6.4 ± 2.5 as detected in microdialysis membrane probe in skin. Compared to commercial nicotine patches, the device in ON state was approximately 2–2.4 times the commercial nicotine patch dose as measured by dialysate nicotine fluxes. These results enable smartphone-controlled, battery operated transdermal delivery devices that can be coupled to remote counseling apps for personalized smoking cessation therapy.

Pharmacokinetics, Tolerability, and Bioequivalence of Two Formulations of Rotigotine in Healthy Chinese Subjects

PurposeThe pharmacokinetic (PK) profile of the rotigotine transdermal patch is well characterized in Caucasian patients with Parkinson's disease (PD) but not in Chinese subjects. This article reports the PK variables, safety, and tolerability of the rotigotine transdermal patch (2 mg/24 hours and 4 mg/24 hours cold-chain PR2.1.1 formulation) in healthy Chinese subjects (SP0913; NCT01675024). A second study (PD0011; NCT02070796) evaluated the relative bioavailability of cold-chain (PR2.1.1) and room temperature–stable (PR2.2.1) formulations of rotigotine in healthy Chinese men. MethodsIn treatment period 1 of SP0913, subjects received a single application of rotigotine 2 mg/24 hours on day 1 followed by a washout period (days 2–6); treatment period 2 (days 6–14) involved multiple doses of rotigotine 2 mg/24 hours (days 7–9) followed by multiple doses of rotigotine 4 mg/24 hours (days 10–12), with patches applied for 24 hours each. In PD0011, subjects received a single dose (2 mg/24 hours) of each rotigotine formulation (PR2.2.1 and PR2.1.1) for 24 hours each in a crossover design. Blood samples were collected at scheduled time points to determine rotigotine plasma concentrations. Safety and tolerability were evaluated by adverse events monitoring. ResultsTwenty-four healthy Chinese subjects (12 males, 12 females) were enrolled and completed SP0913. Geometric mean plasma concentrations of unconjugated and total rotigotine increased to a plateau beginning at ∼8 hours (multiple dose) to 16 hours (single dose) postdose; no characteristic Tmax was observed for unconjugated and total rotigotine. The respective geometric mean Cmax, Cmax,ss, AUC from zero up to the last analytically quantifiable concentration, and AUC0–24,ss values for unconjugated and total rotigotine were similar when rotigotine 2 mg/24 hours was applied as a single dose or multiple-dose regimen. During the multiple-dose period, geometric mean Cmax,ss and AUC0–24,ss of both unconjugated and total rotigotine were ∼2-fold higher for rotigotine 4 mg/24 hours than for rotigotine 2 mg/24 hours. Forty-seven of 50 male Chinese subjects completed PD0011. Primary PK parameters for the room temperature–stable formulation of rotigotine were highly comparable to the cold-chain formulation.Common adverse events included application site pruritus, nausea, dizziness, and constipation (SP0913 only), with no clinically significant changes in other safety measures. ImplicationsPK profiles and derived PK parameters of unconjugated and total rotigotine in healthy Chinese subjects were consistent with findings from other ethnic groups receiving single and multiple doses of the rotigotine transdermal patch. Single and repeated daily doses of the rotigotine transdermal patch were well tolerated. Room temperature–stable and cold-chain formulations were bioequivalent. ClinicalTrials.gov identifiers: NCT01675024 and NCT02070796.

Is Fentanyl Patch End-Of-Dose Failure Associated with Body Mass Index? (FR441A)

•Explain to all patients the nature and possibility of end-of-dose failure to patients when initiating therapy with fentanyl transdermal preparations.•Increase screening of patients on using transdermal fentanyl preparations for end-of-dose failure, with particular attention to patients with cancer cachexia. Transdermal fentanyl is widely used for patients with cancer pain requiring a long-acting opioid analgesic. The delivery of fentanyl in this form relies on a drug reservoir forming in subcutaneous fat. The manufacturer-recommended initial dosing frequency is every 72 hours. However, some patients experience “end-of-dose failure” (EDF) with worsening pain after a shorter interval. No studies have examined whether EDF correlates with body mass index (BMI). To assess whether low BMI is associated with prescription of transdermal fentanyl at q48h dosing frequency. All outpatient fentanyl patch prescriptions dispensed between January 1, 2014 and December 31, 2015 at our academic cancer center were extracted using an institutional database. For each prescription patient age, sex, race, patch dose, dosing frequency, and cancer type, as well as height and weight (used to calculate BMI) were collected. A generalized estimating equations (GEE) model was fit to account for correlation within patient and determine association between BMI and patch frequency. A total of 2,750 patients filled 6,569 fentanyl patch prescriptions over the study period. Patients were a median of 60 years old, 56.1% female, and 73.3% white (11.2% African American, 7.2% Asian). The median number of prescriptions per patient was 1 at a median dose of 37. Among 287 underweight patients (BMI<18.5), 34 (11.8%) received at least one q48h fentanyl patch prescription compared with 62 (10.2%) of obese (BMI>30) patients. Patients who received q48h patch had lower BMI (.58 unit decrease; p<0.01) than patients who received the q72h patch. Lower BMI is associated with q48h fentanyl patch dosing, suggesting that it may also be associated with end-of-dose failure in cancer patients. These patients should be closely monitored and alerted to this possibility.

Pharmacokinetics, Pharmacodynamics, and Safety of Rasagiline Transdermal Patch: A Preliminary Study in Healthy Chinese Subjects.

Rasagiline tablet is an oral MAO-B inhibitor applied in early or advanced Parkinson's disease (PD). However, when patients with PD cannot take their usual oral medications, a rasagiline transdermal patch can be used as a way to offer continuous rasagiline while avoiding plasma concentration peaks and troughs. The objectives of this study were to investigate the pharmacokinetics, pharmacodynamics, and safety of the rasagiline transdermal patch in healthy Chinese subjects. This single-dose, open-label, randomized, parallel-group study was conducted in 15 healthy subjects. Fasted subjects received a single dose of rasagiline (either by transdermal patch-1.25 mg/24 h, 1.25 mg/48 h, 2.5 mg/48 h, or 2.5 mg/72 h, or orally-in the form of a 1-mg tablet) and were monitored over a 168-h observation period to assess pharmacokinetics, pharmacodynamics, and safety. After administration of a single-dose rasagiline transdermal patch, the mean terminal elimination half-life (t 1/2) was 6.06-9.41 h, which was longer than with the 1-mg tablet dose (2.32 ± 0.28 h). The mean dose-normalized maximum plasma concentration (C max,norm(dose)) of the 1-mg tablet dose was twofold higher than that of the transdermal patch groups. The mean dose-normalized areas under the concentration-time curve (AUCnorm(dose)) of 1.25 and 2.5 mg for the rasagiline transdermal patch doses were fourfold and sevenfold higher than that of the 1-mg tablet dose, respectively. Cumulative urinary excretion was about 0.2% of the total dose. Inhibition of MAO-B activity was dose dependent, and the maximal inhibition was 73.9-94.1% at doses ranging from 1.25 to 2.5 mg. The reported adverse events were mild or moderate. The prolonged t 1/2, increased AUC0-t , and more stable plasma drug concentration of the rasagiline patch may permit a longer dosing interval compared to the oral tablet. The rasagiline transdermal patch was safe and well tolerated in healthy Chinese subjects.

Pharmacokinetic and Pharmacodynamic Modeling and Simulation Analysis of Icure Donepezil Patch in Healthy Male Volunteers

Donepezil is a well-known reversible noncompetitive acetylcholinesterase inhibitor for the symptomatic treatment of Alzheimer’s disease. The purpose of this study was to characterize the pharmacokinetics of donepezil patch under development using mixed effect modeling analysis, and to expore optimal dosing regimens of the donepezil patch in comparison with donepezil oral formulation. PK data used in this analysis were from 60 Korean, healthy, male subjects in two Phase 1 studies, where all the subjects received single or multiple doses of donepezil patch of 43.75, 87.5, and 175 mg, and 12 of them received single oral dose of donepezil, 10 mg followed by single dose of donepezil patch. Concentrations of donepezil were measured using validated LC/MS-MS. Donepezil PK were analyzed by nonlinear mixed effect modeling implemented in NONMEM (version 7.3). The PK modeling analysis were conducted seqentially for oral formulation and patch, which describes the data of oral formulation compared to simultaneous analysis of both oral and patch formulations. The final model predicted the real, observed concentration data reasonably well. The Monte-Carlo simulation for plasma donepezil concentration predicted that overall, exposure to plasma donepezil is similar between donepezil 10 mg oral dosing every 24 hours and donepezil patch 175 mg every 72 hours, and between donepezil 5 mg oral dosing every 24 hours and donepezil patch 87.5 mg every 72 hours We developed a population PK model describing the plasma PK of donepezil patch formulation and compared it with that of donepzeil oral formulation in healthy Korean adult males. PK simulation based on the final PK model suggested that donepezil 175 mg patch every 72 hours shows similar concentration profile with oral dosing of donepezil 10 mg every 24 hours, and 87.5 mg patch every 72 hours with oral dosing of 5 mg every 24 hours.

Guideline Watch (October 2014): Practice Guideline for the Treatment of Patients With Alzheimer's Disease and Other Dementias.

(Reprinted with permission from American Psychiatric Association, http://psychiatryonline.org/guidelines).

A novel approach in the detoxification of intravenous buprenorphine dependence.

Background:Opioid dependence remains a significant problem in India, and of late intravenous (IV) buprenorphine use has increased in India, especially in combination with antihistamines and benzodiazepines. Its usage has many serious consequences in the form of needle-transmitted hepatitis and HIV, which is showing an increasing trend. Buprenorphine is a partial agonist at μ-opioid receptors. In tablet form (and rarely as IV), it is widely used in the treatment of opioid detoxification. We assessed the safety and efficacy of transdermal patch of buprenorphine with week long duration of action in the treatment of detoxification of IV buprenorphine dependence in view of its many advantages.Materials and Methods:Six consecutive patients with International Classification of Diseases diagnosis of Opioid Dependence Syndrome (IV buprenorphine) were given a buprenorphine patch for treatment of withdrawal symptoms after receiving consent. Severity of opioid dependence was assessed by using Severity of Opioid Dependence Questionnaire on the day of presentation. Subjective and objective rating for opioid withdrawal was done by subjective opiate withdrawal scale (SOWS) and objective opiate withdrawal scale (OOWS) prepatch and postpatch 3rd and 7th day. Buprenorphine side effect checklist was applied on a daily basis.Results:The patients had a mean age of 30 years, of whom 83.3% are males. All were educated and 50% were currently employed. All of them had additional comorbid substance use as well as a comorbid psychiatric diagnosis. Each of them received a patch of varying dosage. The patch dose used initially was based on clinical considerations alone and was fairly adequate in controlling acute withdrawal symptoms. There is a significant improvement in SOWS and OOWS while comparing the baseline (prepatch) with 3rd and 7th day (postpatch) (P ≤ 0.05). None of the patients reported any side effect with the patch.Conclusion:This study shows that transdermal buprenorphine is safe, useful, and clinically effective, and a 7-day application may provide an alternative means of detoxification. However, the result of the study needs to be replicated in a larger sample in a clinical setting, and a control group receiving a conventional mode of treatment needs to be included.

Determination of tulobuterol in rat plasma using a liquid chromatography-tandem mass spectrometry method and its application to a pharmacokinetic study of tulobuterol patch.

A sensitive and accurate liquid chromatography-tandem mass spectrometry (LC-MS/MS) method has been developed and validated for determination of tulobuterol in rat plasma for the first time. Plasma samples were extracted by liquid-liquid extraction method with methyl tert-butyl ether and the analyte and clenbuterol (IS) were separated on a Venusil MP C18 column (100mm×2.1mm, 3μm) using 0.1% formic acid-water-methanol as mobile phase, with a runtime of 5min. The analyte was detected in multiple reaction monitoring (MRM) mode with positive electrospray ionization. Transitions of m/z 228.2→154.0 for tulobuterol and m/z 277.1→203.0 for the clenbuterol were monitored. The linear range was 0.5-100ng/ml (r=0.9967) for tulobuterol with the lower limit of quantitation of 0.5ng/ml. The intra-day and inter-day precisions were less than 10.3% for the analyte and the accuracy was less than -8.6%. The RSD of matrix effect and recovery yield were within ±15% of nominal concentrations and tulobuterol was stable during stability studies. The validated method has been successfully applied to a pharmacokinetic study of three doses of tulobuterol patch in rats for the first time.

Clinical management of tobacco dependence in inpatient psychiatry: provider practices and patient utilization.

This investigation examined predictors of utilization of nicotine replacement therapy (NRT) during a smoke-free psychiatric hospitalization. Smokers (N=324) were recruited from smoke-free adult inpatient psychiatric units. Exploratory analyses examined correlates of NRT provision and utilization. The prevalence of NRT use was 51% overall and was greater among patients offered NRT on admission (58%) versus later (34%), among patients with more severe depression and nicotine withdrawal, and among those who reported perceptions that NRT decreases nicotine withdrawal, provides a nicotine substitute, and helps with quitting smoking (p<.05, all comparisons). Although the ratio of nicotine patch dose to usual cigarettes per day was 1.2±.7, the ratio was negatively correlated with time to first cigarette (Spearman's ρ=-.30, p<.01), suggesting potential underdosing of more dependent smokers. During smoke-free psychiatric hospitalizations, clinical management of nicotine withdrawal may be enhanced by offering patients NRT directly on admission, educating patients on the benefits of NRT, and increasing the dosage for more dependent smokers.

Escalating Doses of Transdermal Nicotine in Heavy Smokers

Fixed-dose nicotine replacement therapy (NRT) is efficacious for smoking cessation in the general population of smokers. However, it is less effective in populations with psychiatric comorbidities and/or severe tobacco dependence where the percent nicotine replacement is suboptimal. The objective of this pilot study was to determine the effectiveness of nicotine patch dose titration in response to continued smoking in heavily dependent smokers with psychiatric comorbidity. In a single-arm, open-label study adult smokers (mean cigarettes per day, 25.4 ± 13.4; range, 14-43; n = 12) willing to quit were treated with escalating doses of transdermal nicotine and brief counseling intervention if they continued to smoke over a 9-week treatment period. Plasma nicotine and cotinine, along with expired carbon monoxide levels, and the subjective effects of smoking, urge to smoke, demand elasticity, and mood symptoms were also assessed. The mean NRT dose was 32.7 (SD, 16.4) mg/d (range, 7-56 mg/d). Smokers reported significant reductions in both cigarettes per day (mean decrease, 18.4 ± 11.5) confirmed by expired carbon monoxide (mean decrease, 13.5 ± 13.0) with no significant changes in plasma nicotine concentrations during the course of NRT dose titration. There were significant effects on the subjective effects of smoking and measures of smoking behavior. Most commonly reported adverse events were respiratory infections, skin irritation at patch site, nausea, and sleep disturbances, which were generally mild and transient. Titrating doses of NRT to effect with brief intervention hold promise as an effective clinical strategy to assist heavily dependent psychiatrically ill smokers to change their smoking behavior.

A case of topical opioid‐induced delirium mistaken as behavioural and psychological symptoms of dementia in demented state

In Japan, indications for opioid analgesics, once exclusively used as pain killers for patients suffering from malignant cancer, have been expanded for a wide range of pain. Herein we report a patient with opioid-induced delirium associated with the administration of buprenorphine patches that was well below the indicated therapeutic range limit. An 82-year-old woman was referred to us from an orthopaedic practitioner for uncontrollable behavioural problems apparently caused by the beginning of dementia; the patient had gradually developed disorientation, visual hallucinations, and delusions. Laboratory and imaging findings excluded common causes of delirium including Alzheimer's disease and diffuse Lewy body disease. Detailed questioning revealed that the patient's confused state appeared following a buprenorphine patch dose increase and subsequently disappeared after administration was stopped. Delirium has not been reported as a side-effect in clinical trials of buprenorphine patches. However, our findings in this case show that even topical opioids can precipitate the development of a delirious state in elderly patients.