MAP-box: a novel, low-cost and easy-to-fabricate 3D-printed box for the storage and transportation of dissolving microneedle array patches.

Research on the use of microarray patches (MAPs) has progressed at an unprecedented rate over the years, leading to the development of many novel drug delivery systems. As the technology approaches patients, there are several key aspects that ought to be addressed in order to facilitate the smooth translation of MAPs from bench to bedside. One integral factor includes the choice of devices and packaging for the storage of MAPs. In the current work, a slide-and-seal box, MAP-box, was developed for the storage of dissolving MAPs, using fused-deposition modelling. The device has been designed to act as a pill-box for MAPs not only to provide protection for MAPs from the environment, but also to improve patient's adherence to treatment. The overall design of the MAP-box was simple, yet offers the capability of sealing and protecting dissolving MAPs up to 30 days. Donepezil HCl was formulated into a dissolvable MAP, which was used to treat dementia related to Alzheimer's disease. This compound was used as a model formulation to evaluate the utility of the 3D printed MAP-box when placed under three storage conditions: 5 °C and ambient humidity, 25 °C and 65% relative humidity and 40 °C and 75% relative humidity. It was shown that the slide-and-seal box was able to confer protection to MAPs for up to 30 days under accelerated stability study conditions as the drug loading, mechanical properties and insertion properties of MAPs remained unaffected when compared to the unpackaged MAPs stored under these same parameters. These preliminary data provide evidence that the MAP-box prototype may be of great utility for the storage of single or multiple MAPs. Nevertheless, future work will be needed to evaluate their patient usability and its application to different types of MAP systems to fully validate the overall robustness of the prototype.

Dissolving microneedle transdermal patch loaded with Risedronate sodium and Ursolic acid bipartite nanotransfersomes to combat osteoporosis: Optimization, characterization, in vitro and ex vivo assessment.

Osteoporosis is a fatal bone-wearing malady and a substantial reason behind the impermanence of human life and economic burden. Risedronate Sodium along with Ursolic acid has been studied to ameliorate osteoporosis. To bypass problems associated with bioavailability, we have developed a microneedle transdermal patch loaded with optimized formulation nanotransfersomes. It was optimized using three factor, three-level Central composite design with independent variables namely, the concentration of phospholipid, surfactant, and sonication time on dependent variables (vesicle size, entrapment efficiency and Polydispersity index). Vesicles of size 271.9 ± 8.45 nm with PDI 0.184 ± 0.01, having entrapment efficiency of 86.12 ± 5.20% and 85.65 ± 4.88% for RIS and UA respectively were observed. In vitro release study showed the sustained release pattern with 78.16 ± 1.12% and 75.72 ± 1.01% release of RIS and UA respectively. Dissolving MN patch prepared from gelatin was found to have good strength and folding endurance with uniform drug content (98.68 ± 0.004%). Ex vivo permeation study revealed that up to 80% of the drug can be permeated within 24 h. CLSM analysis was also performed to show penetration of RU-NTRs. From the results obtained, we can conclude that dissolving MN patch loaded with RU-NTRs has great potential than its conventional counterpart.

Parches transdérmicos anticonceptivos: evaluación de tecnología sanitaria / Contraceptive transdermal patches: health technology assessment

INTRODUCCIÓN: La anticoncepción es un derecho, y es obligación del Estado garantizar el acceso a métodos anticonceptivos efectivos, seguros y de calidad. Se realizó una evaluación de tecnología sanitaria sobre los parches anticonceptivos transdérmicos. MÉTODOS: Un equipo multidisciplinario e independiente designado por el Comité Provincial de Biotecnologías de Neuquén buscó información epidemiológica, regulatoria y evidencias científicas sobre eficacia, seguridad y adherencia. Se analizó y sistematizó siguiendo metodología GRADE (Grading of Recommendations Assessment, Development and Evaluation) y CASPe (Critical Appraisal Skills Programme Español). RESULTADOS: El único parche autorizado en Argentina para su comercialización libera 33,9 µg/día de etinilestradiol y 203 µg/día de norelgestromina. Su prospecto en Argentina, EE.UU. y Europa lo asocia al doble de riesgo de enfermedad tromboembólica venosa si se compara con las píldoras anticonceptivas que provee el Estado. Esto coincide con resultados de estudios de cohortes de alta calidad. Los parches proveen similar eficacia anticonceptiva a corto plazo, pero con altas tasas de abandono en el seguimiento. La Organización Mundial de la Salud no los ha incluido en su listado de medicamentos esenciales. Los parches son más costosos que otros métodos disponibles. DISCUSIÓN: Sobre la base de los principios de beneficencia, no maleficencia, de precaución y de proporcionalidad, no se recomienda la incorporación de parches.(AU)

INTRODUCTION: Contraception is a right, being an obligation of the State to guarantee access to effective, safe and quality contraceptive methods. A health technology assessment was carried out on transdermal contraceptive patches. METHODS: A multidisciplinary and independent team appointed by the Provincial Biotechnology Committee of Neuquén searched for epidemiological and regulatory information and scientific evidence on efficacy, safety and adherence. It was analyzed and systematized following the GRADE (Grading of Recommendations Assessment, Development and Evaluation) and CASPe (Critical Appraisal Skills Programme Español) methodology. RESULTS: The only patch authorized for commercialization in Argentina releases 33.9 µg/day of ethinylestradiol and 203 µg/day of norelgestromin. Its package insert in Argentina, the US and Europe highlights that the risk of venous thromboembolic disease is twice as high compared to the contraceptive pills provided by the State. This is consistent with results from high-quality cohort studies. Patches provide similar short-term contraceptive efficacy, but with high dropout rates at follow-up. The World Health Organization has not included them in its list of essential medicines. Patches are more expensive than other available methods. DISCUSSION: Based on the principles of beneficence, non-maleficence, precaution and proportionality, the incorporation of patches is not recommended.(AU)

Idiopathic Parkinson's Disease at the End of Life: A Retrospective Evaluation of Symptom Prevalence, Pharmacological Symptom Management and Transdermal Rotigotine Dosing.

BACKGROUND: Distressing symptoms are prevalent in patients with idiopathic Parkinson's disease, yet little is known about symptom burden and subsequent pharmacological management at the end of life. Additionally, when oral administration of antiparkinsonian medications is no longer possible in dying patients, it is becoming common place to initiate transdermal rotigotine, despite a paucity of evidence to guide dosing. OBJECTIVES: To assess: (1) symptom prevalence from the use of anticipatory medicines in patients with idiopathic Parkinson's disease, (2) the prescribing of antiparkinsonian medication at the end of life; and (3) the accuracy of conversion from oral antiparkinsonian medicines to transdermal rotigotine and any associations between rotigotine dosing and end-of-life symptoms. METHODS: A retrospective case review was performed. One hundred consecutive patients with idiopathic Parkinson's disease who died during an inpatient admission at a UK teaching hospital were assessed. RESULTS: The most prevalent terminal symptoms were excess respiratory secretions (58%), pain (52%), agitation (51%) and fever (23%). The majority of patients were converted to transdermal rotigotine (90%). Patients converted to a higher than equivalent dose of rotigotine were more likely to be agitated (p < 0.05), whilst those converted to a lower than equivalent dose were less likely to develop excess respiratory secretions (p < 0.05). The prevalence of pain did not differ according to rotigotine dosing. CONCLUSIONS: This study highlights for the first time use of anticipatory medications at the end of life in patients with idiopathic Parkinson's disease and the prevalence of terminal symptoms. It also demonstrates the widespread use of rotigotine patches, and that lower than equivalent doses may be better tolerated.

Assessment of Drug Delivery Kinetics to Epidermal Targets In Vivo.

It has proven challenging to quantify 'drug input' from a formulation to the viable skin because the epidermal and dermal targets of topically applied drugs are difficult, if not impossible, to access in vivo. Defining the drug input function to the viable skin with a straightforward and practical experimental approach would enable a key component of dermal pharmacokinetics to be characterised. It has been hypothesised that measuring drug uptake into and clearance from the stratum corneum (SC) by tape-stripping allows estimation of a topical drug's input function into the viable tissue. This study aimed to test this idea by determining the input of nicotine and lidocaine into the viable skin, following the application of commercialised transdermal patches to healthy human volunteers. The known input rates of these delivery systems were used to validate and assess the results from the tape-stripping protocol. The drug input rates from in vivo tape-stripping agreed well with the claimed delivery rates of the patches. The experimental approach was then used to determine the input of lidocaine from a marketed cream, a typical topical product for which the amount of drug absorbed has not been well-characterised. A significantly higher delivery of lidocaine from the cream than from the patch was found. The different input rates between drugs and formulations in vivo were confirmed qualitatively and quantitatively in vitro in conventional diffusion cells using dermatomed abdominal pig skin.

Assessment of Immune Responses in an Animal Model of Wheat Food Allergy via Epicutaneous Sensitization.

Wheat allergy is a pathological event involving immunocompetent cells against ingested wheat allergen and is clearly associated with transdermal sensitization. However, the molecular mechanisms involved in the disease etiology are not completely understood. A complex cellular and tissue network linking to food allergy makes it difficult to understand the molecular mechanism of allergenicity. Animal models are valuable tools to deduce basic principles of human disease without invasive intervention trials. A mouse model of wheat allergy has provided insights into effects of skin exposure to wheat protein; it is a plausible route of human sensitization for wheat anaphylaxis. Further investigation of this model will capture the essential occurrence and flow of events, bringing useful clues to develop effective treatment and control strategies against wheat allergy. Here, we describe a method for analyzing the expression of cell surface molecules in single cells isolated from lymphoid tissue with flow cytometry. Sensitization by wheat extracts significantly increases antigen-specific T cells in the spleen. Collecting information regarding the contribution of immune cells to allergic sensitization in the development of wheat allergy would be useful in preventing and treating food allergies.

Capsaicin 8% dermal patch in clinical practice: an expert opinion.

INTRODUCTION: Neuropathic pain (NP) is caused by a lesion or disease of the somatosensory system, which can severely impact patients' quality of life. The current-approved treatments for NP comprise of both centrally acting agents and topical drugs, including capsaicin 8% dermal patches, which is approved for the treatment of peripheral NP. AREAS COVERED: The authors summarize literature data regarding capsaicin use in patients who suffer from NP and discuss the clinical applications of this topical approach. EXPERT OPINION: Overall, the capsaicin 8% dermal patch is as effective in reducing pain intensity as other centrally active agents (i.e. pregabalin). Some studies have also reported fewer systemic side effects, a faster onset of action and superior treatment satisfaction compared with systemic agents. In our opinion, capsaicin 8% dermal patches also present additional advantages, such as a good systemic tolerability, the scarcity of adverse events, the possibility to combine it with other agents, and a good cost-effective profile. It is important to note that, as the mechanism of action of capsaicin 8% is the 'defunctionalization' of small afferent fibers through interaction with TRPV1 receptors, the peripheral expression of this receptor on nociceptor fibers, is crucial to predict patient's response to treatment.

Insurance coverage and utilization of nicotine patches after receipt of a prescription.

Introduction: Changes in reimbursement policy have made nicotine replacement therapy (NRT) much more available, but little is known about what happens to patients after they receive their prescription. This study describes rates of successfully filling prescriptions for NRT and its association with type of insurance. Methods: We identified 224 patients who received a prescription for NRT during an outpatient visit to an academic medical center between January 1st 2016 and February 10th 2017. We conducted telephone surveys to assess whether they tried to fill their prescriptions and if so, determine the effects of insurance type on the ability to successfully fill the prescription. Results: Of 117 patients completing the survey, 23 (19.6%) did not attempt to fill and 6 (5.1%) had no insurance. Of the 90 patients with insurance who attempted to fill their prescription, 67 (74.4%) were successful and 23 (25.6%) were unsuccessful in obtaining medications. Success varied by insurance with successful fills ranging from 34 (87.2%) of those with commercial insurance, 24 (70.6%) with Medicaid, to 9 (52.9%) with Medicare. Of 37 participants living with another smoker, 31 (83.7%) wanted an NRT prescription specifically for their partner; several volunteered that they had shared patches with their partner. Conclusions: Despite widespread coverage for NRT, many patients may still encounter difficulties in getting their prescriptions filled. Some tobacco users might also benefit from getting NRT prescriptions for their partners that smoke.

Patch Pumps: Are They All the Same?

Insulin pumps are used by a steadily increasing number of patients with diabetes. Avoiding certain disadvantages of conventional pumps (ie, the insulin infusion set) might make pump therapy even more attractive. Patch pumps are usually attached by means of an adhesive layer to the skin and have several additional advantages (smaller, more discrete, easier to use, and cheaper than conventional insulin pumps). This review provides a general overview of patch pumps, the technologies used, basic clinical requirements, why a number of developments failed, which clinical studies are needed to provide sufficient evidence for their usage, which costs are associated, what the patient preferences are (which might differ between certain patient groups), and what is the future of patch pumps (ie, artificial pancreas systems).

A population-based study of transdermal fentanyl initiation in Australian clinical practice.

PURPOSE: Although guidelines caution against initiation of transdermal (TD) fentanyl among those who are opioid naïve, there is concern that not all people receive adequate prior opioid exposure. This study examined the percentage of people who are opioid naïve at the time of TD fentanyl initiation in Australia; strengths initiated; and characteristics associated with being opioid naïve. METHODS: This is a national retrospective cohort study derived from a 10% sample of Pharmaceutical Benefits Scheme concessional beneficiaries initiating TD fentanyl between 29 September 2009-31 December 2013. Individuals were deemed opioid naïve if they had no opioid dispensings in the previous 90 days. Logistic regression was used to determine characteristics associated with being opioid naïve, including socio-demographics, likely comorbidities and previous analgesic use. RESULTS: A total of 13,166 people initiated TD fentanyl; 60.4% were female and 76.2% were aged ≥ 65 years. Three in ten (30.4%) were opioid naïve and 63.2% initiated the 12 mcg/h patch. Those who were opioid naïve were more likely to be female (adjusted odds ratio (aOR) 1.35; 95% CI 1.25-1.46), older (aOR 1.85; 95% CI 1.54-2.28 for those ≥ 85 years) and previously dispensed medicines for dementia (aOR 1.37; 95% CI 1.04-1.80). People previously dispensed medicines for cancer were less likely to be opioid naïve (aOR 0.57; 95% CI 0.48-0.67). CONCLUSIONS: Three in ten Australians initiating TD fentanyl are opioid naïve. Our findings suggest that specific patient sub-populations already at increased risk of opioid-related adverse events are not receiving prior opioid treatment before initiation, highlighting the need for greater adherence to current treatment guidelines.

Assessment of prior opioid tolerance among new users of fentanyl transdermal system in FDA's Sentinel System.

PURPOSE: Fentanyl transdermal system (FTS) is intended only for patients with prior opioid tolerance. The purpose of this study is to identify the proportion of new FTS users who had evidence of prior opioid tolerance, by dosage strength, in FDA's Sentinel System. METHODS: We identified new FTS episodes (183-day washout) from 2009 through 2013. Members were <65 years and enrolled in medical and pharmacy coverage for 183 days prior to initial FTS dispensing (index). We assessed the proportion of users with prior tolerance stratified by dosage strength of FTS using four definitions of opioid tolerance: ≥30-mg oxycodone equivalents/day in each of 7 consecutive days immediately prior to index; ≥30-mg oxycodone equivalents/day for any 7 days in the 30 days prior to index (secondary); any dose in each of 7 days in the 7 consecutive days immediately prior to index (tertiary); and any dose for any 7 days in the 30 days prior to index (quaternary). RESULTS: Of 44 450 episodes of 25 mcg/hr FTS, 37% met the primary definition, and 77% met the quaternary definition. Of 3507 episodes of 100 mcg/hr FTS, 57% and 74% met the primary and quaternary definitions, respectively. Those aged 25 to 34 years had the highest proportion of episodes with prior tolerance; those aged 55 to 64 accounted for more of the episodes overall. CONCLUSIONS: In Sentinel, many new users of FTS did not have evidence of prior opioid tolerance by the primary definition, ie, the product label definition, which is the minimum standard for the lowest FTS dose (12 mcg/hr), especially at the highest strength (100 mcg/hr). Validation of this metric is warranted, but our findings suggest the need for further prescriber education regarding appropriate prescribing of FTS.

Dosimetry of indigenously developed 177Lu patch source for surface brachytherapy-Experimental and Monte Carlo methods.

This paper describes the evaluation of dosimetry characteristics of an in-house developed 177Lu skin patch source for treatment of non-melanoma skin cancer. A 177Lu skin patch source based on Nafion-115 membrane backbone containing 3.46 ± 0.01 mCi of activity was used. Activity measurement of the patch source was based on gamma ray spectrometry using a HPGe detector. The efficiencies of the HPGe detector were fitted using an orthogonal polynomial function. The absorbed dose rate to water at 5 µm depth in water was determined using an extrapolation chamber, EBT3 Gafchromic film and compared with Monte Carlo methods. The correction factors such as Bragg-Gray stopping power ratio of water-to-air and chamber wall material being different from water, needed to be applied on measurements for establishing the dose rate at 5 µm depth, were calculated using the Monte Carlo method. Absorbed dose rate at 5 µm depth in water (surface dose rate) measured using an extrapolation chamber and EBT3 Gafchromic film were 9.9 ± 0.7 and 8.2 ± 0.1 Gy h-1 mCi-1 respectively for the source activity of 3.46 ± 0.01 mCi. The surface dose rate calculated using the Monte Carlo method was 8.7 ± 0.2 Gy h-1 mCi-1, which agrees reasonably well with measurement. The measured dose rate per mCi offers scope for ascertaining treatment time required to deliver the dose for propitious therapeutic outcome. Additionally, on-axis depth dose and lateral dose profiles at 5 µm and 1 mm depth in water phantom were also calculated using the Monte Carlo method.

The potential effects of introducing microneedle patch vaccines into routine vaccine supply chains.

BACKGROUND: Microneedle patch (MNP) technology is designed to simplify the process of vaccine administration; however, depending on its characteristics, MNP technology may provide additional benefits beyond the point-of-use, particularly for vaccine supply chains. METHODS: Using the HERMES modeling software, we examined replacing four routine vaccines - Measles-containing vaccine (MCV), Tetanus toxoid (TT), Rotavirus (Rota) and Pentavalent (Penta) - with MNP versions in the routine vaccine supply chains of Benin, Bihar (India), and Mozambique. RESULTS: Replacing MCV with an MNP (5 cm3-per-dose, 2-month thermostability, current single-dose price-per-dose) improved MCV availability by 13%, 1% and 6% in Benin, Bihar and Mozambique, respectively, and total vaccine availability by 1% in Benin and Mozambique, while increasing the total cost per dose administered by $0.07 in Benin, $0.56 in Bihar and $0.11 in Mozambique. Replacing TT with an MNP improved TT and total vaccine availability (3% and <1%) in Mozambique only, when the patch was 5 cm3 and 2-months thermostable but increased total cost per dose administered by $0.14. Replacing Rota with an MNP (at 5-15 cm3-per-dose, 1-2 month thermostable) improved Rota and total vaccine availability, but only improved Rota vaccine availability in Bihar (at 5 cm3, 1-2 months thermostable), while decreasing total vaccine availability by 1%. Finally, replacing Penta with an MNP (at 5 cm3, 2-months thermostable) improved Penta vaccine availability by 1-8% and total availability by <1-9%. CONCLUSIONS: An MNP for MCV, TT, Rota, or Penta would need to have a smaller or equal volume-per-dose than existing vaccine formulations and be able to be stored outside the cold chain for a continuous period of at least two months to provide additional benefits to all three supply chains under modeled conditions.

Bioequivalence assessment of tulobuterol transdermal delivery system in healthy subjects
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OBJECTIVE: The purpose of this study was to evaluate the bioequivalence in the pharmacokinetics of two 2-mg tulobuterol transdermal delivery systems (TDSs) in healthy subjects. MATERIALS AND METHODS: The pharmacokinetic (PK) analysis was performed using data from a randomized, open-label, single-dose, two-way, two-period, crossover study. Eligible subjects received either the Bretol®patch (test drug) or Hokunalin®patch (reference drug) in sequence according to their allocated group. Serial blood samples for PK analyses were collected for up to 48 hours after tulobuterol TDS application. The PK parameters, including the maximum concentration (Cmax) and area under the curve from time zero to the last quantifiable concentration time (AUClast), were estimated by using noncompartmental analysis. The geometric mean ratios (GMRs) of the Cmax and AUClast and their 90% confidence intervals (CIs) were estimated. RESULTS: A total of 27 subjects completed the study as planned. The concentration-time profiles of tulobuterol were similar in both formulations. The GMRs (90% CIs) of Cmax and AUClast were 0.9443 (0.8790 - 1.0144) and 0.9600 (0.8660 - 1.0642), respectively. CONCLUSION: The PK profiles of both tulobuterol TDSs were comparable. In addition, the 90% CIs of the GMR were within the bioequivalence criteria of 0.800 - 1.250. Therefore, the Bretol®patch can be used as an alternative to the Hokunalin®patch for the treatment of patients with asthma and chronic obstructive pulmonary disease.
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Development of a daphnetin transdermal patch using chemical enhancer strategy: insights of the enhancement effect of Transcutol P and the assessment of pharmacodynamics.

OBJECTIVE: The aim of this study was to develop a drug-in-adhesive patch for transdermal delivery of daphnetin (DA), which is a coumarin derivative in Girald Daphne, and to investigate the role of Transcutol P (TP) in the release and percutaneous permeation processes of DA. METHODS: Backing films, permeation enhancers and enhancer content in the transdermal patch were investigated through in vitro experiments using rat skin. Anti-inflammatory and analgesic effects of the optimized formulation were evaluated using the adjuvant arthritis model and the pain model induced by acetic acid, respectively. In addition, the enhancement effect of TP was investigated using differential scanning calorimetry (DSC), FTIR, and molecular dynamic simulation. RESULTS: The optimal formulation, composed of DURO-TAK® 87-2852, CoTranTM 9680, 1% DA, and 10% TP showed anti-inflammatory and analgesic effects. It was found that TP only promoted the release process of DA from its transdermal patch. Furthermore, the decrease of interaction between drug and pressure sensitive adhesive (PSA) as well as the improvement of PSA mobility due to TP addition were the main factors that enhanced the release of DA from patch. CONCLUSIONS: This study successfully used TP to develop a DA patch with good anti-inflammatory and analgesic effects, proving that TP promotes the release of DA by reducing the interaction between DA and PSA and increasing the mobility of PSA.

A nationwide study of the extent and factors associated with fentanyl use in Australia.

OBJECTIVE: To examine fentanyl utilisation in the Australian community and determine the geographic and socio-demographic factors associated with higher rates of fentanyl utilisation. METHODS: National sales data (supplied by IMS Health) were used to estimate fentanyl utilisation (in pack sales and milligrams) in Australia during 2013, mapped to Australian Bureau of Statistics (ABS) Statistical Local Areas (SLAs) and Remoteness Areas. Socio-demographic characteristics and total population estimates of SLAs were obtained from the ABS. SLA-level data on sex, age distribution, income, occupations involving physical labour and number of pharmacies, were included in linear regression analyses to examine their association with fentanyl use. RESULTS: An estimated 12.3 kg (or 859,518 packs) of fentanyl was sold across Australia in 2013, equating to an average of 0.55 mg/person over the year. Transdermal patches accounted for the majority (99%; 850,923 packs) of fentanyl sales. South Australia had the highest rate of utilisation per person. Rates of fentanyl utilisation were higher among more remote areas in three jurisdictions. Overall, higher utilisation rates were observed in SLAs that were less populated (ß 0.12; p < 0.001) and those with a higher proportion of older people (ß 0.12; p < 0.001), low-income households (ß 0.12; p < 0.001) and people working in jobs requiring physical labour (ß 0.08; p < 0.05). CONCLUSIONS: Transdermal fentanyl patches account for the majority of fentanyl utilisation in the Australian community. There is marked variation in fentanyl utilisation across geographic areas, with higher use apparent in areas with a higher proportion of older people and indicators of greater socio-economic disadvantage.

Tobacco dependence treatment in the emergency department: A randomized trial using the Multiphase Optimization Strategy.

BACKGROUND: Tobacco dependence remains the leading preventable cause of death in the developed world. Smokers are disproportionately from lower socioeconomic groups, and may use the hospital emergency department (ED) as an important source of care. A recent clinical trial demonstrated the efficacy of a multicomponent intervention to help smokers quit, but the independent contributions of those components is unknown. METHODS: This is a full-factorial (16-arm) randomized trial in a busy hospital ED of 4 tobacco dependence interventions: brief motivational interviewing, nicotine replacement therapy, referral to a telephone quitline, and a texting program. The trial utilizes the Multiphase Optimization Strategy (MOST) and a novel mixed methods analytic design to assess clinical efficacy, cost effectiveness, and qualitative participant feedback. The primary endpoint is tobacco abstinence at 3months, verified by participants' exhaled carbon monoxide. RESULTS: Study enrollment began in February 2017. As of April 2017, 52 of 1056 planned participants (4.9%) were enrolled. Telephone-based semi-structured participant interviews and in-person biochemical verification of smoking abstinence are completed at the 3-month follow-up. Efficacy and cost effectiveness analyses will be conducted after follow-up is completed. DISCUSSION: The goal of this study is to identify a clinically efficacious, cost-effective intervention package for the initial treatment of tobacco dependence in ED patients. The efficacy of this combination can then be tested in a subsequent confirmatory trial. Our approach incorporates qualitative feedback from study participants in evaluating which intervention components will be tested in the future trial. TRIAL REGISTRATION: Trial (NCT02896400) registered in ClinicalTrials.gov on September 6, 2016.

Eficacia y seguridad del uso de buprenorfina parche transdérmico en pacientes con dolor neuropático / Efficacy and safety of the use of buprenorphine transdermal patch in patients with neuropathic pain

INTRODUCCIÓN: El presente dictamen expone la evaluación de tecnología de la eficacia y seguridad del uso de buprenorfina 35mcg/hr parche transdérmico para el tratamiento del dolor neuropático. El dolor neuropático es consecuencia de un "daño" al sistema somato sensorial, que puede ocurrir por una variedad de etiologías entre las que se encuentran traumatismo vertebro medular, neuropatía diabética, neuralgia post-herpética, neuropatía post-quirúrgica, radiculopatía lumbar, dolor neuropático asociado a cáncer, neuropatía relacionada al virus de inmunodeficiencia humana, dolor fantasma, neuralgia del trigémino, entre otros. A nivel global, la prevalencia del dolor neuropático oscila entre 7% y 10% en población general. El dolor neuropático posee particularidades que implican un desafío para su manejo. Así, éste puede desencadenarse por algún estímulo sensorial o producirse espontáneamente; también puede presentar variaciones de acuerdo al tipo de paciente y la condición específica de fondo, debido a los diferentes mecanismos que operan en cada individuo. Todo ello, dificulta la elección del analgésico, por lo que existe más de un algoritmo de tratamiento para el dolor neuropático, que incluye el uso de medicamentos antiepilépticos, antidepresivos y opioides. En EsSalud, se dispone de medicamentos antiepilépticos y antidepresivos para el tratamiento del dolor neuropático como gabapentina y amitriptilina, entre otros. En caso de requerir el uso de opioides para el control del dolor neuropático se cuenta con tramadol y en el caso de dolor neuropático oncológico, se cuenta además con oxicodona y morfina. Sin embargo, los pacientes que suscitaron la solicitud de uso de buprenorfina transdérmica a ser evaluada en el presente dictamen, poseen condiciones clínicas particulares que dificultan el uso de las opciones de tratamiento incluidas actualmente en el Petitorio Farmacológico de la institución. Por lo que, existe la necesidad de contar con una alternativa eficaz y segura, dentro del grupo de medicamentos opioides, para el tratamiento del dolor neuropático en dicho grupo de pacientes. METODOLOGÍA: Se realizó una búsqueda de la literatura con respecto a la eficacia y seguridad de buprenorfina en parche transdérmico para el dolor neuropático. La búsqueda se inició revisando la información sobre el uso del medicamento de acuerdo con entidades reguladoras como la Food and Drug Administration (FDA), la European Medicines Agency (EMA) y la Dirección General de Medicamentos y Drogas (DIGEMID). Posteriormente, se revisaron las bases de datos de PubMed, TRIPDATABASE y www.clinicaltrials.gov. Adicionalmente, se realizó una búsqueda de evaluaciones de tecnologías y guías de práctica clínica en las páginas web de grupos dedicados a la investigación y educación en salud en general como The National Institute for Health and Care Excellence (NICE). RESULTADOS: De acuerdo con la pregunta PICO, se llevó a cabo una búsqueda de evidencia científica relacionada al uso de buprenorfina transdérmica para el tratamiento de dolor neuropático. En la presente sinopsis se describe la evidencia disponible. CONCLUSIONES: El presente dictamen tuvo como objetivo evaluar la eficacia y seguridad del uso de buprenorfina transdérmica en parches para el tratamiento del dolor neuropático. Como parte de la evaluación se prestó especial atención a los pacientes con enfermedad renal crónica concomitante o que no tienen una vía de administración alternativa para el medicamento analgésico. De acuerdo a lo revisado, no hay evidencia disponible que sugiera que la buprenorfina transdérmica sea más eficaz, comparado con otras opciones de tratamiento incluidas en el Petitorio Farmacológico de EsSalud, para el tratamiento del dolor neuropático. Sin embargo, existe alguna evidencia del uso de buprenorfina transdérmica en pacientes que presentan eventos adversos, los cuales llevan a la suspensión o disminución de la dosis del opioide, o que presentan pobre acceso a la vía de administración del medicamento analgésico, condiciones que incluyen a la insuficiencia renal concomitante y dificultad para otras vías de administración (i.e. vía oral, vía de acceso para bloqueo neural). Así, dentro de la búsqueda realizada se identificó un estudio observacional que evaluó el uso de buprenorfina transdérmica para dolor neuropático, publicado por Filitz et al. Adicionalmente, también se identificó evidencia indirecta en torno al uso de buprenorfina transdérmica en pacientes que presentan dificultad para otras vías de administración. Esta evidencia proviene de dos guías de práctica clínica en pacientes con dolor oncológico, las guías de Scottish Intercollegiate Guidelines Network del 2013 y la guía de European Society for Medical Oncology 2012. Asimismo, debido a la escasez de evidencia científica sólida proveniente de ensayos clínicos aleatorizados y controlados; se incluyó también la opinión de expertos, cuya opinión se condice con la evidencia encontrada. En conclusión, la evidencia encontrada en torno a la eficacia y seguridad del uso de buprenorfina transdérmica como opción de analgésico para pacientes con dolor neuropático no ha probado que este sea más eficaz que otros tratamientos analgésicos actualmente aprobados en el Petitorio Farmacológico de la institución. Sin embargo, existe un grupo de pacientes, los cuales presentan insuficiencia renal concomitante o dificultan para otras vías de administración que requieren una alternativa de analgésico distinta. La evidencia de uso de buprenorfina transdérmica en estos pacientes proviene de estudios observacionales o evidencia indirecta, que de acorde con la opinión de expertos supondría una opción de tratamiento valida. Por lo expuesto, el Instituto de Evaluación de Tecnologías en Salud e Investigación- IETSI, aprueba el uso de buprenorfina transdérmica en pacientes con dolor neuropático que presentan insuficiencia renal concomitante o dificultad para otras vías de administración, y que por lo tanto no puedan utilizar las alterativas incluidas en el Petitorio Farmacológico de EsSalud; según lo establecido en el Anexo N° 1. La vigencia del presente dictamen preliminar es de un año, la continuación de dicha aprobación estará sujeta a los resultados obtenidos de los pacientes que se beneficien con dicho tratamiento y a nueva evidencia que poda surgir en el tiempo.

Assessment of a novel transdermal selective ß1-blocker, the bisoprolol patch, for treating frequent premature ventricular contractions in patients without structural heart disease.

BACKGROUND: The autonomic nervous system involves the genesis of premature ventricular contractions (PVCs). Previous studies demonstrated that heart rate (HR) dependency of idiopathic PVCs has different autonomic mechanisms. Recently, the bisoprolol patch, a novel transdermal ß1-blocker formulation containing bisoprolol, became clinically available. We examined the efficacy of the bisoprolol patch for treating frequent PVCs in patients without structural heart disease (SHD) regarding the HR dependency of PVCs. METHODS: This prospective study included 44 consecutive patients without SHD (25 men, mean age, 63.6±12.3 years) with PVC counts≥3000 beats as measured by 24-hour Holter electrocardiograms (ECGs). PVCs were divided into positive HR-dependent PVCs (P-PVCs) and non-positive HR-dependent PVCs (NP-PVCs) based on the relationship between the hourly PVC density and hourly mean HR. A bisoprolol patch was administered once daily at a dose of 4mg. The 24-hour Holter ECGs were performed before and 1 month after the initiation of the therapy. RESULTS: In 44 patients, there were 24 P-PVCs and 20 NP-PVCs. The bisoprolol patch reduced the PVC count significantly (from 16,563±10,056 to 7892±8817 beats/24hours, p<0.001) in the P-PVC group, while the PVC count did not change significantly (from 16,409±9571 to 13,476±12,191beats/24hours, p=0.34) in the NP-PVC group. Moreover, in the P-PVC group, the patients with mean HRs ≥80 beats/minute had a significantly higher percent improvement in the PVC count than those with mean HRs <80 beats/minute (p=0.0080). The bisoprolol patch resulted in a significant reduction in the PVC count from baseline during each time period for the changes within a 24-hour period in the P-PVC group. CONCLUSIONS: The transdermal bisoprolol patch was effective for a PVC reduction in patients with P-PVCs, particularly in those with faster mean HRs. Furthermore, it demonstrated a stable PVC-reducing effect during the 24-hour period in the P-PVC group.