A Comparative Study of the Antiemetic Effects of α2-Adrenergic Receptor Agonists Clonidine and Dexmedetomidine against Diverse Emetogens in the Least Shrew (Cryptotis parva) Model of Emesis.

In contrast to cats and dogs, here we report that the α2-adrenergic receptor antagonist yohimbine is emetic and corresponding agonists clonidine and dexmedetomidine behave as antiemetics in the least shrew model of vomiting. Yohimbine (0, 0.5, 0.75, 1, 1.5, 2, and 3 mg/kg, i.p.) caused vomiting in shrews in a bell-shaped and dose-dependent manner, with a maximum frequency (0.85 ± 0.22) at 1 mg/kg, which was accompanied by a key central contribution as indicated by increased expression of c-fos, serotonin and substance P release in the shrew brainstem emetic nuclei. Our comparative study in shrews demonstrates that clonidine (0, 0.1, 1, 5, and 10 mg/kg, i.p.) and dexmedetomidine (0, 0.01, 0.05, and 0.1 mg/kg, i.p.) not only suppress yohimbine (1 mg/kg, i.p.)-evoked vomiting in a dose-dependent manner, but also display broad-spectrum antiemetic effects against diverse well-known emetogens, including 2-Methyl-5-HT, GR73632, McN-A-343, quinpirole, FPL64176, SR141716A, thapsigargin, rolipram, and ZD7288. The antiemetic inhibitory ID50 values of dexmedetomidine against the evoked emetogens are much lower than those of clonidine. At its antiemetic doses, clonidine decreased shrews' locomotor activity parameters (distance moved and rearing), whereas dexmedetomidine did not do so. The results suggest that dexmedetomidine represents a better candidate for antiemetic potential with advantages over clonidine.

Case of tizanidine withdrawal showing hallucination, decorticate posture and tremor, with hypersympathetic vital signs.

Tizanidine, an α2-adrenergic receptor agonist commonly prescribed as a muscle relaxant, has been associated with limited cases of acute intoxication or withdrawal. Here, we present a case of tizanidine withdrawal in a woman in her 40s who presented with an unusual combination of systemic and neurological symptoms. These included hallucinations, decorticate posture, limb and eyelid tremors, along with hypertension, tachycardia and tachypnoea. The diagnosis of tizanidine withdrawal was established by a comprehensive assessment of the patient's medical history and the systematic exclusion of other potential diseases. Our approach to managing the withdrawal symptoms was to initiate symptomatic treatment with a combination of a beta-blocker and a calcium channel blocker. Remarkably, this intervention successfully resolved both vital signs and neurological manifestations by the following day. In conclusion, tizanidine withdrawal is associated with a distinct and diagnostically significant neurological syndrome characterised by hallucinations, decorticate posture, tremors and hypersympathetic vital signs.

Diarrhoea of unknown cause: medical treatment in a stepwise mannerManagement of Idiopathic Diarrhoea Based on Experience of Step-Up Medical Treatment.

The basic principle for the treatment of idiopathic diarrhoea (functional diarrhoea K59.1) is to delay transit through the gut in order to promote the absorption of electrolytes and water. Under mild conditions, bulking agents may suffice. With increasing severity, antidiarrhoeal pharmaceuticals may be added in a stepwise manner. In diarrhoea of unknown aetiology, peripherally-acting opioid receptor agonists, such as loperamide, are first-line treatment and forms the pharmaceutical basis of antidiarrheal treatment. As second-line treatment opium drops have an approved indication for severe diarrhoea when other treatment options fail. Beyond this, various treatment options are built on experience with more advanced treatments using clonidine, octreotide, as well as GLP-1 and GLP-2 analogs which require specialist knowledge the field.

Chronic diarrhoea without an established cause is common.There are a small number of clinical trials, often with a limited number of patients or healthy volunteers.Treatment is often carried out on a trial-and-error basis, with considerable variation in the choice of treatment.There is a paucity of guidelines, and there is a gap in knowledge concerning treatment goals, such as the frequency, consistency and form of stool.The stepwise approach to the treatment of chronic idiopathic diarrhoea described in this article is based on clinical knowledge and experience.

Low dose lofexidine for medically directed outpatient opioid tapering in adults with chronic pain: a prospective case series.

BACKGROUND: In adults with chronic pain, mild-to-moderate withdrawal symptoms during medically directed opioid tapering in the outpatient setting may not be accompanied by hypertension or tachycardia. This clinical scenario could limit the use of lofexidine at dosages reported in clinical trials of opioid withdrawal precipitated by abrupt opioid discontinuation. Thus, the primary aim of this prospective case series is to describe the use of low dose lofexidine for opioid withdrawal in patients with chronic pain undergoing medically directed opioid tapering in an outpatient setting. METHODS: Six patients (white 5, Latino 1) admitted to an outpatient interdisciplinary pain rehabilitation program met inclusion and exclusion criteria. Patients self-selected to undergo medically directed opioid tapering, and the medication the patients were prescribed upon admission was used in the taper schedule. Upon initiation of the opioid taper, patients received 0.18 mg of lofexidine every 6 hours. RESULTS: Five of the six patients were women, and the median morphine milligram equivalents at baseline were 36.9. The median taper duration was 15 days, and the median duration of lofexidine administration was 14 days. Withdrawal scores were mild throughout the taper in four patients, and two patients with fibromyalgia experienced single episodes of moderately severe withdrawal symptoms at the median morphine milligram equivalent midpoint of the taper. No hypotension or sustained bradycardia were observed, and no adverse effects related to lofexidine were reported. CONCLUSION: The observations from this prospective case series suggest that low-dose lofexidine may be a feasible adjunct medication to attenuate withdrawal symptoms in adults with chronic pain undergoing outpatient opioid tapering.

An isocratic RP-HPLC-UV method for simultaneous quantification of tizanidine and lidocaine: application to in vitro release studies of a subcutaneous implant.

Implantable devices have been widely investigated to improve the treatment of multiple diseases. Even with low drug loadings, these devices can achieve effective delivery and increase patient compliance by minimizing potential side effects, consequently enhancing the quality of life of the patients. Moreover, multi-drug products are emerging in the pharmaceutical field, capable of treating more than one ailment concurrently. Therefore, a simple analytical method is essential for detecting and quantifying different analytes used in formulation development and evaluation. Here, we present, for the first time, an isocratic method for tizanidine hydrochloride (TZ) and lidocaine (LD) loaded into a subcutaneous implant, utilizing reversed-phase high-performance liquid chromatography (RP-HPLC) coupled with a UV detector. These implants have the potential to treat muscular spasticity while providing pain relief for several days after implantation. Chromatographic separation of the two drugs was accomplished using a C18 column, with a mobile phase consisting of 0.1% TFA in water and MeOH in a 58 : 42 ratio, flowing at 0.7 ml min-1. The method exhibited specificity and robustness, providing accurate and precise results. It displayed linearity within the range of 0.79 to 100 µg ml-1, with an R2 value of 1 for the simultaneous analysis of TZ and LD. The developed method demonstrated selectivity, offering limits of detection and quantification of 0.16 and 0.49 µg ml-1 for TZ, and 0.30 and 0.93 µg ml-1 for LD, respectively. Furthermore, the solution containing both TZ and LD proved stable under various storage conditions. While this study applied the method to assess an implant device, it has broader applicability for analysing and quantifying the in vitro drug release of TZ and LD from diverse dosage forms in preclinical settings.

Baclofen and Tizanidine Adverse Effects Observed Among Community-Dwelling Adults Above the Age of 50 Years: A Systematic Review.

OBJECTIVE: This review highlights adverse effects of baclofen and tizanidine in older community-dwelling adults. DATA SOURCES: A literature search was conducted, including search terms of "adverse effect," "baclofen," "elderly," "falls," "fractures," and "tizanidine." Studies were included if they described community-dwelling adults aged 50 years and older who received oral baclofen or tizanidine. The Federal Drug Administration Adverse Event Reporting System (FAERS) data were compiled for adverse effect incidence. STUDY SELECTION AND DATA EXTRACTION: The literature search was completed in July 2019 and updated in June 2023. Reviews performed by 2 independent reviewers yielded 15 records. FAERS identified 486 (baclofen) and 305 (tizanidine) adverse effects of interest. DATA SYNTHESIS: Two retrospective cohort studies evaluating baclofen use in older adults showed increased hospitalizations for encephalopathy in chronic kidney disease (7.2% vs 0.1%) and end-stage renal disease (daily dose 20 mg or more; relative risk [RR] 19.8, 95% CI = [14.0-28.0]). Other articles were case reports; 10 articles reported dyskinesias, encephalopathy or disorientation, and drowsiness associated with baclofen, and 5 articles reported bradycardia and/or hypotension with tizanidine. The FAERS Public Dashboard revealed 12.1% and 28.7% overall incidence of adverse effects of interest, with a 27.8% and 29.2% incidence of falls for baclofen and tizanidine, respectively. Baclofen and tizanidine are associated with concerning adverse effects in older adults. Alternative agents should be considered, but, if necessary, providers should start at lower doses and increase slowly. CONCLUSIONS: This review highlights the importance of using baclofen and tizanidine with caution in older adults.

Research on the Influence of Informal Employment on Residents' Happiness in China: Empirical Analysis Based on CLDS Data.

The influence of informal employment on residents' happiness has gained wide attention around the world. However, few studies focus on this topic in China. Using the 2016 wave of the China Labor Force Dynamics Survey (CLDS) data, we examined the effect of informal employment and its mechanisms on residents' happiness in China. Our study shows there is a significant negative correlation between informal employment and residents' happiness in China. Moreover, the correlation between informal employment and residents' happiness is stronger for residents who are female, migrating, and with a rural household registration. In addition, we investigated possible mechanisms of the effect, including individual income, social respect, unemployment expectations, and social security, and found that informal employment reduces the happiness of residents by widening the gap in unemployment probability and social insurance level among residents.

A Disproportionality Analysis of Drug-Drug Interactions of Tizanidine and CYP1A2 Inhibitors from the FDA Adverse Event Reporting System (FAERS).

INTRODUCTION: Tizanidine is primarily metabolized via cytochrome P450 (CYP) 1A2 and therefore medications that inhibit the enzyme will affect the clearance of tizanidine, leading to increased plasma concentrations of tizanidine and potentially serious adverse events. OBJECTIVES: Our aim was to study the occurrence of adverse events reported in the FDA Adverse Event Reporting System (FAERS) involving the combination of tizanidine and drugs that inhibit the metabolic activity of CYP1A2. METHODS: A disproportionality analysis of FAERS reports from 2004 quarter 1 through 2020 quarter 3 was conducted to calculate the reporting odds ratio (ROR) of reports mentioning tizanidine in a suspect or interacting role or having any role, a CYP1A2 inhibitor, and the following adverse events: hypotension, bradycardia, syncope, shock, cardiorespiratory arrest, and fall or fracture. RESULTS: A total of 89 reports were identified mentioning tizanidine, at least one CYP1A2 inhibitor, and one of the adverse events of interest. More than half of the reports identified tizanidine as having a suspect or interacting role (n = 59, 66.3%), and the reports more frequently involved women (n = 58, 65.1%). The median age was 56.1 years (standard deviation 17.1). Some of the important safety signals included interactions between tizanidine in a suspect or interacting role and ciprofloxacin (ROR for hypotension 28.1, 95% confidence interval [CI] 19.2-41.2) or fluvoxamine (ROR for hypotension 36.9, 95% CI 13.1-103.4), and also when reported in "any role" with ciprofloxacin (ROR for hypotension 6.3, 95% CI 4.7-8.5), fluvoxamine (ROR for hypotension 11.4, 95% CI 4.5-28.8), and zafirlukast (ROR for falls 16.0, 95% CI 6.1-42.1). CONCLUSIONS: Reports involving tizanidine and a CYP1A2 inhibitor have higher odds of reporting hypotension. This study suggests that concurrent use of tizanidine with CYP1A2 inhibitors may lead to serious health consequences associated with low blood pressure such as falls and fractures.

Understanding Interindividual Variability in the Drug Interaction of a Highly Extracted CYP1A2 Substrate Tizanidine: Application of a Permeability-Limited Multicompartment Liver Model in a Population Based Physiologically Based Pharmacokinetic Framework.

Tizanidine, a centrally acting skeletal muscle relaxant, is predominantly metabolized by CYP1A2 and undergoes extensive hepatic first-pass metabolism after oral administration. As a highly extracted drug, the systemic exposure to tizanidine exhibits considerable interindividual variability and is altered substantially when coadministered with CYP1A2 inhibitors or inducers. The aim of the current study was to compare the performance of a permeability-limited multicompartment liver (PerMCL) model, which operates as an approximation of the dispersion model, and the well stirred model (WSM) for predicting tizanidine drug-drug interactions (DDIs). Physiologically based pharmacokinetic models were developed for tizanidine, incorporating the PerMCL model and the WSM, respectively, to simulate the interaction of tizanidine with a range of CYP1A2 inhibitors and inducers. Whereas the WSM showed a tendency to underpredict the fold change of tizanidine area under the plasma concentration-time curve (AUC ratio) in the presence of perpetrators, the use of PerMCL model increased precision (absolute average-fold error: 1.32-1.42 versus 1.58) and decreased bias (average-fold error: 0.97-1.25 versus 0.63) for the predictions of mean AUC ratios as compared with the WSM. The PerMCL model captured the observed range of individual AUC ratios of tizanidine as well as the correlation between individual AUC ratios and CYP1A2 activities without interactions, whereas the WSM was not able to capture these. The results demonstrate the advantage of using the PerMCL model over the WSM in predicting the magnitude and interindividual variability of DDIs for a highly extracted sensitive substrate tizanidine. SIGNIFICANCE STATEMENT: This study demonstrates the advantages of the PerMCL model, which operates as an approximation of the dispersion model, in mitigating the tendency of the WSM to underpredict the magnitude and variability of DDIs of a highly extracted CYP1A2 substrate tizanidine when it is administered with CYP1A2 inhibitors or inducers. The physiologically based pharmacokinetic modeling approach described herein is valuable to the understanding of drug interactions of highly extracted substrates and the source of its interindividual variability.

Risk of tizanidine-induced adverse events after concomitant exposure to ciprofloxacin: A cohort study in the U.S.

BACKGROUND: Tizanidine's potent muscle relaxant properties and short onset of action makes it desirable for pain management. However, concomitant use of tizanidine with ciprofloxacin, a strong inhibitor of the P450-CYP1A2 cytochrome metabolic pathway of tizanidine, can result in increased tizanidine plasma levels and associated adverse outcomes, particularly hypotension. The aim of this study was to assess the risk of hypotension with coadministration of tizanidine and ciprofloxacin. METHODS: An observational nested cohort study of patients 18 years or older on tizanidine was conducted using data from electronic health records from 2000 to 2018 in the US. We estimated the prevalence and risk of hypotension associated with the DDI between tizanidine and ciprofloxacin using multivariable logistic regression models. RESULTS: Our analysis included 70,110 encounters of patients on tizanidine across 221 hospitals. Most encounters included females (65.7%), whites (82.4%), with an average age of 56 years (SD 14.9) and an Elixhauser comorbidity index mean of 1.6 (SD 2.3). Ciprofloxacin was co-administered with tizanidine in 2487 encounters (3.6%). Compared to patients who did not receive ciprofloxacin, co-administration of tizanidine and ciprofloxacin was associated with an increased likelihood of hypotension (adjusted odds ratio: 1.43, 95% Confidence Intervals:1.25-1.63, p-value<0.001). CONCLUSIONS: Our findings suggest that the concomitant use of tizanidine and ciprofloxacin is associated with an elevated risk of hypotension. The prevalence of co-administration of drugs with a documented interaction highlights the need for continuous education across providers to avoid the incidence of DDI related adverse events and further complications and to improve patient outcomes.

Development of Biocompatible Nanoparticles of Tizanidine Hydrochloride in Orodispersible Films: In vitro Characterization, Ex vivo Permeation, and Cytotoxic Study on Carcinoma Cells.

BACKGROUND: The main limitations of the therapeutic effectiveness of tizanidine hydrochloride (TNZ) are its low bioavailability due to its tendency to undergo first-pass metabolism and short biological half-life. These factors make it an ideal candidate for formulating orally disintegrating films. OBJECTIVE: The present study was aimed to prepare nanoparticles of tizanidine hydrochloride using biodegradable polymers and loading them on orodispersible films to obtain a sustained release dissolution profile with improved permeability and further study the cytotoxicity on A549 lung carcinoma cells, MCF7 breast cancer cells, and HOP 92 non-small lung adenocarcinoma cells. METHODS: The fast-dissolving film of TNZ HCl was prepared by the solvent-casting method and characterized using scanning electron microscopy, FTIR, and XRD, and evaluated for critical quality attributes for this type of dosage form such as disintegration time, tensile strength, drug content, dissolution, and ex vivo permeability. In vitro cytotoxicity studies were also conducted on cancer cell lines to confirm the cytotoxic effect. RESULTS: The polymeric matrix containing the drug provided a rapid disintegration time varying between 7±2 and 30±2 seconds, adequate tensile strength between 1.4 and 11.25 N/mm2, and improved permeability through porcine buccal mucosa when compared to the reference product. CONCLUSION: A study of the cytotoxic effect on the MCF-7 breast cancer cells and A549 lung carcinoma cells revealed that tizanidine hydrochloride nanoparticles at 2.3 mg/film exhibited an IC50 value of 65.1 % cytotoxicity on MCF-7, approximately 100% on HOP92, and 83.5 % on A549 lung carcinoma cells, thus paving the way for a new paradigm of research for a cytotoxic study on MCF-7, HOP92, and A549 cell lines using the subject drug model prepared as oral films or biodegradable nanoparticles in oral films for site-specific targeting.

Sex-dependent antiallodynic effect of α2 adrenergic receptor agonist tizanidine in rats with experimental neuropathic pain.

The purpose of this study was to investigate the mechanism of antiallodynic effect of tizanidine in neuropathic rats. Spinal nerve ligation reduced withdrawal threshold which was interpreted as tactile allodynia. Increasing doses of tizanidine induced a dose-dependent antiallodynic effect in nerve injured rats. Tizanidine was more effective in female than male neuropathic rats. This drug induced a lower antiallodynic effect in ovariectomized, compared with non-ovariectomized, neuropathic rats, while systemic reconstitution of estradiol (E2) levels in ovariectomized neuropathic females fully restored the antiallodynic effect of tizanidine. Naloxone reduced the antiallodynic effect of tizanidine in male but not in female neuropathic rats. Ovariectomy restored the antagonizing effect of naloxone in the antiallodynic effect of tizanidine, whereas treatment with E2 abolished the effect of naloxone on tizanidine activity. Rauwolscine (α2 antagonist) and imiloxan (α2B antagonist) completely abated tizanidine-induced antiallodynic effect in female neuropathic rats. In contrast, BRL-44408 (α2A antagonist) partially decreased the effect of tizanidine while JP-1302 (α2C antagonist) was ineffective. Rauwolscine, imiloxan and BRL-44408 decreased withdrawal threshold in naïve female rats. Rauwolscine did not modify withdrawal threshold in naïve male rats. AGN192403 (I1 antagonist), BU224 (I2 antagonist), prazosin (α1 antagonist) and methiothepin (5-HT antagonist) did not modify tizanidine-induced antiallodynia in neuropathic females and males. These data indicate that tizanidine exhibits a sex-dependent antiallodynic effect in neuropathy. Data also suggest that activation of adrenergic α2B and α2A and opioid receptors participate in the antiallodynic effect of tizanidine in female and male, respectively, neuropathic rats.

Effect of Topically Applied 0.5% Apraclonidine Versus 0.5% Timolol Maleate on Intraocular Pressure of Healthy Horses.

This study aims to assess the effect of topical 0.5% apraclonidine on Intraocular pressure (IOP) in horses and compare the effects of timolol maleate 0.5% with 0.5% apraclonidine in the equine eye. Twenty healthy female thoroughbred horses were used. Horses were divided into two groups. Ten horses received single dose of 0.2 mL of 0.5% apraclonidine in one randomly selected eye and the contralateral eye received single dose of 0.2 mL of artificial tears. In the second group, 10 horses received single dose of 0.2 mL of 0.5% timolol maleate in one eye and the opposite eye received single dose of placebo (0.2 mL of artificial tears). Intraocular pressure was measured using rebound tonometer at the baseline and 30, 60, 120, 240, 360 minutes, and 24 hours after topical ophthalmic drops instillation. Any ocular side effects were recorded at each time point. Mean (SD) baseline IOPs of the treated and placebo eyes were 26.2(3.1) and 23.5(3.4) in apraclonidine group, and 25.7(2.6) and 23.2(3.3) in timolol group. In the apraclonidine group, significant reduction in the mean IOP started after 60 minutes (P= .005) and was still present after 24 hours (P < .001). In timolol group, IOP was reduced in the treated eyes, but this reduction was only significant in the treated eyes at T24h (P= .03). The highest reduction in IOP in timolol group was observed at T360 (21.0(2.2); 14.7%). Mean IOP was decreased prominently by apraclonidine compared to timolol in treated eyes. In conclusion, single dose of topical 0.5% apraclonidine reduced IOP significantly among normal horses in the present study. Further investigations are necessary for evaluating efficacy and safety of apraclonidine in horses.

The evaluation of patient demographics, etiologies and apraclonidine test results in adult Horner's syndrome.

PURPOSE: We aimed to demonstrate the patient demographics, etiologies and apraclonidine test results in adult Horner's syndrome. METHODS: This retrospective study was performed by the analysis of medical data of patients who were given 0.5% apraclonidine test. Patients' past medical history, demographic data, etiologies, accompanying neurological findings and pharmacological test results were assessed. RESULTS: Forty patients (21 females and 19 males) with a mean age of 50.3 ± 11.6 years were evaluated. Apraclonidine 0.5% test was positive in 37 patients (92.5%). An etiology could be identified in 20 patients (central [9 patients, 45%], preganglionic [9 patients, 45%] and postganglionic [2 patients, 10%]). Neurological findings accompanying Horner's syndrome were present in 8 patients. CONCLUSION: Despite detailed investigations, in a significant number of patients with Horner's syndrome an underlying cause may not be detected. Among the identifiable lesions, central and preganglionic involvements are still the first leading causes of Horner's syndrome. In addition, apraclonidine test may not be positive in all patients and a negative response does not exclude Horner's syndrome.

Liquid chromatography-tandem mass spectrometry and confirmation by liquid chromatography-high-resolution mass spectrometry hair tests to evidence use of tizanidine by racing cyclists.

Tizanidine, an imidazoline derivative close to clonidine, is a central alpha-2 adrenergic receptor agonist. Therapeutically, the drug is used as a muscle relaxant under the trade names Sirdalud™ or Zanaflex™. The drug is not prohibited by the World Anti-Doping Agency but, for therapeutic purposes, can only be obtained via a nominative temporary use authorization. The French public health police requested the laboratory to test for tizanidine in head hair specimens collected from international racing cyclists. Using Liquid chromatography-tandem mass spectrometry (LC/MS-MS) and confirmation by liquid chromatography-high-resolution mass spectrometry (LC/HRMS), after pH 9.5 borate buffer overnight incubation of 20 mg and subsequent solvents extraction, tizanidine was identified in the hair of three athletes at 1.1, 3.7, and 11.1 pg/mg. This is the first evidence that tizanidine is incorporated in human hair. However, it was not possible to interpret the data in terms of doses and frequency of use due to a lack of controlled study.

Safety of apraclonidine eye drops in diagnosis of Horner syndrome in an outpatient pediatric ophthalmology clinic.

PURPOSE: To describe the efficacy and systemic side effects of apraclonidine drops 0.5% in children clinically suspected of having Horner syndrome. METHODS: The medical records of patients with clinically suspected Horner syndrome who underwent testing with apraclonidine 0.5% eyedrops were reviewed retrospectively. The following data were retrieved from the record: allergic reactions, somnolence, shallow respiration, pallor, or excessive fussiness noted by the examiner or parents. RESULTS: A total of 46 patients presenting with anisocoria and tested with apraclonidine 0.5% were included. Of these, 15 had a positive result, with reversal of anisocoria. The mean age of patients was 3.2 years (median, 0.91; mode, 0.25 years). Twenty-four patients were ≤1 year of age; 19 were ≤6 months. No systemic side effects were noted during the examination or reported by parents in any patients. CONCLUSIONS: The use of topical apraclonidine eyedrops has been described as an effective test for Horner syndrome. However, concerns have been raised regarding the potential systemic side effects in children, especially those under the age of 6 months. In our cohort, no systemic side effects were reported, including in those under 6 months of age.

The impact of lofexidine on stress-related opioid craving and relapse: Design and methodology of a randomized clinical trial.

Opioid Use Disorders (OUDs) and drug overdose deaths are increasing at alarmingly high rates in the United States. Stress and dysregulation in biologic stress response systems such as the hypothalamic-pituitary-adrenal axis and noradrenergic system appear to play an important role in the pathophysiology of substance use disorders and relapse to drug use, particularly for women. Alpha-2 adrenergic agonist medications effectively decrease noradrenergic activity and have demonstrated benefit in preventing relapse to substance use and decreasing stress-reactivity and craving in cocaine- and nicotine-dependent women, compared to men. Alpha-2 adrenergic agonists may help decrease stress reactivity in individuals with OUDs and prevent relapse to drug use, but gender differences have yet to be systematically explored. We describe the rationale, study design and methodology of a randomized, double-blind, placebo-controlled clinical trial examining gender differences in stress, craving and drug use among adult men and women with OUD taking methadone or buprenorphine and randomly assigned to an alpha-2 adrenergic agonist, lofexidine, compared to placebo. In addition, we describe methods for measuring daily stress, craving and drug use in participant's natural environment as well as participant's physiological (i.e., heart rate, cortisol) and psychological (i.e., stress, craving) response to laboratory social and drug cue stressors. Lastly, we detail methods adopted to sustain research activity while following guidelines for the COVID-19 pandemic. ClinicalTrials.gov Registration Number: NCT03718065.

[Focus on tizanidine in primary care medecine]. / Le point sur la tizanidine en médecine de premier recours.

Tizanidine is an alpha2 agonist with central action whose myorelaxant effects are often used off-label against primary backpain in clinical practice. It is mainly metabolized by the liver. The concomitant use of CYP1A2 inhibitor drugs increases the plasmatic concentration and thus can cause serious adverse effects. Severe hypotension is the most memorable example. Its narrow therapeutic range and the interindividual different sensitivity to the molecule justify using it wisely. A clinical case is reported as illustration.

La tizanidine est un agoniste alpha-2-adrénergique d'action centrale dont l'effet myorelaxant est utilisé « hors indication ¼ en pratique médicale pour les lombalgies primaires. Elle est principalement métabolisée au niveau hépatique. Lorsqu'elle est administrée de manière concomitante à un inhibiteur du CYP1A2, sa concentration plasmatique augmente, entraînant potentiellement plusieurs effets indésirables. L'hypotension sévère en est l'exemple le plus probant. Sa marge thérapeutique étroite et la sensibilité variable des sujets à la molécule justifient son utilisation judicieuse. Un cas clinique illustratif est rapporté.

Derma roller mediated transdermal delivery of tizanidine invasomes for the management of skeletal muscle spasms.

Tizanidine hydrochloride (TIZ) is a skeletal muscle relaxant used to treat spasms, a sudden involuntary muscle contraction. The currently available oral dosage forms exhibit low oral bioavailability due to high first-pass metabolism. Frequent administration of the drug is thus necessary because of the short half-life of the drug. Transdermal delivery is an excellent alternative, but the skin's outer stratum corneum barrier prevents most drugs from being effectively delivered into the bloodstream. Here we present a pre-clinical investigation of derma roller mediated delivery of TIZ invasome gel as a potential approach for treating muscle spasm. Further, specific terpenes namely limonene and pinene in different concentrations and their impact on the properties of the prepared TIZ invasomes, including particle size, drug entrapment, and ex vivo drug release, were investigated. TIZ invasomes were incorporated into a gel and delivered to rats with and without pre-treatment of the skin with a derma roller. Pre-treated skin achieved maximum drug plasma concentrations within 3 ± 0.00 h of gel application and maintained for 24 h. In the untreated skin the maximum plasma drug levels was achieved at the end of 6 ± 0.00 h. The findings were further supported by in vivo efficacy studies conducted using rotarod and actophotometer. Overall, the study indicates that derma roller mediated transdermal delivery of TIZ loaded invasomes is a promising strategy for enhancing the bioavailability of TIZ.