Challenging Case: A Multidisciplinary Approach to Demystifying Chronic Sleep Impairment in an Infant with a Complex Medical and Behavioral Profile.

CASE: X is a 22-month-old White male infant with a complex medical history, including diagnoses of FBXO11 mutation, hypotonia, restrictive lung disease and mild intermittent asthma, laryngotracheomalacia, obstructive sleep apnea (OSA), feeding difficulties with a history of aspiration, gastroesophageal reflux disease (GERD), and developmental delays. X's medical presentation has resulted in multiple prior medical admissions for respiratory failure due to acute illnesses, procedures and treatments including gastrojejunostomy (GJ) tube dependence, supraglottoplasty to reshape tissues of the upper larynx, and the use of biphasic positive airway pressure (BiPAP) at night and room air during the day when he is at baseline. In addition, he has nocturnal events characterized by significant agitation, screaming, crying, body stiffening and limb movements with pauses in breathing, mouth breathing, restless sleep, and difficulty waking in the morning with concomitant daytime fatigue despite above treatments for OSA. There is no history of congenital heart disease or sudden unexplained death. Family history is noncontributory because parents are negative for the FBXO11 variant.X's sleep disruption has led to significant sleep deficits for both X and his caregivers, who spend much of the night strategizing on how to console him. X has undergone several sleep studies, starting when X was aged 4 months, at several children's hospitals across the nation to determine the cause of his chronic sleep disturbance, which yielded limited information and treatment success. As an infant, X received a medical workup and was subsequently treated with a proton pump inhibitor (PPI) for reflux. At 12 months, he was diagnosed with disordered sleep with myoclonic jerks and started on melatonin and gabapentin for involuntary movements. At 13 months, gabapentin was weaned back because of intolerance, and at 15 months, nortriptyline and clonidine were started because of worsening symptoms to target potential neuropathic pain. While most of his symptoms were at night, he had occasional daytime screaming episodes, particularly when experiencing illness. Gabapentin and clonidine were stopped because nortriptyline seemed most effective.At 17 months, the results from a sleep study led to a diagnosis of night terrors, and several clinicians agreed that X's sleep disruption was behavioral in nature. At this time, an infant mental health consultant met with a sleep psychologist on the family's behalf to support family in considering systematic desensitization therapy to increase tolerance to wearing his BiPAP mask, as well as other behavioral and sleep hygiene strategies, which were tried on several occasions and again, resulted in limited improvement in functioning.At 19 months, X's multidisciplinary team reconsidered a night terror diagnosis after a failed trial of clonazepam and pursued a differential diagnosis of periodic limb movement disorder (PLMD). X trialed gabapentin again, but this time only a nighttime dose, per sleep medicine and psychiatry recommendation. While this brought some temporary relief from nighttime distress, despite increasing to the highest dose for age and weight (15 mg/kg/dose), this became less effective, and he was weaned off at 22 months. He had been on iron supplementation since age 6 months and received an iron infusion at 22 months because of persistently low ferritin levels and PLMD in sleep.At 24 months, X was briefly trialed on levetiracetam. While no evidence for seizures on EEG was present, this medication was chosen for involuntary movements and genetic risk for seizures. However, this medication was not useful. At 25 months, an evaluation with a movement disorder physiatrist resulted in a diagnosis of nocturnal paroxysmal dystonia, and he was started on baclofen, which has provided some, but not complete relief to nighttime symptoms. Parents are reporting he has more "good nights" than "bad nights," but "bad nights" come in stretches of a few days in length with no known trigger or relief.Most recently, X was evaluated by general genetics. Whole exome sequencing (WES) was pursued which revealed a pathogenic de novo variant in FBXO11 and provides a likely cause for his neurodevelopmental phenotype. However, he has some features not explained by FBX011; thus, reanalysis of his WES was performed and revealed a de novo variant of uncertain significance in RAF1. Because pathogenic variants in RAF1 have been associated with dilated cardiomyopathy and Noonan spectrum disorder, it was recommended that X be followed periodically in a cardiac genetics clinic. Family is well connected into the FBXO11 community, including supportive Facebook groups. Parents have shared that they do not feel X's breathing issues and pain fit with the phenotype of other children with FBXO11 mutations.X is also enrolled in a medical child care program to facilitate development and social-emotional functioning and receives learning, speech, occupational, physical, and feeding therapy while in attendance. Despite periods of absence due to contracting numerous viral illnesses over the past several months, X continues to make progress across developmental therapies and happily engages when at the program.What additional diagnostic tests and treatment should be considered to better understand X's medical and behavioral presentation? What are the implications of chronic sleep deprivation and stress on the behavior and development of infant with X's profile? What are important psychosocial considerations because it relates to children with medical complexity (CMC), particularly for X and his family to support caregiver, family, and X's quality of life and overall well-being?

Anxiolytic-like effects of an mGluR 5 antagonist and a mGluR 2/3 agonist, and antidepressant-like effects of an mGluR 7 agonist in the chick social separation stress test, a dual-drug screening model of treatment-resistant depression.

Modulation of glutamate receptors has demonstrated anxiolytic and/or antidepressant effects in rodent stress models. The chick social-separation stress paradigm exposes socially raised aves to an isolation stressor which elicits distress vocalizations (DVocs) in an attempt to re-establish contact. The model presents a state of panic during the first 5 min followed by a state of behavioral despair during the last 60 to 90 min. Making it useful as a dual anxiolytic/antidepressant screening assay. Further research has identified the Black Australorp strain as a stress-vulnerable, treatment-resistant, and ketamine-sensitive genetic line. Utilizing this genetic line, we sought to evaluate modulation of glutamatergic receptors for potential anxiolytic and/or antidepressant effects. Separate dose-response studies were conducted for the following drugs: the AMPA PAM LY392098, the mGluR 5 antagonist MPEP, the mGluR 2/3 agonist LY404039, the mGluR 2/3 antagonist LY341495, and the mGluR 7 agonist AMN082. The norepinephrine α2 agonist clonidine and the NMDA antagonist ketamine were included as comparison for anxiolytic (anti-panic) and antidepressant effects, respectively. As in previous studies, clonidine reduced DVoc rates during the first 5 min (attenuation of panic) and ketamine elevated DVoc rates (attenuation of behavioral despair) during the last 60 min of isolation. The mGluR 2/3 agonist LY404039 and the mGluR 5 antagonist MPEP decreased DVoc rates during the first 5 min of isolation indicative of anxiolytic effects like that of clonidine while the mGluR 7 agonist AMN082 elevated DVoc rates in the later hour of isolation, representative of antidepressant effects like that of ketamine. Collectively, these findings suggest that certain glutamate targets may be clinically useful in treating panic disorder and/or treatment-resistant depression.

Comparative Efficacy of Adjuvant Nonopioid Analgesia in Adult Cardiac Surgical Patients: A Network Meta-Analysis.

OBJECTIVES: To compare the relative efficacy of adjuvant nonopioid analgesic regimens in adult cardiac surgical patients. DESIGN: This frequentist, random-effects network meta-analysis (NMA) was prospectively registered on PROSPERO (CRD42021282913) and conducted according to the Preferred Reporting Items for Systematic Review and Meta-Analyses for Network Meta-Analyses (PRISMA-NMA). The risk of bias (RoB) and confidence of evidence were assessed by RoB 2 and Confidence in Network Meta-Analysis, respectively. Relevant databases were searched from inception to October 9, 2021. SETTING: A total of 124 (N = 26,257) randomized controlled trials were included, of which 110 were analyzed. PARTICIPANTS: Trials enrolling adults (≥18 years of age) undergoing cardiac surgery that compared nonopioid analgesics against other nonopioid analgesics, placebo, or no additional treatment, as adjuvants to standard analgesic management, and reported at least 1 of the outcomes of interest. MEASUREMENT AND MAIN RESULTS: Outcomes of interest included resting postoperative pain scores at 24 hours. Compared with standard care and/or placebo, pain scores were reduced significantly by 10 different regimens, including acetaminophen (N = 176; mean difference [MD] -0.66 points, 95% CI -1.16 to -0.15 points; high confidence), magnesium (N = 323; -0.05 points, 95% CI -0.07 to -0.02 points; high confidence), gabapentin (N = 96; MD -0.40 points, 95% CI -0.71 to -0.09; moderate confidence), and clonidine (N = 64; MD v0.38 points, 95% CI -0.73 to v0.04 points; moderate confidence). Indomethacin, diclofenac, magnesium, and gabapentin significantly reduced 24-hour opioid consumption. Four regimens significantly decreased the intensive care unit length of stay. Hydrocortisone, dexmedetomidine, and clonidine significantly decreased the duration of mechanical ventilation. Magnesium decreased, while methylprednisolone significantly increased, the risk of myocardial infarction. CONCLUSIONS: Given the increasing emphasis on enhanced recovery after surgery(ERAS) protocols and the eventual goal of limiting opiate prescriptions postoperatively, the authors' data suggested far greater use of nonopioid adjuncts to minimize pain and enhance recovery following cardiac surgery.

Intracranial hemorrhage after a single dose of Yohimbine in a chronic user of clonidine.

INTRODUCTION: Yohimbine, an alpha-2 adrenoreceptor antagonist found in a variety of supplements, has been historically used to treat libido, erectile dysfunction, xerostomia, and as a weight loss enhancement. Yohimbine toxicity causes a sympathomimetic syndrome as demonstrated by the case below of a female who developed an intracranial hemorrhage (ICH) following an ingestion of yohimbine. CASE: This case follows a 39-year-old female who presented to the emergency department (ED) with complaints of nausea, emesis, and flushing following the ingestion of a female sexual enhancement supplement labeled to contain yohimbine (BioXgenic Nature's Desire) one hour prior. The patient took her prescribed 0.1 mg clonidine when the symptoms commenced. Upon arrival, the patient's blood pressure was 198/93. She developed neurological sequelae including a left-sided facial droop and weakness of her right extremities. A computed tomography scan demonstrated an acute basal ganglia hemorrhage with mild mass effect and mild subarachnoid hemorrhage. She was transferred to a regional referral hospital and discharged 16 days later to a rehabilitation center with persistent neurological sequelae. DISCUSSION: This patient exhibited sympathetic toxicity temporally associated with yohimbine ingestion. Our patient also had a variety of risk factors that increased the likelihood of a poor outcome with yohimbine. Chronic use of clonidine is known to down-regulate alpha-2 receptors. This leads to dependence of clonidine to maintain adrenergic homeostasis and could potentiate the effects of yohimbine. To compound effects, our patient was also taking bupropion and desvenlafaxine, which inhibit norepinephrine reuptake, likely worsening our patient's sympathomimetic response. Despite the temporal relationship of our patient's ICH and ingestion of yohimbine, a definitive relationship cannot be inferred due to our lack of confirmatory testing of yohimbine content and possibility of adulterants. The U.S. Food and Drug Administration (FDA) does not regulate the supplement market strictly, with multiple studies illustrating variation among ingredients of supplements despite stated quantities on the labels. CONCLUSION: Dietary supplements are not required by the FDA to undergo efficacy or safety testing, necessitating clear post-marketing communication regarding potential adverse events from various supplements. Users should be aware of yohimbine-containing products and the possible side effects of toxicity. It is crucial that physicians and patients be aware of possible drug-supplement interactions of yohimbine and the presentation of sympathomimetic syndromes.

Use of clonidine in the treatment of Irukandji syndrome: A 4-year retrospective cohort study on safety, efficacy and clinical utility.

OBJECTIVE: Irukandji syndrome (IS) is an extremely painful condition that causes a significant catecholamine surge and sympathetic autonomic response related to the envenomation from certain types of jellyfish. Current management involves intravenous fluids, magnesium sulphate and large doses of opioids for symptom control. Clonidine, a centrally acting alpha-2 agonist, is often used as an analgesic adjunct to reduce opioid requirements in acute pain. The present study explores the safety and efficacy of clonidine in reducing opioid requirements in IS. METHODS: All patients diagnosed with IS at Cairns Hospital between 1 March 2016 and 30 April 2020, and participants from the Magnesium in Irukandji Study Trial, were included in this retrospective study (n = 114). Cases were separated into two groups depending on whether or not they received clonidine, and subsequently analysed according to pre- and post-intervention opioid requirements, clonidine dose administered and adverse effects. RESULTS: Notably, 39 patients with IS received ≥1 mcg/kg clonidine and the remaining 75 did not. There was no difference in oral morphine equivalent daily dose (oMEDD) between groups before clonidine administration; however, there was a significant reduction in oMEDD required after patients received clonidine (26.1 mg; 95% CI 4.6-47.7) compared with those who did not (66.6 mg; 95% CI 56.9-86.1) (F = 8.722, df = 1 × 224, P = 0.003). One episode of hypotension occurred following the intervention. CONCLUSION: Patients with IS who received clonidine required significantly lower opioid requirements than those who did not receive clonidine. Clonidine was safe to administer and should be considered early when treating IS. The optimal clonidine dose remains unclear and requires prospective studies to validate our findings.

A Comprehensive Review of the Use of Alpha 2 Agonists in Spinal Anesthetics.

BACKGROUND: Spinal Anesthesia was the first regional anesthetic technique to be performed. It was performed by Dr. August Bier, known for the Bier block, and his colleagues on August 16, 1898. Dr. Bier opted for, what he referred to at the time as "cocainization of the spinal cord" by introducing 15 mg of cocaine intrathecally prior to the operation. The surgery was largely uneventful and painless. The patient only experienced some vomiting and a headache postoperatively. Dr. Bier's use of neuraxial anesthesia aimed to directly inject local anesthetics in and around the central nervous system (CNS) for more direct control of pain and anesthesia. Local anesthetics were an important discovery in anesthesiology. However, since the advent of local anesthetics and spinal anesthesia as an alternative technique to general anesthesia, much has been learned about both the benefits and adverse effects of local anesthetics. It was quickly learned that use of local anesthetics would be limited by their potential for life-threatening toxic effects. For this reason, there was a push towards development of novel local anesthetics that had a larger therapeutic window with less likelihood of serious side effects. In addition to developing newer local anesthetics, the idea of adding adjuvants provided an opportunity to potentially limit the life-threatening events. These adjuvants would include medications such as epinephrine and alpha-2 agonists, such as clonidine and dexmedetomidine. Other adjuvants include opioids, glucocorticoids, and mineralocorticoids. OBJECTIVES: In this review, we will delve further into the indications, contraindications, uses, mechanisms, and future of spinal anesthesia and its adjuvants. STUDY DESIGN: A literature review of recent publications in the field of alpha 2 agonists used in spinal anesthetics was carried out from 2015 to present day. Consensus opinions were formulated in various areas. SETTING: This literature review was carried out at various medical universities throughout the nation and Europe. LIMITATIONS: As research has only just begun in this field data is limited at this time. CONCLUSIONS: The use of spinal anesthesia provides a reliable dermatome blockade to facilitate many different surgical procedures. The combination of local anesthetics with opioid medications within the subarachnoid space has been the standard of care. Adjuvant medications like alpha 2 agonists may play a significant role in prolonging spinal blockade as well as limiting cardiovascular complications such as hypotension and bradycardia. The use of alpha 2 agonists instead of opioid medications intrathecally decreases pruritus and delayed respiratory depression. Animal models have demonstrated the synergistic effects of utilizing alpha 2 agonists with opioids in the subarachnoid space. The addition of clonidine to fentanyl and local anesthetic demonstrated a shorter time to neural blockade, but no significant change in duration of the spinal. Interestingly alpha 2 agonists with local anesthetics showed increase block duration compared to opioid with local anesthetics. Further human trials need to be undertaken to analyze the effectiveness of alpha 2 agonists in the intrathecal space, but preliminary data does indicate it is an exemplary alternative to opioids.

Effect of adding clonidine to lidocaine on ocular hemodynamics during sub-Tenon's anesthesia: randomized double-blind study.

INTRODUCTION AND OBJECTIVES: Different regional anesthesia techniques for ophthalmology can have hemodynamic effects on the eye. We assessed the effects of adding clonidine to lidocaine on Intraocular Pressure (IOP), Ocular Pulse Amplitude (OPA), and Ocular Perfusion Pressure (OPP) after the sub-Tenon's technique for cataract surgery. METHODS: The study included 40 patients randomly allocated into two groups: sub-Tenon's blockade with Lidocaine plus Saline Solution (LS) or Lidocaine plus Clonidine (LC). IOP, OPA and OPP were measured before anesthesia, and 1, 5 and 10 minutes after the injection of anesthetic solution. RESULTS: There was no difference between the groups in IOP, OPA, and OPP baseline values. After the injection of the anesthetic solution, the IOP increased in both groups at minute one, with a mean difference of +4.67 mmHg (p = 0.001) and +2.15 mmHg (p = 0.013) at 5 minutes. The increase was lower in the LC group when compared to LS (p = 0.027). OPA decreased in both groups, with a baseline difference, after 1 minute, of -0.85 mmHg (p =  -0.85 mmHg (p = 0.001), and at 5 and 10 minutes with differences of -1.17 (p = 0.001) and -0.89 mmHg (p = 0.001), respectively. The highest decrease was observed in group LC in relation to group LS (p = 0.03). There was no difference in OPP in relation to baseline measurements. CONCLUSIONS: Adding clonidine to lidocaine for sub-Tenon's anesthesia reduced IOP and OPA without significant changes in OPP.

Opioid treatment for opioid withdrawal in newborn infants.

BACKGROUND: Neonatal abstinence syndrome (NAS) due to opioid withdrawal may result in disruption of the mother-infant relationship, sleep-wake abnormalities, feeding difficulties, weight loss, seizures and neurodevelopmental problems. OBJECTIVES: To assess the effectiveness and safety of using an opioid for treatment of NAS due to withdrawal from opioids in newborn infants. SEARCH METHODS: We ran an updated search on 17 September 2020 in CENTRAL via Cochrane Register of Studies Web and MEDLINE via Ovid. We also searched clinical trials databases, conference proceedings and the reference lists of retrieved articles for eligible trials. SELECTION CRITERIA: We included randomised controlled trials (RCTs), quasi- and cluster-RCTs which enrolled infants born to mothers with opioid dependence and who were experiencing NAS requiring treatment with an opioid. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed trial eligibility and risk of bias, and independently extracted data. We used the GRADE approach to assess the certainty of evidence. MAIN RESULTS: We included 16 trials (1110 infants) with NAS secondary to maternal opioid use in pregnancy. Seven studies at low risk of bias were included in sensitivity analysis. Opioid versus no treatment / usual care: a single trial (80 infants) of morphine and supportive care versus supportive care alone reported no difference in treatment failure (risk ratio (RR) 1.29, 95% confidence interval (CI) 0.41 to 4.07; very low certainty evidence). No infant had a seizure. The trial did not report mortality, neurodevelopmental disability and adverse events. Morphine increased days hospitalisation (mean difference (MD) 15.00, 95% CI 8.86 to 21.14; very low certainty evidence) and treatment (MD 12.50, 95% CI 7.52 to 17.48; very low certainty evidence), but decreased days to regain birthweight (MD -2.80, 95% CI -5.33 to -0.27) and duration (minutes) of supportive care each day (MD -197.20, 95% CI -274.15 to -120.25). Morphine versus methadone: there was no difference in treatment failure (RR 1.59, 95% CI 0.95 to 2.67; 2 studies, 147 infants; low certainty evidence). Seizures, neonatal or infant mortality and neurodevelopmental disability were not reported. A single study reported no difference in days hospitalisation (MD 1.40, 95% CI -3.08 to 5.88; 116 infants; low certainty evidence), whereas data from two studies found an increase in days treatment (MD 2.71, 95% CI 0.22 to 5.21; 147 infants; low certainty) for infants treated with morphine. A single study reported no difference in breastfeeding, adverse events, or out of home placement. Morphine versus sublingual buprenorphine: there was no difference in treatment failure (RR 0.79, 95% CI 0.36 to 1.74; 3 studies, 113 infants; very low certainty evidence). Neonatal or infant mortality and neurodevelopmental disability were not reported. There was moderate certainty evidence of an increase in days hospitalisation (MD 11.45, 95% CI 5.89 to 17.01; 3 studies, 113 infants), and days treatment (MD 12.79, 95% CI 7.57 to 18.00; 3 studies, 112 infants) for infants treated with morphine. A single adverse event (seizure) was reported in infants exposed to buprenorphine. Morphine versus diluted tincture of opium (DTO): a single study (33 infants) reported no difference in days hospitalisation, days treatment or weight gain (low certainty evidence). Opioid versus clonidine: a single study (31 infants) reported no infant with treatment failure in either group. This study did not report seizures, neonatal or infant mortality and neurodevelopmental disability. There was low certainty evidence for no difference in days hospitalisation or days treatment. This study did not report adverse events. Opioid versus diazepam: there was a reduction in treatment failure from use of an opioid (RR 0.43, 95% CI 0.23 to 0.80; 2 studies, 86 infants; low certainty evidence). Seizures, neonatal or infant mortality and neurodevelopmental disability were not reported. A single study of 34 infants comparing methadone versus diazepam reported no difference in days hospitalisation or days treatment (very low certainty evidence). Adverse events were not reported. Opioid versus phenobarbital: there was a reduction in treatment failure from use of an opioid (RR 0.51, 95% CI 0.35 to 0.74; 6 studies, 458 infants; moderate certainty evidence). Subgroup analysis found a reduction in treatment failure in trials titrating morphine to ≧ 0.5 mg/kg/day (RR 0.21, 95% CI 0.10 to 0.45; 3 studies, 230 infants), whereas a single study using morphine < 0.5 mg/kg/day reported no difference compared to use of phenobarbital (subgroup difference P = 0.05). Neonatal or infant mortality and neurodevelopmental disability were not reported. A single study (111 infants) of paregoric versus phenobarbital reported seven infants with seizures in the phenobarbital group, whereas no seizures were reported in two studies (170 infants) comparing morphine to phenobarbital. There was no difference in days hospitalisation or days treatment. A single study (96 infants) reported no adverse events in either group. Opioid versus chlorpromazine: there was a reduction in treatment failure from use of morphine versus chlorpromazine (RR 0.08, 95% CI 0.01 to 0.62; 1 study, 90 infants; moderate certainty evidence). No seizures were reported in either group. There was low certainty evidence for no difference in days treatment. This trial reported no adverse events in either group. None of the included studies reported time to control of NAS. Data for duration and severity of NAS were limited, and we were unable to use these data in quantitative synthesis. AUTHORS' CONCLUSIONS: Compared to supportive care alone, the addition of an opioid may increase duration of hospitalisation and treatment, but may reduce days to regain birthweight and the duration of supportive care each day. Use of an opioid may reduce treatment failure compared to phenobarbital, diazepam or chlorpromazine. Use of an opioid may have little or no effect on duration of hospitalisation or treatment compared to use of phenobarbital, diazepam or chlorpromazine. The type of opioid used may have little or no effect on the treatment failure rate. Use of buprenorphine probably reduces duration of hospitalisation and treatment compared to morphine, but there are no data for time to control NAS with buprenorphine, and insufficient evidence to determine safety. There is insufficient evidence to determine the effectiveness and safety of clonidine.

The Influence of Xylazine and Clonidine on Lung Ultrasound-Induced Pulmonary Capillary Hemorrhage in Spontaneously Hypertensive Rats.

Induction of pulmonary capillary hemorrhage (PCH) by lung ultrasound (LUS) depends not only on physical exposure parameters but also on physiologic conditions and drug treatment. We studied the influence of xylazine and clonidine on LUS-induced PCH in spontaneously hypertensive and normotensive rats using diagnostic B-mode ultrasound at 7.3 MHz. Using ketamine anesthesia, rats receiving saline, xylazine, or clonidine treatment were tested with different pulse peak rarefactional pressure amplitudes in 5 min exposures. Results with xylazine or clonidine in spontaneously hypertensive rats were not significantly different at the three exposure pulse peak rarefactional pressure amplitudes, and thresholds were lower (2.2 MPa) than with saline (2.6 MPa). Variations in LUS PCH were not correlated with mean systemic blood pressure. Similar to previous findings for dexmedetomidine, the clinical drug clonidine tended to increase susceptibility to LUS PCH.

Paroxysmal localized Hyperhidrosis, a case-report: When excessive sweating occurs in combination with severe headaches.

BACKGROUND: Paroxysmal localized hyperhidrosis is a rare disorder of the central autonomic nervous system. No association between paroxysmal hyperhidrosis and severe headache has been previously described in literature.Case description: A 65-year-old woman with idiopathic paroxysmal localized hyperhidrosis combined with severe holocranial headache attacks is described in this case report. Extensive diagnostic testing by means of laboratory examinations, 24-hour urinalyses, chest X-ray, abdominal ultrasound and computed tomography scans, and brain and spinal cord magnetic resonance imaging could not identify an underlying disorder. A diagnosis of idiopathic paroxysmal localized hyperhidrosis was made, and the patient was successfully treated with clonidine 0.075 mg three times a day, without any side effects. CONCLUSION: Paroxysmal localized hyperhidrosis is a rare central autonomic nervous system disorder that can occur in combination with severe headache. Both the headache and paroxysmal hyperhidrosis complaints were treated effectively with clonidine in the patient described in this case-report.

Characterization of two group III potato CDPKs, StCDPK22 and StCDPK24, that contain three EF-Hand motifs in their CLDs.

Four members of the potato (Solanum tuberosum L.) calcium-dependent protein kinase (CDPK) family StCDPK22/23/24 and StCDPK27, present three functional EF-hands motifs in their calmodulin-like domain (CLD). StCDPK22/23/24 are clustered in clade III-b1 with tomato and Arabidopsis CDPKs that lack the first EF-hand motif, while StCDPK27 is clustered in clade III-b3 with CDPKs that lack EF-hand 2. Members of each clade share similar intron-exon structures and acylation profiles. 3D model predictions suggested that StCDPK22 and StCDPK24 are active kinases that undergo a conformational switch in the presence of Ca2+ even when lacking one functional EF-hand motif; however, assays performed with recombinant proteins indicated that StCDPK24:6xHis was active in all the conditions tested, and its activity was enhanced in the presence of Ca2+, but StCDPK22:6xHis had scarce or null activity. Both kinases share with AtCPK8 the same autophosphorylation pattern in the autoinhibitory (AD) and C-terminal variable (CTV) domains, suggesting that it could be a characteristic of clade III-b1. RT-qPCR analysis revealed that StCDPK22 is mainly expressed in early stages of tuberization, but not limited to, while StCDPK24 expression is more ubiquitous. In silico analysis predicted several abiotic stress-responsive elements in its promoters. Accordingly, StCDPK24 expression peaked at 10 h in in vitro plants exposed to salt shock and then declined. Moreover, a significant increase was observed at 2 h in stems of salt-treated greenhouse plants, suggesting that this CDPK could participate in the early events of the signaling cascade triggered in response to salt.

Reducing the dose of neuromuscular blocking agents with adjuncts: a systematic review and meta-analysis.

BACKGROUND: Acute global shortages of neuromuscular blocking agents (NMBA) threaten to impact adversely on perioperative and critical care. The use of pharmacological adjuncts may reduce NMBA dose. However, the magnitude of any putative effects remains unclear. METHODS: We conducted a systematic review and meta-analysis of RCTs. We searched Medline, Embase, Web of Science, and Cochrane Database (1970-2020) for RCTs comparing use of pharmacological adjuncts for NMBAs. We excluded RCTs not reporting perioperative NMBA dose. The primary outcome was total NMBA dose used to achieve a clinically acceptable depth of neuromuscular block. We assessed the quality of evidence using the GRADE (Grades of Recommendation, Assessment, Development, and Evaluation) criteria. Data are presented as the standardised mean difference (SMD); I2 indicates percentage of variance attributable to heterogeneity. RESULTS: From 3082 records, the full texts of 159 trials were retrieved. Thirty-one perioperative RCTs met the inclusion criteria for meta-analysis (n=1962). No studies were conducted in critically ill patients. Reduction in NMBA dose was associated with use of magnesium (SMD: -1.10 [-1.44 to -0.76], P<0.001; I2=85%; GRADE=moderate), dexmedetomidine (SMD: -0.89 [-1.55 to -0.22]; P=0.009; I2=87%; GRADE=low), and clonidine (SMD: -0.67 [-1.13 to -0.22]; P=0.004; I2=0%; GRADE=low) but not lidocaine (SMD: -0.46 [-1.01 to -0.09]; P=0.10; I2=68%; GRADE=moderate). Meta-analyses for nicardipine, diltiazem, and dexamethasone were not possible owing to the low numbers of studies. We estimated that 30-50 mg kg-1 magnesium preoperatively (8-15 mg kg h-1 intraoperatively) reduces rocuronium dose by 25.5% (inter-quartile range, 14.7-31). CONCLUSIONS: Magnesium, dexmedetomidine, and clonidine may confer a clinically relevant sparing effect on the required dose of neuromuscular block ing drugs in the perioperative setting. SYSTEMATIC REVIEW REGISTRATION: PROSPERO: CRD42020183969.

Paeoniflorin Alleviates Abnormalities in Rats with Functional Dyspepsia by Stimulating the Release of Acetylcholine.

INTRODUCTION: Paeoniflorin is a main active component in traditional Chinese medicine. Paeoniae alba radix is widely used as a spasmolytic and pain-relieving agent for abdominal spasmodic pain. Functional dyspepsia (FD) is characterized by pain or burning in the epigastrium, fullness, bloating and nausea. However, limited information is available about the effect of paeoniflorin on FD. MATERIALS AND METHODS: In this study, iodoacetamide or clonidine-induced FD rat models were established to investigate the impacts of paeoniflorin on FD induced by different pathophysiologic disturbances. RESULTS: We found the therapeutic effect of paeoniflorin through assessing the gastric emptying, gastric accommodation and visceral hypersensitivity. This function of paeoniflorin was related to the release of acetylcholine (ACh), which was accompanied by reduced acetylcholinesterase (AchE) activity in stomach and hypothalamus. Paeoniflorin administration inhibited the cyclo-oxygenase-2 (COX-2) expression and increased the level of ghrelin in the stomach. Besides, the levels of occludin and ZO-1 were elevated in the duodenum from paeoniflorin-treated rats, suggesting the impaired duodenal barrier was ameliorated. DISCUSSION: These results indicate that paeoniflorin possesses the ability to alleviate functional dyspepsia.

A Critical Review of the Role of the Cannabinoid Compounds Δ9-Tetrahydrocannabinol (Δ9-THC) and Cannabidiol (CBD) and their Combination in Multiple Sclerosis Treatment.

Many people with MS (pwMS) use unregulated cannabis or cannabis products to treat the symptoms associated with the disease. In line with this, Sativex, a synthetic combination of cannabidiol (CBD) and Δ9-tetrahydrocannabinol (Δ9-THC) has been approved to treat symptoms of spasticity. In animals, CBD is effective in reducing the amounts of T-cell infiltrates in the spinal cord, suggesting CBD has anti-inflammatory properties. By doing this, CBD has shown to delay symptom onset in animal models of multiple sclerosis and slow disease progression. Importantly, combinations of CBD and Δ9-THC appear more effective in treating animal models of multiple sclerosis. While CBD reduces the amounts of cell infiltrates in the spinal cord, Δ9-THC reduces scores of spasticity. In human studies, the results are less encouraging and conflict with the findings in animals. Drugs which deliver a combination of Δ9-THC and CBD in a 1:1 ratio appear to be only moderately effective in reducing spasticity scores, but appear to be almost as effective as current front-line treatments and cause less severe side effects than other treatments, such as baclofen (a GABA-B receptor agonist) and tizanidine (an α2 adrenergic receptor agonist). The findings of the studies reviewed suggest that cannabinoids may help treat neuropathic pain in pwMS as an add-on therapy to already established pain treatments. It is important to note that treatment with cannabinoid compounds may cause significant cognitive dysfunction. Long term double-blind placebo studies are greatly needed to further our understanding of the role of cannabinoids in multiple sclerosis treatment.

Effect of Apraclonidine and Diclofenac on Early Changes in Intraocular Pressure After Selective Laser Trabeculoplasty.

PRéCIS:: Adjuvant diclofenac and apraclonidine eye drop given in conjunction with selective laser trabeculoplasty (SLT) do not significantly impact medium-term intraocular pressure (IOP) reduction compared with placebo, but apraclonidine can be used to blunt immediate postlaser pressure spikes. PURPOSE: There is limited high-grade evidence guiding the choice of eye drops given before and after SLT. The authors chose to measure IOP during the first 24 hours, at 1 week, 6 weeks, and 6 months after SLT, and compare the effect of apraclonidine before SLT and diclofenac after SLT, with placebo. MATERIALS AND METHODS: In this double-blind, randomized, placebo-controlled trial, patients with open-angle glaucoma or ocular hypertension referred for SLT were recruited between 2016 and 2018. Patients were randomized to receive either apraclonidine pre-SLT with placebo post-SLT, placebo pre-SLT with diclofenac post-SLT, or placebo before and after SLT. RESULTS: Sixty eyes from 35 patients were treated with 360-degree SLT. Twenty-four-hour IOP measurements with patient self-monitoring after SLT demonstrated a moderate IOP spike at 1 hour and 2 hours post-SLT in the placebo and diclofenac study arms (mean=+4.05±0.58 mm Hg and +4.47±0.73, respectively, P<0.001 vs. pre-SLT IOP), which was prevented by apraclonidine (mean=-2.41±0.88 mm Hg, P<0.0001 vs. other study arms post-SLT). There were no significant differences between the 3 arms of the study on the long-term IOP reduction achieved by SLT (6 wk: P=0.51, 6 mo: P=0.42). CONCLUSIONS: Neither the use of apraclonidine before SLT nor diclofenac after SLT significantly influenced the IOP reduction induced by SLT. Except for a slight and transient reduction in intraocular inflammation, there was no beneficial effect of diclofenac on early IOP changes or the degree of patient discomfort relative to placebo.

Italian consensus on treatment of spasticity in multiple sclerosis.

BACKGROUND: Spasticity is a frequent multifactorial manifestation of multiple sclerosis (MS), affecting mostly the chronic courses of the disease. Its impact on patient functioning and quality of life is profound. Treatment of spasticity includes oral and intrathecal anti-spastic drugs, muscle injections with relaxant agents, physical therapy, electrical and magnetic stimulation and peripheral nerve stimulation, alone or in various combinations. METHODS: This Italian consensus on the treatment of spasticity in MS was produced by a large group of Italian MS experts in collaboration with neurophysiologists, experts in the production of guidelines and patients' representatives operating under the umbrella of the Italian Neurological Society, the Associazione Italiana Sclerosi Multipla and the European Charcot Foundation. This guideline was developed in accordance with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. A total of 11 questions were formulated following the PICO framework (patients, intervention, comparator, outcome). Controlled studies only were included in the analysis. RESULTS: Despite some consistent limitations due to the poor methodological quality of most studies, there was a consensus on a strong recommendation for the use of intrathecal baclofen, oromucosal spray of nabiximols and intramuscular injection of botulinum toxin. The level of recommendation was weak for oral baclofen, tizanidine, gabapentin, benzodiazepines and transcranial magnetic stimulation. CONCLUSIONS: There is a clear need for new larger multicentre well-designed clinical trials with a duration that allows the persistence of the effects and the long-term safety of the interventions to be evaluated.

The role of Smyrnium cordifolium Boiss extract and curzerene on withdrawal syndrome in mice.

Morphine is the most effective medication to relieve pain, antinociception and withdrawal syndrome, but clinical application of these compounds is greatly affected by the occurrence of addiction. The aim of this research was the influence of SE and curzerene (Cur) on withdrawal syndrome signs in mice contrasted with clonidine. Extraction of the S. cordifolium extract (SE) was done by the Soxhlet method. Addiction was produced using the subcutaneous injections of morphine for 7 days. To estimate the influences of SE and Cur, the 64 male mice were separated into eight of 8. Sets 1, 2 and 3 were treated SE (100,200,300 mg/kg). Sets 4, 5 and 6 were treated Cur (0.03, 0.06, 0.12mg/kg). The findings showed that curzerene was the most important effective component S. cordifolium extract. Curzerene and SE reduced the mean of weight loss, diarrhea, and wet dog shakes in morphine-dependent mice in comparison with clonidine. All doses of Curzerene and SE extract reduced the locomotor activity and body weight loss when compared to the control group in morphine-dependent mice but not to clonidine compared. The SE (100mg/kg) and Cur (0.03mg/kg) are reduced signs of withdrawal syndrome equally to clonidine. SE (200 mg/kg) and Cur (0.06 mg/kg), are reduced of the body weight loss significantly in relation to clonidine (P<0.05). SE (200 mg/kg) and Cur (0.06 mg/kg), are reduced of diarrhea significantly in relation to clonidine (P<0.01). This was while SE (300mg/kg) and cur (0.12mg/kg) had deadly effect. Curzerene and SE are able to decrease the signs of withdrawal syndrome, which might have a human therapeutic capacity. Curzerene may be one of the terpenoids responsible for the effect of the S. cordifolium extract. Nevertheless, more investigations are needed to determine the exact mechanism of the effect of SE and curzerene.

[HTA and non-hormonal menopause treatment]. / HTA et traitements non-hormonaux de la ménopause.

Serotonin reuptake inhibitors, clonidine, gabapentin and pregabalin have shown moderate efficacy in menopausal disorders. The effect of phytoestrogens is reported to be modest, but the side effects are not well known.

Hypertensive Urgency: An Undesirable Complication of a "Male Performance" Herbal Product.

BACKGROUND: Hypertensive urgency is a clinical scenario that may be associated with herbal supplement use and that requires special consideration with regard to emergency department management. CASE REPORT: A 49-year-old man presented to the emergency department with palpitations and severely elevated blood pressure without evidence of end organ dysfunction. Hypertension failed to be controlled with multiple doses of oral clonidine and intravenous labetalol. The patient later admitted to using an herbal supplement containing yohimbine, a selective ⍺2-adrenoreceptor antagonist specifically linked to cases of refractory hypertension. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Between 17-35% of the U.S. adult population may use herbal supplements on a sporadic or regular basis; pharmacologically active agents in herbal supplements may affect both a patient's presentation and response to treatment. Most patients do not mention over-the-counter and herbal products in their medication profile unless specifically asked, and therefore it is important for emergency physicians to be aware of the pharmacologic effects of herbal supplements in the evaluation and treatment of refractory severe hypertension.

Antiasthmatic potential of Zizyphus jujuba Mill and Jujuboside B. - Possible role in the treatment of asthma.

Zizyphus jujuba Mill, a famous oriental traditional medicine, has been reported to exhibit diverse activities in biological systems including the respiratory system. However, a little information is available on its antiasthmatic activity. Jujuboside B (JB) is a natural saponin and one of the active constituent of fruits of Zizyphus jujuba. In the present investigation, JB was isolated from ethanolic extracts of fruits of Zizyphus jujuba (EZJF). EZJF and JB were then evaluated for anti-asthmatic activity using various screening methods. JB was additionally evaluated using ovalbumin (OVA) -induced allergic asthma in mice. Results obtained in the present study showed that EZJF and JB significantly inhibited clonidine-induced catalepsy, milk-induced leucocytosis and eosinophilia, clonidine-induced mast cell degranulation, and passive paw anaphylaxis. The number of inflammatory cells in bronchoalveolar lavage (BAL) fluid was considerably lowered and the severity of pulmonary inflammation was alleviated in the mice pretreated with JB. The high-level expression of T-helper type 2 (TH2) cytokines was markedly reduced in the serum, BAL fluid, and lung homogenates. Thus EZJF and JB showed potent anti-asthmatic activity. Hence EZJF and JB possess a potential role in the treatment of asthma.