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1.
J Vet Med Sci ; 83(10): 1570-1581, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34470979

RESUMO

The activation of α2 adrenergic receptors contributes to analgesia not only in the central nervous system but also in the peripheral nervous system. We reported that noradrenaline inhibits the activity of transient receptor potential vanilloid 1 (TRPV1) evoked by capsaicin through α2 receptors in cultured rat dorsal root ganglion (DRG) neurons. However, it is unclear whether activation of TRPV1 expressed in peripheral nerve terminals is inhibited by α2 receptors and whether this phenomenon contributes to analgesia. Therefore, we examined effects of clonidine, an α2 receptor agonist, on several types of nociceptive behaviors, which may be caused by TRPV1 activity, and subtypes of α2 receptors expressed with TRPV1 in primary sensory neurons in rats. Capsaicin injected into hind paws evoked nociceptive behaviors and clonidine preinjected into the same site inhibited capsaicin-evoked responses. This inhibition was not observed when clonidine was injected into the contralateral hind paws. Preinjection of clonidine into the plantar surface of ipsilateral, but not contralateral, hind paws reduced the sensitivity to heat stimuli. Clonidine partially reduced formalin-evoked responses when it was preinjected into ipsilateral hind paws. The expression level of α2C receptor mRNA quantified by real-time PCR was highest followed by those of α2A and α2B receptors in DRGs. α2A and α2C receptor-like immunoreactivities were detected with TRPV1-like immunoreactivities in the same neurons. These results suggest that TRPV1 and α2 receptors are coexpressed in peripheral nerve terminals and that the functional association between these two molecules causes analgesia.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Clonidina/uso terapêutico , Manejo da Dor , Receptores Adrenérgicos alfa 2 , Canais de Cátion TRPV/fisiologia , Animais , Nociceptividade , Dor , Nervos Periféricos , Ratos
2.
Life Sci ; 284: 119912, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34461082

RESUMO

AIMS: Sudden unexpected death in epilepsy (SUDEP) is a serious and underestimated public health burden. Both clinical and animal studies show that seizure-induced respiratory arrest (S-IRA) is the primary cause of death in SUDEP. Our previous studies demonstrated that atomoxetine, a norepinephrine reuptake inhibitor (NRI), suppresses S-IRA in DBA/1 mice, suggesting that noradrenergic neurotransmission modulates S-IRA. However, it remains unclear which adrenoceptors are implicated in S-IRA in DBA/1 mice. MATERIALS AND METHODS: Naïve DBA/1 mice exhibit a low incidence of S-IRA, but after primed by acoustic stimulation, they become consistently susceptible to S-IRA. Atomoxetine, adrenoceptor agonists, antagonists or vehicle was intraperitoneally (i.p.) administered alone or in combination, and the effects of drug treatments on S-IRA incidence and seizure behaviors were examined. KEY FINDINGS: The incidence of S-IRA in primed DBA/1 mice was significantly reduced by clonidine, an α2 adrenoceptor agonist, as compared with that of the vehicle control. However, compared with the vehicle control, S-IRA was not altered by cirazoline, an α1 agonist. Consistent with previous reports, atomoxetine reduced S-IRA in primed DBA/1 mice. The suppressing effect of atomoxetine on S-IRA was prevented by injection of an α2 adrenoceptor antagonist, yohimbine or atipamezole, but not by prazosin, an α1 antagonist. Administration of α1 or α2 antagonists alone did not promote the incidence of S-IRA in nonprimed DBA/1 mice. SIGNIFICANCE: These data demonstrate that noradrenergic neurotransmission modulates S-IRA predominantly via α2 adrenoceptors in DBA/1 mice, indicating that selective activation of α2 adrenoceptors can potentially prevent SUDEP.


Assuntos
Receptores Adrenérgicos alfa 2/metabolismo , Respiração , Convulsões/complicações , Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Antagonistas Adrenérgicos alfa/farmacologia , Animais , Cloridrato de Atomoxetina/farmacologia , Clonidina/farmacologia , Imidazóis/farmacologia , Camundongos Endogâmicos DBA
3.
Rev Med Liege ; 76(7-8): 614-619, 2021 Jul.
Artigo em Francês | MEDLINE | ID: mdl-34357714

RESUMO

Intracerebroventricular (ICV) infusion of morphine is a well-known technique to relieve intractable neoplasic pain when conventional analgesic strategies reach their limits. Through this case report, we present indications, assets, and drawbacks of this procedure in such conditions. We also describe the adaptation of the systemic analgesic treatment to allow discharge from the hospital to home settings. Thanks to the ICV infusion of a mixture of morphine, bupivacaine and clonidine, the patient was weaned from oral opioid medications and reached an acceptable level of comfort. This allowed him to be discharged from the hospital to go back home with a specific setting of mobile palliative care structure. The patient's family followed training about the device to prevent any technical trouble and to react in case of unwanted events.


Assuntos
Clonidina , Dor Intratável , Analgésicos Opioides/uso terapêutico , Bupivacaína/uso terapêutico , Clonidina/uso terapêutico , Humanos , Infusões Intraventriculares , Masculino , Morfina/uso terapêutico , Dor Intratável/tratamento farmacológico , Dor Pós-Operatória , Cuidados Paliativos
4.
Rev Med Suisse ; 17(746): 1374-1376, 2021 Aug 04.
Artigo em Francês | MEDLINE | ID: mdl-34397185

RESUMO

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.


Assuntos
Clonidina , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Clonidina/análogos & derivados , Humanos , Atenção Primária à Saúde
5.
Cochrane Database Syst Rev ; 7: CD002059, 2021 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-34231914

RESUMO

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.


Assuntos
Entorpecentes/uso terapêutico , Síndrome de Abstinência Neonatal/tratamento farmacológico , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Buprenorfina/uso terapêutico , Clorpromazina/uso terapêutico , Clonidina/uso terapêutico , Diazepam/uso terapêutico , Humanos , Hipnóticos e Sedativos/uso terapêutico , Recém-Nascido , Metadona/uso terapêutico , Morfina/uso terapêutico , Ópio/uso terapêutico , Fenobarbital/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto
6.
Anesth Analg ; 133(3): 620-629, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34153021

RESUMO

BACKGROUND: Peripheral nerve block (PNB) with perineural local anesthetic is used for anesthesia or analgesia with many benefits. To extend these benefits, various adjuvant drugs have been used to prolong the duration of analgesia. We aimed to evaluate the effectiveness of various adjuvants at prolonging the duration of sensory and motor blockade for PNB. METHODS: A network meta-analysis of placebo-controlled and active randomized controlled trials was performed comparing 10 adjuvants. Embase, PubMed, Web of Science, and Cochrane library were searched, with articles before May 21, 2020 included. Two authors independently selected studies and extracted data. The primary outcomes were sensory block (SB) and motor block (MB) time, and the secondary outcome was time of first analgesia rescue (FAR). Effect size measures were described as mean differences (MD) with 95% confidence intervals (CIs). Confidence in evidence was assessed using Confidence in Network Meta-Analysis (CINeMA). The study protocol was preregistered with the prospectively registered systematic reviews in health and social care international database (PROSPERO), as number CRD42020187866. RESULTS: Overall 16,364 citations were identified, of which 53 studies were included with data for 3649 patients. In network meta-analyses, 4 of 7 included treatment strategies were associated with more efficacious analgesia compared with placebo therapy, including dexamethasone (SB time: 5.73 hours, 95% CI, 4.16-7.30; MB time: 4.20 hours, 95% CI, 2.51-5.89; time of FAR: 8.71 hours, 95% CI, 6.63-10.79), dexmedetomidine (SB time: 4.51 hours, 95% CI, 3.52-5.50; MB time: 4.04 hours, 95% CI, 2.98-5.11; time of FAR: 5.25 hours, 95% CI, 4.08-6.43), fentanyl (SB time: 3.59 hours, 95% CI, 0.11-7.06; MB time: 4.42 hours, 95% CI, 0.78-8.06), and clonidine (SB time: 2.75 hours, 95% CI, 1.46-4.04; MB time: 2.93 hours, 95% CI, 1.69-4.16; time of FAR: 3.35 hours, 95% CI, 1.82-4.87). In a subgroup analysis, addition of dexamethasone to ropivacaine significantly increased the time of FAR when compared to dexmedetomidine (time of FAR: 5.23 hours, 95% CI, 2.92-7.54) or clonidine (time of FAR: 6.61 hours, 95% CI, 4.29-8.92) with ropivacaine. CONCLUSIONS: These findings provide evidence for the consideration of dexmedetomidine, dexamethasone, and clonidine as adjuvants to prolong the duration of PNB. The addition of dexamethasone to ropivacaine has a longer time of FAR compared with clonidine or dexmedetomidine.


Assuntos
Adjuvantes Anestésicos/administração & dosagem , Anestésicos Locais/administração & dosagem , Atividade Motora/efeitos dos fármacos , Bloqueio Nervoso , Sistema Nervoso Periférico/efeitos dos fármacos , Limiar Sensorial/efeitos dos fármacos , Adjuvantes Anestésicos/efeitos adversos , Anestésicos Locais/efeitos adversos , Clonidina/administração & dosagem , Dexmedetomidina/administração & dosagem , Esquema de Medicação , Interações Medicamentosas , Humanos , Bloqueio Nervoso/efeitos adversos , Metanálise em Rede , Medição de Risco , Fatores de Risco , Fatores de Tempo
7.
Eur J Pharm Sci ; 165: 105920, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34192586

RESUMO

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.


Assuntos
Clonidina , Espasmo , Administração Cutânea , Animais , Clonidina/análogos & derivados , Sistemas de Liberação de Medicamentos , Músculo Esquelético , Ratos
8.
Cochrane Database Syst Rev ; 5: CD002053, 2021 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-34002380

RESUMO

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 a sedative versus control (placebo, usual treatment or non-pharmacological treatment) for NAS due to withdrawal from opioids and determine which type of sedative is most effective and safe for NAS due to withdrawal from opioids. SEARCH METHODS: We ran an updated search on 17 September 2020 in CENTRAL via CRS Web and MEDLINE via Ovid. We searched clinical trials databases, conference proceedings and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. SELECTION CRITERIA: We included trials enrolling infants with NAS born to mothers with an opioid dependence with more than 80% follow-up and using randomised, quasi-randomised and cluster-randomised allocation to sedative or control. DATA COLLECTION AND ANALYSIS: Three review authors assessed trial eligibility and risk of bias, and independently extracted data. We used the GRADE approach to assess the certainty of the evidence. MAIN RESULTS: We included 10 trials (581 infants) with NAS secondary to maternal opioid use in pregnancy. There were multiple comparisons of different sedatives and regimens. There were limited data available for use in sensitivity analysis of studies at low risk of bias. Phenobarbital versus supportive care: one study reported there may be little or no difference in treatment failure with phenobarbital and supportive care versus supportive care alone (risk ratio (RR) 2.73, 95% confidence interval (CI) 0.94 to 7.94; 62 participants; very low-certainty evidence). No infant had a clinical seizure. The study did not report mortality, neurodevelopmental disability and adverse events. There may be an increase in days' hospitalisation and treatment from use of phenobarbital (hospitalisation: mean difference (MD) 20.80, 95% CI 13.64 to 27.96; treatment: MD 17.90, 95% CI 11.98 to 23.82; both 62 participants; very low-certainty evidence). Phenobarbital versus diazepam: there may be a reduction in treatment failure with phenobarbital versus diazepam (RR 0.39, 95% CI 0.24 to 0.62; 139 participants; 2 studies; low-certainty evidence). The studies did not report mortality, neurodevelopmental disability and adverse events. One study reported there may be little or no difference in days' hospitalisation and treatment (hospitalisation: MD 3.89, 95% CI -1.20 to 8.98; 32 participants; treatment: MD 4.30, 95% CI -0.73 to 9.33; 31 participants; both low-certainty evidence). Phenobarbital versus chlorpromazine: there may be a reduction in treatment failure with phenobarbital versus chlorpromazine (RR 0.55, 95% CI 0.33 to 0.92; 138 participants; 2 studies; very low-certainty evidence), and no infant had a seizure. The studies did not report mortality and neurodevelopmental disability. One study reported there may be little or no difference in days' hospitalisation (MD 7.00, 95% CI -3.51 to 17.51; 87 participants; low-certainty evidence) and 0/100 infants had an adverse event. Phenobarbital and opioid versus opioid alone: one study reported no infants with treatment failure and no clinical seizures in either group (low-certainty evidence). The study did not report mortality, neurodevelopmental disability and adverse events. One study reported there may be a reduction in days' hospitalisation for infants treated with phenobarbital and opioid (MD -43.50, 95% CI -59.18 to -27.82; 20 participants; low-certainty evidence). Clonidine and opioid versus opioid alone: one study reported there may be little or no difference in treatment failure with clonidine and dilute tincture of opium (DTO) versus DTO alone (RR 0.09, 95% CI 0.01 to 1.59; 80 participants; very low-certainty evidence). All five infants with treatment failure were in the DTO group. There may be little or no difference in seizures (RR 0.14, 95% CI 0.01 to 2.68; 80 participants; very low-certainty evidence). All three infants with seizures were in the DTO group. There may be little or no difference in mortality after discharge (RR 7.00, 95% CI 0.37 to 131.28; 80 participants; very low-certainty evidence). All three deaths were in the clonidine and DTO group. The study did not report neurodevelopmental disability. There may be little or no difference in days' treatment (MD -4.00, 95% CI -8.33 to 0.33; 80 participants; very low-certainty evidence). One adverse event occurred in the clonidine and DTO group. There may be little or no difference in rebound NAS after stopping treatment, although all seven cases were in the clonidine and DTO group. Clonidine and opioid versus phenobarbital and opioid: there may be little or no difference in treatment failure (RR 2.27, 95% CI 0.98 to 5.25; 2 studies, 93 participants; very low-certainty evidence). One study reported one infant in the clonidine and morphine group had a seizure, and there were no infant mortalities. The studies did not report neurodevelopmental disability. There may be an increase in days' hospitalisation and days' treatment with clonidine and opioid versus phenobarbital and opioid(hospitalisation: MD 7.13, 95% CI 6.38 to 7.88; treatment: MD 7.57, 95% CI 3.97 to 11.17; both 2 studies, 91 participants; low-certainty evidence). There may be little or no difference in adverse events (RR 1.55, 95% CI 0.44 to 5.40; 2 studies, 93 participants; very low-certainty evidence). However, there was oversedation only in the phenobarbital and morphine group; and hypotension, rebound hypertension and rebound NAS only in the clonidine and morphine group. AUTHORS' CONCLUSIONS: There is very low-certainty evidence that phenobarbital increases duration of hospitalisation and treatment, but reduces days to regain birthweight and duration of supportive care each day compared to supportive care alone. There is low-certainty evidence that phenobarbital reduces treatment failure compared to diazepam and very low-certainty evidence that  phenobarbital reduces treatment failure compared to chlorpromazine. There is low-certainty evidence of an increase in days' hospitalisation and days' treatment with clonidine and opioid compared to phenobarbital and opioid. There are insufficient data to determine the safety and incidence of adverse events for infants treated with combinations of opioids and sedatives including phenobarbital and clonidine.


Assuntos
Hipnóticos e Sedativos/uso terapêutico , Síndrome de Abstinência Neonatal/tratamento farmacológico , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Viés , Clorpromazina/uso terapêutico , Clonidina/uso terapêutico , Diazepam/uso terapêutico , Humanos , Recém-Nascido , Entorpecentes/uso terapêutico , Fenobarbital/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
9.
Ultrasound Med Biol ; 47(8): 2331-2338, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33972153

RESUMO

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.


Assuntos
Anti-Hipertensivos/uso terapêutico , Capilares , Clonidina/uso terapêutico , Hemorragia/tratamento farmacológico , Hemorragia/etiologia , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Pulmão/irrigação sanguínea , Xilazina/uso terapêutico , Animais , Hemorragia/diagnóstico por imagem , Masculino , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Ondas Ultrassônicas , Ultrassonografia
10.
BMC Res Notes ; 14(1): 191, 2021 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-34001271

RESUMO

OBJECTIVE: The naked mole rat (NMR) (Heterocephalus glaber) is increasingly considered an important biomedical research model for various conditions like hypoxic brain injury, cancer and nociception. This study was designed to investigate the effects of clonidine and yohimbine, an alpha-2 (α2) adrenoceptor agonist and antagonist respectively in the tail flick and hot plate tests. RESULTS: A significant difference in tail flick latency was noted between saline control and 30 µg/kg clonidine, which was reduced after administration of 30 µg/kg yohimbine. A significant difference in hot plate latency was also noted between saline control and 30 µg/kg clodinine during the periods 30, 45, 60, 75 and 90 min after administration, and between saline control and 10 µg/kg clonidine during 30 min after administration. The hot plate latency by 30 µg/kg clonidine was also reduced by 30 µg/kg yohimbine during 30 min after administration. Since the tail-flick and hot plate tests mediate the effects at spinal and supraspinal levels respectively, the present study indicates the presence and involvement of noradrenergic receptors in thermal antinociception at spinal and supraspinal levels of the NMR, similar to what has been found in other mammals.


Assuntos
Clonidina , Ratos-Toupeira , Analgésicos/farmacologia , Animais , Clonidina/farmacologia , Ioimbina/farmacologia
11.
J Med Case Rep ; 15(1): 250, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33931107

RESUMO

BACKGROUND: Hypokalemia has been rarely attributed to tizanidine, although the precise mechanism is unclear. Severe hypokalemia is a well-established cause of abnormalities involving cardiac conduction. Given this agent's well-known cardiac arrhythmogenic potential, awareness of potential concomitant electrolyte abnormalities is important. CASE PRESENTATION: Electrolyte disorders, including hypokalemia, are rare complications of the antispasmodic medicine tizanidine when taken in doses as outlined by the manufacturer's prescribing instructions. Although cases of severe hypokalemia have also been described in the literature in association with this agent, such reports are few. We report a Caucasian case of an intentional overdose involving a very large ingestion of tizanidine. In addition to the characteristic abnormalities on the electrocardiogram, our patient developed electrolyte derangements as well as self-limited acute kidney injury. These biochemical abnormalities included profound hypokalemia that was refractory to aggressive replacement over the ensuing several days, before eventually dissipating. A thorough assessment of the etiology of this hypokalemia was consistent with a defect in renal potassium handling. CONCLUSION: In our patient with intentional tizanidine overdose, severe and refractory hypokalemia appears to have been due to a transient potassium wasting nephropathy.


Assuntos
Hipopotassemia , Nefropatias , Clonidina/efeitos adversos , Clonidina/análogos & derivados , Humanos , Hipopotassemia/induzido quimicamente , Potássio
12.
J Headache Pain ; 22(1): 30, 2021 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-33902431

RESUMO

BACKGROUND: Episodic headache with spontaneous hypothermia constitute an uncommon association and is not well recognized in the International Classification of Headache Disorders (ICHD-3). Spontaneous periodic hypothermia, also called Shapiro's syndrome, is a rare disease characterized by hypothermia attacks associated or not with hyperhidrosis without any triggering factor. CASE PRESENTATION: We report a rare case of Shapiro's syndrome variantrevealed by episodes of headache with spontaneous hypothermia witheffectiveness of clonidine therapy in a 76-year-old Parkinson's disease woman. CONCLUSIONS: In the literature, apart from Shapiro's syndrome, headache withhypothermia seem to occur very rarely. In our case,these symptoms may be considered as a very rare non-motor fluctuation ofParkinson's disease.


Assuntos
Hiperidrose , Hipotermia , Idoso , Agenesia do Corpo Caloso , Clonidina/uso terapêutico , Feminino , Cefaleia , Humanos , Hipotermia/complicações , Síndrome
13.
J Psychiatr Res ; 137: 480-485, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33798975

RESUMO

Posttraumatic stress disorder (PTSD) symptoms of hyperarousal are mediated through sympathetic nervous system hyperactivity. PTSD symptoms, including distressing thoughts and memories, flashbacks, hyperarousal, and sleep disturbances, have been linked with elevated norepinephrine levels in the cerebrospinal fluid. Clonidine, an alpha2-adrenergic agonist, reduces the release of norepinephrine and has been suggested as a treatment for PTSD. However, literature for use of clonidine in PTSD is limited. The objective of this study was to evaluate clinical records of patients with PTSD treated with clonidine to assess reported efficacy and safety. A cohort of veterans with PTSD treated with clonidine at a midwestern VA hospital between July 2015 and January 2018 were studied retrospectively. Medical records of 79 patients with moderate to severe PTSD symptoms were reviewed by three independent clinicians using the Clinical Global Impressions (CGI) scale to quantify symptom severity (CGI-S) before starting clonidine and subjects' change in symptoms (CGI-I) after starting clonidine. Data on adverse events were also collected. Subgroup analyses were conducted on the impact of comorbid diagnoses, concurrent medications, and substance use. Mean CGI-S score at baseline was 4.8 (5 = markedly ill). After treatment with low-dose clonidine, 72% of patients experienced improvement, and 49% scored "much improved" or "very much improved." Adverse effects were reported by 18 out of 79 subjects. In this retrospective analysis of veterans prescribed clonidine for PTSD, CGI-I scores suggested improvement in PTSD symptoms, and minimal side effects were reported. In addition, some comorbid diagnoses and concurrent medications were correlated with variations in outcomes.


Assuntos
Transtornos do Sono-Vigília , Transtornos de Estresse Pós-Traumáticos , Veteranos , Clonidina , Humanos , Estudos Retrospectivos , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Resultado do Tratamento
14.
Yakugaku Zasshi ; 141(4): 591-598, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-33790124

RESUMO

The Japanese Pharmacopoeia (JP) is an official normative guide for maintaining the authenticity of properties and qualities of medicine in Japan. The JP is revised every 5 years, and partial amendments are made from time to time to keep abreast with progress in science and technology and international harmonization. We are conducting a related study on the elimination of toxic reagents from the JP. The elimination of toxic reagents is an important study in relation to the five pillars of the revision of the 18th JP, "Improvement in quality by proactively introducing the latest knowledge and technological advances". In addition, "Internationalization of the JP" is an important issue to be addressed during revision of the JP. Considering international harmonization of the JP, it is important to incorporate the test methods that have been used in other pharmacopoeia, such as the United States Pharmacopeia (USP) and the European Pharmacopoeia (EP) in the JP. To achieve the above, herein, we selected clonidine hydrochloride, which is listed in the 17th JP. A potentiometric titration method is used as a quantitative method for clonidine hydrochloride in the 17th JP; in contrast, a HPLC method is utilized in the USP and the EP. In this study, we synthesized impurities of clonidine hydrochloride and determined their purities using quantitative NMR. In addition, the complete separation conditions of these compounds by HPLC were examined, and simultaneous analysis was performed.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida de Alta Pressão/normas , Clonidina/análise , Internacionalidade , Farmacopeias como Assunto/normas , Japão , Espectroscopia de Ressonância Magnética/métodos
15.
Plant Physiol Biochem ; 162: 716-729, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33799183

RESUMO

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.


Assuntos
Arabidopsis , Solanum tuberosum , Arabidopsis/genética , Arabidopsis/metabolismo , Calmodulina/metabolismo , Clonidina/análogos & derivados , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Solanum tuberosum/genética , Solanum tuberosum/metabolismo
16.
J Clin Anesth ; 71: 110254, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33752119

RESUMO

STUDY OBJECTIVE: The primary goal of this study was to determine if the addition of clonidine to ropivacaine prolonged periumbilical numbness compared to ropivacaine alone in pediatric patients receiving ultrasound guided rectus sheath nerve blocks for laparoscopic appendectomy. The secondary goals were to evaluate differences in perioperative pain scores, analgesic consumption, sedation, anxiolysis, and hemodynamic effects from clonidine. DESIGN: This was a single center, randomized, double-blinded prospective study. SETTING: This study was conducted within the pediatric operating rooms at the Children's Hospital of Pittsburgh, a large university-based academic medical center. PATIENTS: Fifty pediatric patients (ages 10-17 years old) without pre-existing cognitive impairment, developmental delay or chronic pain undergoing laparoscopic appendectomy during weekday hours were enrolled and randomized to control versus intervention groups. INTERVENTION: Ultrasound guided rectus sheath nerve block injections were performed at the beginning of surgery with either ropivacaine 0.5% plus normal saline or ropivacaine 0.5% plus clonidine (2 mcg/kg, maximum of 100 mcg). MEASUREMENTS: The duration of periumbilical numbness, Numeric Pain Rating Scale scores, University of Michigan Sedation Scale, State-Trait Anxiety Inventory for Children, analgesic consumption, heart rate, blood pressure, and mean arterial pressures, were recorded for each patient at several time points in the perioperative setting. MAIN RESULTS: There were no significant differences in demographic characteristics between groups. The median duration of periumbilical numbness did not significantly differ between the ropivacaine only and the ropivacaine plus clonidine groups 540.0 minutes [360.0 -1015.0] (median [interquartile range (IQR)]) versus 823.5 minutes [509.5- 1080.0], p = 0.451. There were no significant differences in perioperative analgesic consumption, pain and anxiety scores, PACU sedation, or hemodynamic instability. CONCLUSIONS: The addition of clonidine did not significantly prolong rectus sheath nerve block duration and was well tolerated in pediatric patients. Perioperative analgesia, hemodynamics, anxiety, and PACU sedation did not differ between groups. TRIAL REGISTRATION: Clinical Trials NCT02439281.


Assuntos
Laparoscopia , Bloqueio Nervoso , Adolescente , Amidas/efeitos adversos , Anestésicos Locais , Apendicectomia/efeitos adversos , Criança , Clonidina/efeitos adversos , Método Duplo-Cego , Humanos , Bloqueio Nervoso/efeitos adversos , Dor Pós-Operatória/etiologia , Dor Pós-Operatória/prevenção & controle , Estudos Prospectivos , Ropivacaina
17.
Intensive Care Med ; 47(3): 316-324, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33591422

RESUMO

PURPOSE: Haloperidol and clonidine are commonly used to treat agitation in delirious intensive care unit (ICU) patients, but it is unclear whether these agents may shorten the duration of delirium. The objective of this study was to determine whether haloperidol, clonidine, or their combined administration to delirious ICU patients results in delirium resolution. METHODS: This was a cohort study on a mixed ICU, excluding patients with a primary neurological disorder. The main outcome was the probability of delirium resolution, using propensity score matching and Markov multinomial logistic regression models for daily transitions. Secondary outcomes were delirium duration, number of delirium days, ventilation days, length of stay in the ICU and hospital, and ICU mortality. RESULTS: A total of 3614 patients were included (1165 delirious [32%]; 2449 non-delirious [68%]). Delirium occurred on 4708 (18.9%) of 24,906 days. The probability of delirium resolution was lower in delirious patients who received haloperidol (OR 0.47, 95% CI 0.39-0.57), clonidine (OR 0.78, 95% CI 0.63-0.97), or both (OR 0.45, 95% CI 0.36-0.56) compared to untreated delirious patients. Delirious patients who received haloperidol, clonidine, or both had generally longer delirium duration, more delirium and ventilation days, and spent more time in the ICU and in hospital than untreated delirious patients. These agents had no effect on ICU mortality. CONCLUSION: Haloperidol and clonidine use in delirious ICU patients may be associated with reduced probability of delirium resolution. This finding, however, merits further investigation given inherent limitations of this observational analysis.


Assuntos
Delírio , Haloperidol , Clonidina/uso terapêutico , Estudos de Coortes , Estado Terminal , Delírio/tratamento farmacológico , Haloperidol/uso terapêutico , Humanos , Unidades de Terapia Intensiva , Estudos Prospectivos
18.
Pediatrics ; 147(3)2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33632932

RESUMO

BACKGROUND AND OBJECTIVES: Despite the neonatal opioid withdrawal syndrome (NOWS) epidemic in the United States, evidence is limited for pharmacologic management when first-line opioid medications fail to control symptoms. The objective with this study was to evaluate outcomes of infants receiving secondary therapy with phenobarbital compared with clonidine, in combination with morphine, for the treatment of NOWS. METHODS: We performed a retrospective cohort study of infants with NOWS from 30 hospitals. The primary outcome measures were the length of hospital stay, duration of opioid treatment, and peak morphine dose. Outcomes were compared by group by using analysis of variance and multivariable linear regression controlling for relevant confounders. RESULTS: Of 563 infants with NOWS treated with morphine, 32% (n = 180) also received a secondary medication. Seventy-two received phenobarbital and 108 received clonidine. After adjustment for covariates, length of hospital stay was 10 days shorter, and, in some models, duration of morphine treatment was 7.5 days shorter in infants receiving phenobarbital compared with those receiving clonidine, with no difference in peak morphine dose. Infants were more likely to be discharged from the hospital on phenobarbital than clonidine (78% vs 29%, P < .0001). CONCLUSIONS: Among infants with NOWS receiving morphine and secondary therapy, those treated with phenobarbital had shorter length of hospital stay and shorter morphine treatment duration than clonidine-treated infants but were discharged from the hospital more often on secondary medication. Further investigation is warranted to determine if the benefits of shorter hospital stay and shorter duration of morphine therapy justify the possible neurodevelopmental consequences of phenobarbital use in infants with NOWS.


Assuntos
Analgésicos/uso terapêutico , Clonidina/uso terapêutico , Tempo de Internação/estatística & dados numéricos , Morfina/uso terapêutico , Síndrome de Abstinência Neonatal/tratamento farmacológico , Fenobarbital/uso terapêutico , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/uso terapêutico , Esquema de Medicação , Quimioterapia Combinada/métodos , Feminino , Humanos , Recém-Nascido , Modelos Lineares , Masculino , Morfina/administração & dosagem , Estudos Retrospectivos
19.
Trials ; 22(1): 149, 2021 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-33596969

RESUMO

BACKGROUND: First-line pharmacotherapy for neuropathic pain entails the use of systemic antidepressants and anticonvulsants. These drugs are not optimally effective and poorly tolerated, especially for older patients with comorbid conditions. Given the high number of such patients, there is a need for a greater repertoire of safer and more effective analgesics. Clonidine and pentoxifylline are vasodilator agents that work synergistically to enhance tissue perfusion and oxygenation. The topical administration of these drugs, individually and in combination, has shown anti-nociceptive properties in rodent models of neuropathic pain. A topically-administered combination of clonidine and pentoxifylline also effectively reduced the intensity of both spontaneous and evoked pain in healthy volunteers with experimentally-induced neuropathic pain. The next step in advancing this formulation to clinical use is the undertaking of a phase II clinical study to assess its efficacy and safety in neuropathic pain patients. METHODS/DESIGN: This is a study protocol for a randomized, double-blind, placebo-controlled, phase II clinical trial with a cross-over design. It is a single-centered, 5-week study that will enroll a total of 32 patients with post-traumatic peripheral neuropathic pain. Patients will be treated topically with either a combination of clonidine and pentoxifylline or placebo for a period of 2 weeks each, in randomly assigned order across patients, with an intervening washout period of 1 week. The primary outcome measures of the study are the intensity of spontaneous pain recorded daily in a pain diary with a visual analog scale, and the degree of mechanical allodynia evoked by a brush stimulus. The secondary outcome measures of the study include scores of pain relief and change in the area of punctate hyperalgesia. This trial has been prospectively registered with ClinicalTrials.gov on November 1, 2017. ClinicalTrials.gov Identifier: NCT03342950 . DISCUSSION: The analgesic use of topical treatment with clonidine and pentoxifylline in combination has not been investigated in post-traumatic neuropathic pain. This study could generate the first evidence for the efficacy and safety of the formulation in alleviating pain in patients with neuropathic pain. Furthermore, this trial will provide objective grounds for the investigation of other agents that enhance tissue oxygenation in the topical treatment of peripheral neuropathic pain. TRIAL REGISTRATION: This trial has been registered with ClinicalTrials.gov owned by NIH's US National Library of Medicine. ClinicalTrials.gov NCT03342950 . Registered on November 1, 2017 (trial was prospectively registered). PROTOCOL VERSION AND IDENTIFIERS: This is protocol version 5, dated June 2018. McGill University Health Center (MUHC) Reaseach Ethics Board (REB) identification number: TTNP 2018-3906.


Assuntos
Neuralgia , Pentoxifilina , Analgésicos/efeitos adversos , Clonidina/efeitos adversos , Método Duplo-Cego , Humanos , Neuralgia/diagnóstico , Neuralgia/tratamento farmacológico , Neuralgia/etiologia , Medição da Dor , Pentoxifilina/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto
20.
Drug Dev Ind Pharm ; 47(3): 394-402, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33615926

RESUMO

OBJECTIVE: The purpose of the present study was to prepare a clonidine hydrochloride (CH) sustained-release suspension. METHODS: The processes involved in the drug formulation included drug loading, impregnating, and suspension preparation. Clonidine hydrochloride drug-resin complexes (CH-DRC) were prepared using the bath method and the CH-DRC impregnated before the microencapsulation process. Based on the bottom spray fluidized bed coating method, the CH microencapsulated drug-resin complexes (CH-MC) were also prepared using Surelease® (the suspension of ethyl cellulose aqueous dispersion) as the coating material. The effects of coating (process/formulation) on the in vitro release of coating microcapsule were evaluated via single factor investigation and orthogonal design optimization. The CH-MC with optimized formulation was further dispersed in a suitable medium to obtain a sustained-release suspension. Rats were given commercial CH ordinary tablets and the CH sustained-release suspension via intragastric administration. The plasma concentration-time curve and related pharmacokinetic parameters were investigated using the non-compartment model. RESULTS: The Tmax of the CH sustained-release suspension was delayed from 2 h to 5 h compared with the CH ordinary tablets. Similarly, the Cmax was reduced from 32.138 µg·mL-1 to 18.150 µg·mL-1 with the concentration-time curve being more gentle compared with the commercially CH ordinary tablets. After oral administration, the relative bioavailability of CH sustained-release suspension (AUC0-24 of 137.703 µg·h·mL-1) to its CH ordinary tablets (AUC0-24 of 123.337 µg·h·mL-1) was 111.65%. CONCLUSIONS: The findings showed that the CH sustained-release suspension for oral administration was successfully formulated.


Assuntos
Clonidina , Animais , Disponibilidade Biológica , Preparações de Ação Retardada , Composição de Medicamentos , Ratos , Suspensões , Comprimidos
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