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71.
Benno Roesch Mary Corcoran Mary Haffey Annette Stevenson Phillip Wang Jaideep Purkayastha Patrick Martin James Ermer 《Drugs in R&D》2013,13(1):53-61
Background
α2-Adrenoceptor agonists are used adjunctively to psychostimulants in treating attention-deficit/hyperactivity disorder (ADHD) when psychostimulants alone do not sufficiently reduce symptoms. However, data on the pharmacokinetic profiles and safety of combination treatments in ADHD are needed.Objective
The primary objective of this study was to evaluate the pharmacokinetic profiles of guanfacine extended release (GXR) and methylphenidate hydrochloride (MPH) extended release, alone and in combination.Study Design
This was an open-label, randomized, three-period crossover, drug–drug interaction study.Setting
The study was conducted at a single clinical research center.Participants
Thirty-eight healthy adults were randomized in this study.Interventions
Subjects were administered single oral doses of GXR (Intuniv®; Shire Development LLC, Wayne, PA, USA) 4 mg, MPH (Concerta®; McNeil Pediatrics, Titusville, NJ, USA) 36 mg, or GXR and MPH combined.Main Outcome Measures
Guanfacine, dexmethylphenidate (d-MPH), and l-methylphenidate (l-MPH) levels were measured with blood samples collected predose and up to 72 h postdose. Safety evaluations included treatment-emergent adverse events (TEAEs), vital signs, and electrocardiograms (ECGs).Results
Thirty-five subjects completed the study. Analyses of the 90 % confidence intervals (CIs) for the geometric mean ratios of the maximum plasma concentration (Cmax) and area under the concentration–time curve extrapolated to infinity (AUC∞) values for guanfacine and d-MPH following administration of GXR or MPH alone or combined met strict bioequivalence criteria (90 % CIs within the interval of 0.80–1.25). Overall, combining GXR and MPH did not alter the pharmacokinetic parameters of either medication. Sixteen subjects (42.1 %) had at least one TEAE. The most commonly reported TEAEs included headache and dizziness following GXR, MPH, and GXR and MPH combined. Two subjects had clinically significant abnormalities in ECG results following coadministration: both events were mild and resolved the same day.Conclusions
In this short-term, open-label study of healthy adults, coadministration of GXR and MPH did not result in significant pharmacokinetic drug–drug interactions. No unique TEAEs were observed with coadministration of GXR and MPH compared with either treatment alone. 相似文献72.
73.
Background
HIV/AIDS has been described as the fourth largest cause of death globally and leading cause of death in Africa. HIV/AIDS has been a devastating inferno for nearly 30 years, and has particularly impacted countries in sub-Saharan Africa. In most African countries, it has been reported that the HIV infection amongst the military has been shown to be about 2 to 5 times higher than their civilian counterparts.Objective
To address the knowledge level of HIV/AIDS and risk-related behaviours in military personnel, a well-described high risk groups for HIV/AIDS.Methods
A cross-sectional study among army personnel in 82 Division Nigerian Army Headquarters Enugu, which has a population of about 1777. A random sampling in all the departments of 82 Division Nigerian Army Headquarters was done using the ballot method to select the respondents. Approval for the study was obtained from the General Officer in Command (GOC) of the 82 Division Nigerian Army Headquarters Enugu.Results
There were no significant differences between the risk related behavior variables when comparisons were made between those under 30 years, and those 30 years and above. Furthermore, more respondents under 30 years (48.0%) did not seek medical treatment when infected with another STI before having sex again as against 45% of those above 30 years. Most of the respondents (9.1%) under the age of 30 years believed that HIV/AIDS could be contracted through mosquito bites as against 2.8% of those above 30 years.Conclusion
The knowledge level of HIV/AIDS among the army personnel was high, though misconceptions about transmission modes like getting HIV through the bites of mosquitoes and casual body contacts were noted, especially among those under 30 years of age. 相似文献74.
75.
There is a relationship between arterial blood pressure, cardiac output and vascular resistance described mathematically, that helps us to understand short-term control of blood pressure in terms of a hydraulic system. Arterial baroreceptors are specialized sensors which mediate a rapid response to sudden changes in pressure through interaction with the autonomic nervous system. This in turn influences heart rate, inotropic state and vascular tone, altering distribution of blood between arterial and venous systems, thus compensating for acute changes in total blood volume. Total blood volume is controlled predominantly by the kidney, with the renin–angiotensin–aldosterone system acting as both the ‘sensor’ of blood pressure/volume (via renin release in the juxtaglomerular apparatus) and the ‘effector’ of blood pressure/volume (via aldosterone secretion by the adrenal cortex). Overall control is shared; the baroreceptors being responsible for mediating short-term changes, and renal mechanisms determining the long-term control of blood pressure. These systems have to be adaptable in order to deal with physiological variation in the delivery of blood to tissues from rest to exercise, and with the large shifts in blood volume seen in acute haemorrhage. Pathophysiological changes in these systems lead to maladaptive responses, with systemic hypertension the most commonly seen. 相似文献
76.
Stress affects a constellation of physiological systems in the body and evokes a rapid shift in many neurobehavioral processes. A growing body of work indicates that the endocannabinoid (eCB) system is an integral regulator of the stress response. In the current review, we discuss the evidence to date that demonstrates stress-induced regulation of eCB signaling and the consequential role changes in eCB signaling have with respect to many of the effects of stress. Across a wide array of stress paradigms, studies have generally shown that stress evokes bidirectional changes in the two eCB molecules, anandamide (AEA) and 2-arachidonoyl glycerol (2-AG), with stress exposure reducing AEA levels and increasing 2-AG levels. Additionally, in almost every brain region examined, exposure to chronic stress reliably causes a downregulation or loss of cannabinoid type 1 (CB1) receptors. With respect to the functional role of changes in eCB signaling during stress, studies have demonstrated that the decline in AEA appears to contribute to the manifestation of the stress response, including activation of the hypothalamic–pituitary–adrenal (HPA) axis and increases in anxiety behavior, while the increased 2-AG signaling contributes to termination and adaptation of the HPA axis, as well as potentially contributing to changes in pain perception, memory and synaptic plasticity. More so, translational studies have shown that eCB signaling in humans regulates many of the same domains and appears to be a critical component of stress regulation, and impairments in this system may be involved in the vulnerability to stress-related psychiatric conditions, such as depression and posttraumatic stress disorder. Collectively, these data create a compelling argument that eCB signaling is an important regulatory system in the brain that largely functions to buffer against many of the effects of stress and that dynamic changes in this system contribute to different aspects of the stress response. 相似文献
77.
目的:通过分析精神分裂症患者中枢多巴胺代谢产物-血浆高香草酸浓度(pHVA)与临床指征的关系,进一步探讨多巴胺神经递质及其药物治疗在精神分裂症的作用。方法在46例长期药物治疗、58例未治疗精神分裂症患者中,采用高液相色谱连接电化学分析仪测定PHVA;测前评定阳性症状量表(SAPS)和阴性症状量表(SANS)。结果(1)与62例健康对照组比,治疗组PH-VA显著减低,未治疗组显著增高,以阴性症状组为 相似文献
78.
Transcranial magnetic stimulation does not improve mild cognitive impairment in Parkinson's disease 下载免费PDF全文
79.
Mechanisms of status epilepticus: α‐Amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor hypothesis 下载免费PDF全文
Prolonged seizures of status epilepticus (SE) result from failure of mechanisms of seizure termination or activation of mechanisms that sustain seizures. Reduced γ‐aminobutyric acid type A receptor–mediated synaptic transmission contributes to impairment of seizure termination. However, mechanisms that sustain prolonged seizures are not known. We propose that insertion of GluA1 subunits at the glutamatergic synapses causes potentiation of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic receptor (AMPAR)‐mediated neurotransmission, which helps to spread and sustain seizures. The AMPAR‐mediated neurotransmission of CA1 pyramidal neurons was increased in animals in SE induced by pilocarpine. The surface membrane expression of GluA1 subunit–containing AMPARs on CA1 pyramidal neurons was also increased. Blockade of N‐methyl‐d ‐aspartate receptors 10 minutes after the onset of continuous electrographic seizure activity prevented the increase in the surface expression of GluA1 subunits. N‐methyl‐d ‐aspartate receptor antagonist MK‐801 in conjunction with diazepam also terminated seizures that were refractory to MK‐801 or diazepam alone. Future studies using mice lacking the GluA1 subunit expression will provide further insights into the role of GluA1 subunit–containing AMPAR plasticity in sustaining seizures of SE. 相似文献
80.
Xin Ren Anastasia Brodovskaya John L. Hudson Jaideep Kapur 《The Journal of neuroscience》2021,41(36):7623
There is uncertainty regarding when and which groups of neurons fire synchronously during seizures. While several studies found heterogeneous firing during seizures, others suggested synchronous neuronal firing in the seizure core. We tested whether neuronal activity during seizures is orderly in the direction of the excitatory neuronal connections in the circuit. There are strong excitatory connections laterally within the septotemporally organized lamella and inhibitory trans-lamellar connections in the hippocampus, which allow testing of the connectivity hypothesis. We further tested whether epileptogenesis enhances synchrony and antiseizure drug administration disrupts it. We recorded local field potentials from CA1 pyramidal neurons using a small microelectrode array and kindled rats by a rapid, recurrent hippocampal stimulation protocol. We compared cross-correlation, theta phase synchronization, entropy, and event synchronization. These analyses revealed that the firing pattern was correlated along the lamellar, but not the septotemporal, axis during evoked seizures. During kindling, neuronal synchrony increased along the lamellar axis, while synchrony along the septotemporal axis remained relatively low. Additionally, the theta phase distribution demonstrated that CA1 pyramidal cell firing became preferential for theta oscillation negative peak as kindling progressed in the lamellar direction but not in the trans-lamellar direction. Last, event synchronization demonstrated that neuronal firings along the lamellar axis were more synchronized than those along the septotemporal axis. There was a marked decrease in synchronization and phase preference after treatment with phenytoin and levetiracetam. The synchrony structure of CA1 pyramidal neurons during seizures and epileptogenesis depends on anatomic connectivity and plasticity.SIGNIFICANCE STATEMENT We could improve the efficacy of brain stimulation to treat seizures by understanding the structure of synchrony. Electrical stimulation may disrupt seizures by desynchronizing neurons, but there is an uncertainty on which groups of neurons fire synchronously or chaotically during seizures. Here, we demonstrate that neurons linked by excitatory connections fire synchronously during seizures, and this synchrony is modulated by epileptogenesis and antiseizure drugs. Closed-loop brain stimulation carefully targeted to disrupt synchrony may improve the treatment of seizures. 相似文献