Intensity-dependent regional cerebral blood flow during 1-Hz repetitive transcranial magnetic stimulation (rTMS) in healthy volunteers studied with H215O positron emission tomography: I. Effects of primary motor cortex rTMS.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) affects the excitability of the motor cortex and is thought to influence activity in other brain areas as well. We combined the administration of varying intensities of 1-Hz rTMS of the motor cortex with simultaneous positron emission tomography (PET) to delineate local and distant effects on brain activity. METHODS: Ten healthy subjects received 1-Hz rTMS to the optimal position over motor cortex (M1) for producing a twitch in the right hand at 80, 90, 100, 110, and 120% of the twitch threshold, while regional cerebral blood flow (rCBF) was measured using H(2)(15)O and PET. Repetitive transcranial magnetic stimulation (rTMS) was delivered in 75-pulse trains at each intensity every 10 min through a figure-eight coil. The regional relationship of stimulation intensity to normalized rCBF was assessed statistically. RESULTS: Intensity-dependent rCBF increases were produced under the M1 stimulation site in ipsilateral primary auditory cortex, contralateral cerebellum, and bilateral putamen, insula, and red nucleus. Intensity-dependent reductions in rCBF occurred in contralateral frontal and parietal cortices and bilateral anterior cingulate gyrus and occipital cortex. CONCLUSIONS: This study demonstrates that 1-Hz rTMS delivered to the primary motor cortex (M1) produces intensity-dependent increases in brain activity locally and has associated effects in distant sites with known connections to M1.     

Pharmacokinetics of peptide T in patients with Acquired Immunodeficiency Syndrome (AIDS)

1. The pharmacokinetics of Dalal-peptide T-NH2 (peptide T) was determined during phase I clinical trials in patients with acquired immunodeficiecy disease (AIDS) and AIDS related complex (ARC). Drug levels were determined by specific RIA, and in some cases with HPLC analysis, after intraveneous (i.v.) or intranasal (i.n.), via metered sprayer, administration.

2. The plasma kinetics appeared to be bi-phasic with a first compartment half-life of 30 to 60 minutes and a second plasma clearence rate of 4 to 6 hours, observed for both routes of administration. Peptide T, in one individual was confirmed to be present at 6 hrs in plasma, determined after HPLC isolation followed by specific RIA.

3. Bioavailabilty, determined for a 2 mg test dose in six individuals was 9.3 ± 6.9 nmol/L. Peak plasma levels of 41 ± 30 nmol/L after 10 mg i.n., 2.8 ± 5.9 nmol/L after 2mg i.n., and 0.13 ± 0.07 nmol/L after 0.4 mg i.n. were observed. In two individuals tested, peptide T was detected in CSF at levels 20% of the corresponding plasma level 90 and 145 minutes post i.v. administration. Peptide T was not detected in urine. I.N. administration was well tolerated for times up to 21 months.     

Muscarinic Receptors Activate Calcium Channels and Calcium Dependent Potassium Channels in NIE-115 Neuroblastoma Cells

Abstract: Responses of NIE-115 neuroblastoma cells to application of carbachol were studied using intracellular recording techniques. Activation of muscarinic cholinergic receptors by carbachol resulted in a depolarization of the cells. The response was blocked by pirenzepine (1 μM) and by CoCl₂ (5 mM), verapamil (10 μM) and gallopamil (10 μM), and prolonged by quinine (5 mM). It is suggested that muscarinic receptors increase the membrane calcium permeability, and that the influx of calcium activates calcium dependent potassium channels.     

Normal calcium homeostasis

Conclusion This introduction to normal calcium provides a basis for an understanding of the investigation of calcium disorders, which now follows.     

A Retrospective Review of the Use and Safety of Droperidol in a Large, High-risk, Inner-city Emergency Department Patient Population

Droperidol (DROP) is used in the emergency department (ED) for sedation, analgesia, and its antiemetic effect. Its ED safety profile has not yet been reported in patients (pts). OBJECTIVES: To document the use of DROP in high-risk pts (those with head injury, alcohol or cocaine intoxication, and/or remote or recent seizures), and to determine the number of serious and minor adverse events (AEs)-seizures, hypotension, extrapyramidal side effects (EPSEs)-after DROP. METHODS: The ED database (EmSTAT) was queried to determine who received intramuscular or intravenous DROP in the ED in 1998; further chart review was done if the patient was considered high risk for or had experienced an AE. Multiple regression analysis using a random-effects model determined the significance of each variable in the occurrence of AEs. RESULTS: 2,468 patients (aged 20 months to 98 years; 112 < or =17 years; 141 > or =66 years) received DROP for agitation (n = 1,357), pain (1,135), anxiety (99), vomiting (173), or other reasons (50). There were 945 pts considered high risk; 933 charts were reviewed (DROP mean dose 4.1 +/- 2.0 mg); of these, 50 patient visits did not meet the criteria for high risk. There were 622 pts with head trauma (401 with alcohol use), including 47 with computed tomography (CT) scans positive for brain injury, 64 with cocaine use, and 197 with recent or remote seizures (137 with alcohol use). Minor AEs such as transient hypotension occurred in 96 pts after DROP (73 with alcohol use); 20 received intravenous fluids, while an additional 28 pts (8 with alcohol use) received rescue medications for EPSEs. Six possible serious AEs occurred in pts with serious comorbidities; 2 cases of respiratory depression, 3 post-DROP seizures, and 1 cardiac arrest (resuscitated) 11 hours after DROP in a cocaine-intoxicated pt (normal QT interval). There was no significant difference among high-risk groups in the occurrence of AEs. CONCLUSIONS: The vast majority of pts who received DROP in the ED did not experience an AE. A few serious AEs were noted following DROP in patients with serious comorbidities; it is not clear that DROP was causative.     

Clonidine and Dexmedetomidine Potently Inhibit Peristalsis in the Guinea Pig Ileum In Vitro

Background: Inhibition of intestinal peristalsis is a major side effect of drugs used for anesthesia or for analgesia and sedation of patients in the intensive care unit. This in vitro study examined the effect of clonidine and dexmedetomidine on intestinal peristalsis and analyzed some of their mechanisms of action.

Methods: In isolated segments of the guinea pig small intestine, peristalsis was triggered by a perfusion-induced rise of the intraluminal pressure. The peristaltic pressure threshold to elicit a peristaltic wave was used to quantify drug effects on peristalsis. Vehicle (Tyrode's solution), clonidine (10 nm-100 [mu]m), or dexmedetomidine (0.1-100 nm) were added extraserosally to the organ bath. In other series of experiments, clonidine or dexmedetomidine was administered after pretreatment with yohimbine, prazosin, apamin, naloxone, or vehicle. Clonidine was also tested after blockade of NO synthase with l-NAME and in the presence of the inactive enantiomer d-NAME.

Results: Clonidine and dexmedetomidine concentration-dependently increased peristaltic pressure threshold and inhibited peristalsis (clonidine: EC50 = 19.6 [mu]m; dexmedetomidine: EC50 = 12.0 nm). The inhibition caused by clonidine could be prevented by pretreatment with yohimbine, naloxone, and apamin, but not by prazosin, l-NAME, or d-NAME. Inhibition caused by dexmedetomidine was prevented by yohimbine only.