Dose-dependent enhancement of in vivo GABA(A)-benzodiazepine receptor binding by isoflurane.

BACKGROUND: Abundant in vitro and animal model data suggest the postsynaptic gamma-aminobutyric acid receptor type A (GABA(A)-R) is an important target for volatile general anesthetics, but the relevance of these models is untested in humans. Because benzodiazepines have also been shown to act via a specific GABA(A)-R site, they provide sensitive probes for the GABA(A)-R. Availability of the 11C-labeled benzodiazepine ligand, flumazenil, allowed us to quantitatively test in humans whether the volatile anesthetic isoflurane affects GABA(A)-Rs in vivo in a dose-dependent manner. METHODS: 11C-flumazenil positron emission tomography scans were obtained in 12 healthy subjects while awake (control condition) and anesthetized with either 1.0 or 1.5 minimum alveolar concentration isoflurane (n = 7 and 5, respectively; isoflurane conditions). Regions of interest included areas of high, intermediate, and low GABA(A)-benzodiazepine site density. For each subject and experimental condition, the binding of 11C-flumazenil, expressed as distribution volume (which linearly correlates to maximal binding site density and apparent ligand affinity), was obtained by curve fitting using a two-compartment model. RESULTS: The ratio of distribution volume increased significantly in each examined region during the isoflurane conditions compared with control conditions (P < 0.01, one-tailed t test). Furthermore, the increases in ratio of distribution volume during the 1.5-minimum alveolar concentration isoflurane condition were significantly greater than those measured during 1.0 minimum alveolar concentration isoflurane inhalation (P < 0.002, one-tailed t test). CONCLUSIONS: Isoflurane exposure appeared to enhance receptor-specific 11C-flumazenil binding in a dose-dependent manner. The results suggest the possibility that a conformational change of the GABA(A)-R is involved in the mechanism of action of isoflurane in the living human brain.

In vivo imaging of nitrous oxide-induced changes in cerebral activation during noxious heat stimuli.

BACKGROUND: Although previous studies have provided some insight into the pharmacologic aspects of nitrous oxide analgesia, the neural circuits mediating its antinociceptive effect remain relatively unexplored. Position emission tomography was used in nine volunteers to identify the loci of nitrous oxide-modulated cerebral responses to a peripheral noxious stimulus. METHODS: Nitrous oxide-pain interactions were studied by comparing regional cerebral blood flow responses to a 48 degrees C tonic heat stimulus, applied to each volunteer's left forearm, during room air inhalation with those obtained while 20% nitrous oxide was administered. Two cerebral blood flow scans were obtained with the 15O-water technique during each condition. Locations of specific regional activation related to pain, and nitrous oxide, were identified using the statistical parametric mapping method, with a significance level of P < 0.01. Pain was rated by visual analog scale and the values were compared using Wilcoxon rank sum analysis. RESULTS: Pain produced cerebral activation in the contralateral thalamus, anterior cingulate, and supplementary motor area. Adding nitrous oxide during pain stimulation abolished activation in these areas but was associated with activation in the contralateral infralimbic and orbitofrontal cortices. In parallel, mean visual analog scale scores decreased significantly from 67 +/- 4 (SEM) to 54 +/- 5 (P < 0.05). CONCLUSIONS: Nitrous oxide, at 20% concentration, appears to modulate pain processing in the brain's medial pain system, and also activates the infralimbic and orbitofrontal cortices. The potential contribution of the affected brain areas to nitrous oxide analgesia is discussed.

Regional brain activity changes associated with fentanyl analgesia elucidated by positron emission tomography.

Recent positron emission tomography (PET) studies have demonstrated areas of pain processing in the human brain. Given the inhibitory effects of opioids on neuronal activity, we predicted that fentanyl's analgesic effects would be associated with suppression of pain-evoked responses in these distinct brain areas. To test this, PET was used to measure cerebral blood flow responses, as reflections of regional neuronal activity, to painful and nonpainful thermal stimuli both in the absence and presence of fentanyl in humans. During each PET scan in nine healthy volunteers a tonic heat source was placed against the subject's left forearm, delivering a preset temperature of either 40 degrees C (nonpainful) or 47-48 degrees C (painful). Subjects underwent eight blood flow studies, each consisting of 50 mCi [15O]water injection and a PET scan. The first four studies were performed during placebo administration in the stimulus sequence: nonpainful, painful, painful, nonpainful. This sequence was then repeated during intravenous (i.v.) administration of fentanyl 1.5 micrograms/kg [corrected]. Significant differences in regional cerebral blood flow (rCBF) between the placebo and the fentanyl conditions during nonpainful and painful stimuli were identified using statistical parametric mapping. It was found that pain increased rCBF in the anterior cingulate, ipsilateral thalamus, prefrontal cortex, and contralateral supplementary motor area. Fentanyl increased rCBF in the anterior cingulate and contralateral motor cortices, and decreased rCBF in the thalamus (bilaterally) and posterior cingulate during both stimuli. During combined pain stimulation and fentanyl administration, fentanyl significantly augmented pain-related rCBF increases in the supplementary motor area and prefrontal cortex. This activation pattern was associated with decreased pain perception, as measured on a visual analog scale. In contrast to our hypothesis, these data indicate that fentanyl analgesia involves augmentation of pain-evoked cerebral responses in certain areas, as well as both activation and inhibition in other brain regions unresponsive to pain stimulation alone.

In vivo imaging of human limbic responses to nitrous oxide inhalation.

Human behavioral studies have shown that nitrous oxide, in subanesthetic concentrations, impairs psychomotor function, cognitive performance, and learning and memory processes. However, the cerebral mechanisms of such effects remain unknown. Positron emission tomography (PET) was used to map the brain areas associated with nitrous oxide effects. Regional cerebral blood flow (rCBF) was measured in eight volunteers, during room air (control) or 20% nitrous oxide (nitrous oxide) inhalation using 15(O)-water, to reflect regional neuronal activity. To control for the possibility that 20% nitrous oxide uncoupled cerebral blood flow and metabolism, in four of the subjects, regional cerebral metabolic rate (rCMR) was also measured using 18F-deoxyglucose during the two experimental conditions. Results of rCBF and rCMR scans were compared between conditions using the statistical parametric mapping method, and areas of nitrous oxide-related activation or deactivation were identified at a significance level of 0.005. Percent changes in rCBF scan pixels from these activated or deactivated areas were then compared with those of stereotactically corresponding rCMR scan pixels with t statistics (P < 0.05 was defined as a significant difference). It was found that cerebral blood flow and metabolism were not uncoupled by 20% nitrous oxide, since percent changes in rCBF and rCMR, detected during nitrous oxide inhalation, did not differ significantly from each other (P < 0.05). Nitrous oxide inhalation was associated with significant activation in the anterior cingulate cortex, a limbic area known to mediate psychomotor and cognitive processes. Deactivation was found in the posterior cingulate, hippocampus, parahippocampal gyrus, and visual association cortices in both hemispheres; the former two regions are known to mediate learning and memory. These areas identified by PET in vivo may provide the neuroanatomical basis for the behavioral responses associated with subanesthetic nitrous oxide inhalation.

Human brain activity response to fentanyl imaged by positron emission tomography.

Positron emission tomography (PET) is a noninvasive imaging technique that can be used to observe drug actions on human brain in vivo. We used 15O-water PET scanning in six volunteers to examine the effects on regional cerebral activity as reflected by regional cerebral blood flow (rCBF) of a small intravenous bolus of fentanyl. rCBF was compared between scans obtained after fentanyl or a placebo using three separate statistical criteria including a pixel-by-pixel t statistic; significance was stringently defined at P values < 0.01. Anatomic locations of regional cerebral activity changes were verified by aligning rCBF PET scans with cranial magnetic resonance images using mathematical coregistration. Fentanyl administration was associated with significant increases in rCBF consistent with regional neuronal activation in both cingulate and orbitofrontal and medial prefrontal cortices, as well as caudate nuclei. These areas are responsive to nociceptive stimuli and are involved in avoidance learning, reward and addiction, visceromotor control, maintenance of attention, and pain-related affective behavior. Significant decreases were noted in both frontal and temporal areas and the cerebellum, a distribution far less extensive than that of opiate receptors in general. These data indicate that fentanyl's effects are highly localized and specifically affect cerebral regions associated with a range of pain-related behaviors.

[The effect of copper and cobalt supplementation on the digestibility of fibrous feed in sheep]. / Vplyv prídavku medi a kobaltu na strávitel'nost fibróznych krmiv u oviec.

The effects of an addition of copper, cobalt, and copper + cobalt on the in vitro digestibility of hay, treated beech sawdust and cellulose by the rumen fluid of sheep fed a complete food ration, complete food ration with 15% treated beech sawdust and a diet consisting of 80% hay and 20% barley were investigated, respectively. The rumen fluid obtained from animals fed a complete food ration showed the significantly higher digestibility of hay (Tab. I) when Cu (P less than 0.05), Co, or Cu + Co (P less than 0.001) had been added into the rumen. The cellulose digestibility increased only after Co application (P less than 0.05). The microelements supplementation in all three forms had a very significant effect on the digestibility of treated beech sawdust by the rumen fluid of sheep fed a diet with 15% sawdust content, although the initial digestibility by the rumen fluid in the control animals (without microelements) was only 44.9%. A similar trend was also observed in the cellulose digestibility, but after Co application this increase was not significant. The rumen fluid of animals fed hay (80%) and barley (20%) showed the highest digestibility. The digestibility of sawdust reached 60% and the of cellulose 95.9% without microelements supplementation (control). In this case the effect of microelement supplementation on the sawdust digestibility was manifested only in the case of cobalt by the digestibility decrease (P less than 0.001). The cellulose digestibility also decreased after administration of Cu (P less than 0.01) and Co (P less than 0.05). The Cu + Co supplementation did not influence its digestibility.(ABSTRACT TRUNCATED AT 250 WORDS)

[How to choose a basic drug for psoriatic arthritis?]. / Hogyan válasszunk bázisszert arthritis psoriaticában?

On the basis of an earlier retrospective study in 270 psoriatic arthritis (PA) patients and according to the data of the literature 1. aurotherapy for the patients having mild skin changes and active joint involvement (mainly polyarticular type), 2. sulfasalazine for the patients having moderate skin changes and moderate articular activity, 3. etretinate for the patients having widespread skin involvement and mild articular activity, 4. methotrexate for the patients having both severe skin and severe articular involvement were introduced by the authors. The experiences of prospective study of 52 patients treated with disease modifying antirheumatic drugs (DMARDs) during 3-6 months are reported (21: aurothiomalate, 13: sulfasalazine, 4: methotrexate, 14: etretinate). Morning stiffness (MS), visual analog scale (VAS), number of swollen joints (No), psoriasis area and severity index (PASI) and erythrocyte sedimentation rate (ESR) were monitored. The methotrexate proved to be the most effective in every parameters, except the ESR. Regarding PASI the etretinate was the second most effective. Among the monitored parameters ESR and VAS showed significant improvement at every drugs. Withdrawal was necessary in 7 cases during aurotherapy (7/21), in 4 cases during sulfasalazine (4/13), in 4 cases during etretinate (4/14), meanwhile there was not withdrawal during methotrexate therapy. Low frequency of skin exacerbation (4/52) doesn't contraindicate the introduction of these drugs. If the choice and monitoring of psoriatic arthritis patients is correct we can detect really good results with DMARDs in PA.

Effect of monensin on rumen ciliate protozoa in sheep.

In a first experiment 4 rams consumed over a period of 70 days 0; 82; 208 and 345 mg of monensin daily, respectively. All doses of monensin caused a marked decrease in total numbers of rumen protozoa in samples taken after this period. More than 90% of total protozoal numbers belonged to the genus Entodinium. The sensitivity of the genus Entodinium to monensin was found to be lower than that of genera Dasytricha and Isotricha. In the second experiment 24 lambs were fed hay and concentrates in the ratio 60:40% (groups 1 and 2) and 40:60% (groups 3 and 4). Groups 2 and 4 received 40 mg monensin per animal daily during 16 weeks. The decrease in protozoal numbers due to monensin in samples taken after this period was significant (P less than 0.001) in lambs fed the concentrate diet (groups 3 and 4) and also in lambs from groups 1 and 2 fed the roughage diet (P less than 0.05). The statistical evaluation of the inhibition of total protozoal numbers by monensin (%) in lambs fed both diets has shown that the antiprotozoal effect of monensin was significantly more intensive with the concentrate diet (P less than 0.025) than with the roughage diet.