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 47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To define the effect of aging on the pharmacokinetics of volatile anesthetics, we determined the end-tidal and mixed expired anesthetic concentrations of isoflurane, enflurane, halothane, and methoxyflurane during 30 min of simultaneous administration and for 5-12 days of elimination in seven healthy young patients (31 +/- 1.8 yr [mean +/- SEM]) and in 11 healthy aged patients (73.2 +/- 3.1 yr [mean +/- SEM]). A five-compartment mammillary function was fit to the end-tidal and mixed expired anesthetic elimination data simultaneously using ordinary least-squares analysis. We assumed the compartments to represent the following tissue groups: lungs and pulmonary capillary blood (V1), vessel-rich tissues (i.e., liver, heart, kidneys, and brain) muscle, an unidentified fourth compartment, perhaps fat adjacent to well-perfused tissues, and fat tissues. The tissue volumes and perfusions estimated for these compartments approximated values from the literature. In general, the volume of the fourth and fifth compartments increased with age, and perfusion to the second and fifth compartments decreased with age. Aging delayed anesthetic elimination and increased the apparent volume of distribution at steady state. These observations are compatible with decreased tissue perfusion and an increase in the ratio of fat/lean body weight in the elderly. Our mammillary analysis described the behavior of less soluble anesthetics such as isoflurane well, but that of highly soluble anesthetics such as methoxyflurane less well.
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PMID:Age affects the pharmacokinetics of inhaled anesthetics in humans. 186 26

The effects of ethanol consumption during pregnancy on maternal, placental, and fetal tissue amino acid levels and metabolism were investigated. Pregnant Sprague-Dawley rats were given 35% ethanol-calorie liquid diet, ad libitum, from gestation day 7 to 21. Control rats were pair-fed with isocaloric sucrose substituted for ethanol. Ethanol consumption decreased fetal body weight and increased placental weight. Twenty-four amino acids were determined in six tissues (maternal plasma and liver, placenta, fetal plasma, liver, and brain) by HPLC with orthophthalaldehyde derivatization. The effects of ethanol on free amino acid levels differed from tissue to tissue. In general, ethanol affected more amino acids in maternal plasma, fetal plasma, and liver. Maternal liver, placenta, and fetal brain amino acids were more resistant to ethanol effect. Two essential amino acids, histidine and tryptophan, were consistently decreased in fetal tissues by maternal ethanol consumption. The values (ethanol vs. control, nmole/ml or g, mean +/- SEM, N = 20) of fetal plasma, liver, and brain for histidine were 51.8 +/- 6.0 vs. 85.3 +/- 4.5 (p = 0.001), 269.0 +/- 26.4 vs. 503.7 +/- 47.3 (p = 0.0004), and 117.9 +/- 7.7 vs. 154.6 +/- 8.7 (p = 0.0055), respectively; and for tryptophan were 105.7 +/- 3.1 vs. 132.2 +/- 4.1 (p = 0.0001), 128.8 +/- 3.7 vs. 144.3 +/- 6.0 (p = 0.0407), and 83.4 +/- 7.2 vs. 103.6 +/- 3.2 (p = 0.0198), respectively. Histidine was also decreased in placenta by ethanol (138.1 +/- 6.6 vs. 189.1 +/- 11.8 nmole/g, p = 0.0014).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Gestational ethanol consumption on tissue amino acid levels: decreased free histidine and tryptophan in fetal tissues with concomitant increase in urinary histamine excretion. 237 28

Adenosine is a neuromodulator and potent vasoactive metabolite involved in various CNS regulatory mechanisms. We have recently shown that the newborn has maturationally related deficiency in adenosine production. The brains of Sprague-Dawley rats studied at ages 1, 7, 21 and 60 days (n = 6-12/group) showed that adenosine and its metabolites (measured by high-pressure liquid chromatography) is deficient in the newborn. Adenosine brain concentration was 0.99 nmol/g brain in newborn rats (day 0-1) and progressively increased postnatally to an adult value of 14.4 nmol/g brain. Inosine, a degradative product of adenosine by deaminase is significantly increased in newborns (mean +/- SEM = 48.3 +/- 14.3 nmol/g brain) relative to the 7-day-old rat (7.4 +/- 1.1 nmol/g brain) and to the adult (17.8 +/- 3.6 nmol/g brain). Thus, newborns have deficient adenosine brain concentration and this is due in part to increased deamination of adenosine. However, adenosine brain production may be augmented by ischemic-hypoxic insult. This was tested in 2 age groups of rats: 7 days old (n = 35) and adults (n = 35). Under nembutal anesthesia, bilateral carotid arteries were exposed and loosely tied, then both carotids were ligated and 5 animals from each group were decapitated and heads immediately frozen in liquid N2 at 5, 15, 30, 60, 120 and 300 s after ligation. Similar animals with carotids exposed but not ligated served as control (time zero). Brains were removed and assayed for adenosine and metabolites using high-pressure liquid chromatography.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Ontogeny of adenosine production and degradation and its implications in neonatal cerebral blood flow regulation. 269 8

Leukotrienes C4 and D4 are arachidonic acid metabolites that constrict blood vessels and enhance vascular permeability; their biosynthesis is initiated by the reaction of arachidonic acid with 5-lipoxygenase enzyme. After bilateral carotid artery occlusion for 15 minutes and reperfusion of the gerbil brain for 15 minutes, we determined the brain tissue concentrations of leukotrienes C4 and D4 by radioimmunoassay; they had increased from a baseline concentration of less than 1 to a mean +/- SEM concentration of 12.8 +/- 3.9 pmol/g brain. We also studied the effect of a flavonoid 5-lipoxygenase inhibitor on leukotriene production in the reperfused gerbil brain. A water-soluble flavonoid (5-hexyloxy-3',4'-dihydroxy-6,7-dimethoxyflavone 4'-disodium phosphate) was administered intravenously at a dose of 200 mg/kg body wt; 15 minutes later, both carotid arteries were occluded. The enhanced production of leukotrienes C4 and D4 in the reperfused brain was reduced by approximately 80% (from a mean +/- SEM of 12.8 +/- 3.9 to 2.2 +/- 1.3 pmol/g brain) in the presence of the 5-lipoxygenase inhibitor. The flavonoid did not affect the production of prostaglandin D2, the concentration of which also increased in the reperfused ischemic brain.
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PMID:A flavonoid inhibitor of 5-lipoxygenase inhibits leukotriene production following ischemia in gerbil brain. 291 14

Midazolam (Mid) is widely used as an anesthetic adjunct. To test its anesthetic effect vs. concentration relationships, it is desirable to establish stable and predictable Mid concentrations in plasma (and brain). Therefore, the pharmacokinetics of Mid in the enflurane-anesthetized dog were determined, and the ability of Mid to reduce the enflurane concentration required for anesthesia was measured and correlated with the Mid concentration in plasma [MID]. Mongrel dogs (n = 9) were anesthetized with enflurane and the enflurane EC50 (MAC--the end-tidal concentration at which one-half of the dogs respond to the noxious stimulation of clamping of the tail, and one-half do not) was determined. Group 1 (n = 5) received Mid 2.5 mg/kg iv over 60 sec. Plasma for determination of [MID] was collected and the enflurane EC50 was determined repeatedly over the 7-8-hr period following injection. Based on the pharmacokinetic parameters determined for Group 1, dogs in Group 2 (n = 4) received Mid as a continuous infusion of 21 micrograms kg-1 min-1 for 5 hr accompanied by an initial loading dose (3 mg/kg infused over 20 min) designed to produce a stable [MID] of 1000 ng/ml in plasma. Enflurane MAC and [MID] were determined regularly during the infusion and for 6 hr after discontinuation of the infusion. There were no important differences in the pharmacokinetic parameters determined for Group 1 vs. Group 2: t1/2,z = 98 +/- 5 vs. 95 +/- 10 min (mean +/- SEM); V = 3.94 +/- 0.27 vs. 2.98 +/- 25 L/kg; Cl = 28.5 +/- 3.1 vs. 22.3 +/- 1.1 ml kg-1 min-1, respectively. When administered as a continuous intravenous infusion (Group 2), [MID] remained stable at 949 +/- 53 ng/ml for more than 5 hr. The enflurane EC50 was reduced by 55% and the reduction remained stable during the 5 hours of Mid infusion. After a single iv bolus dose or after discontinuation of the continuous infusion, the degree of enflurane EC50 reduction diminished toward the control (i.e., enflurane alone) value as [MID] declined. Mid-azolam's pharmacokinetics and plasma concentration vs. effect relationships have been determined to be consistent under two different experimental conditions.
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PMID:Pharmacokinetics and pharmacodynamics of midazolam in the enflurane-anesthetized dog. 322 25

A Mr 26,000 corticotropin (ACTH)-like material is present in glacial acetic acid extracts of all normal rat extrapituitary tissues. In the present study, beta-melanotropin (beta-MSH) immunoactivity was detected in glacial acetic acid extracts of normal rat extrapituitary tissues. beta-MSH immunoactivity was also present in all extracts (mean +/- SEM, fmol/mg of protein): brain, 71.0 +/- 16.3; stomach, 11.5 +/- 1.6; kidney, 8.9 +/- 0.8; colon, 8.2 +/- 1.1; small intestine, 6.5 +/- 1.1; liver, 4.3 +/- 0.5; and heart, 3.2 +/- 0.5. Except in brain extracts, beta-MSH and ACTH immunoactivities of tissue extracts were strongly correlated to each other (r = 0.79; n = 42). When tissue extracts (except brain) were passed through a Sephadex G-75 (superfine) column, ACTH and beta-MSH immunoactivities were eluted in a single peak corresponding to Mr 26,000. In contrast, for brain extracts, the MrS of major peaks of ACTH and beta-MSH immunoactivities were 4,500 and 8,000, respectively; a smaller peak of Mr 26,000 ACTH/beta-MSH-like material was also eluted. Specific anti-ACTH immunocolumns, which did not bind purified synthetic beta-MSH, adsorbed both ACTH and beta-MSH immunoactivities of all tissue extracts except those of brain. One-third of the beta-MSH immunoactivity in brain extracts adsorbed to the anti-ACTH immunocolumn, but two-thirds of beta-MSH immunoactivity passed through the column. We conclude that ACTH and beta-MSH immunoactivities are present in all normal rat extrapituitary tissues and exist in most tissues on the same molecule. This Mr 26,000 molecule is closely related to the pituitary ACTH/beta-lipotropin common precursor.
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PMID:Corticotropin/lipotropin common precursor-like material in normal rat extrapituitary tissues. 657 17

Over a period of 28 months, 29 patients who sustained uncal herniation originating from fronto-temporal acute subdural hematoma with major contusion and swelling of the temporal lobe were treated surgically. These 29 patients were divided into two groups according to whether or not they underwent aggressive temporal resection in two study periods. During the initial 16 months, from February 1991 to June 1992, 16 of the 29 (group A) underwent classic surgery (subtemporal decompression for evacuation of the hematoma and debridement of the contused brain). In the 12 months from July 1992 to June 1993, the remaining 13 patients (group B) underwent an aggressive temporal lobectomy in addition to the afore-mentioned procedures, including 10 complete temporal lobectomies and three anterior temporal lobectomies. In group A, there were nine operative deaths, with a mortality of 56%, and the mean Glasgow Outcome Scale (GOS) score was 2.2 +/- 0.4 (mean +/- SEM) after 24 to 36 months of follow-up. In group B, one patient died after operation, and the mean GOS score was 4.0 +/- 0.4 in a follow-up period of 12 to 24 months. Compared with group A, group B showed a better survival rate and more favorable functional outcome. Favorable recovery in group B was noted only after a complete temporal lobectomy (good in seven and moderate disability in three). The three patients who underwent an anterior temporal lobectomy had unfavorable recoveries (two vegetative states and one death).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Aggressive temporal lobectomy for uncal herniation in traumatic subdural hematoma. 754 54

The transgenic TGR(mRen-2)27 rat, in which the Ren-2 mouse renin gene is transfected into the genome of the Sprague-Dawley rat, develops severe hypertension at a young age that responds to inhibitors of angiotensin-converting enzyme and to antagonists of the type 1 angiotensin II (Ang II) receptor. Despite this evidence that the hypertension is Ang II dependent, TGR(mRen-2)27 rats have suppressed renal renin and renin mRNA content, and there is controversy concerning the plasma levels of renin and Ang II in these rats. We investigated the effect of the transgene on circulating and tissue levels of angiotensin and bradykinin peptides in 6-week-old male homozygous TGR(mRen-2)27 rats. Systolic blood pressure of TGR(mRen-2)27 rats was 212 +/- 4 mm Hg (mean +/- SEM, n = 25) compared with 108 +/- 2 mm Hg (n = 29) for age- and sex-matched Sprague-Dawley rats. Compared with control rats, TGR(mRen-2)27 rats had increased plasma levels of active renin (4.5-fold), prorenin (300-fold), and Ang II (fourfold) as well as tissue levels of Ang II (twofold to fourfold in kidney, adrenal, heart, aorta, brown adipose tissue, and lung and 18-fold in brain). Plasma angiotensinogen levels were reduced to 73% of control, and plasma aldosterone levels were increased fourfold. Plasma angiotensin-converting enzyme was reduced to 64% of control. Compared with control rats, TGR(mRen-2)27 rats had increased bradykinin levels in brown adipose tissue (1.9-fold) and lung (1.6-fold).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Angiotensin and bradykinin peptides in the TGR(mRen-2)27 rat. 759 Oct 27

We investigated the role of ATP in the active efflux of doxorubicin (DOX) mediated by P-glycoprotein (P-gp), the multidrug-resistance (MDR) gene product, at the blood-brain barrier. In transient brain ischemic rats prepared with 4-vessel occlusion of vertebral and common carotid arteries for 20 min, a procedure that depleted their brain ATP content to 3% that of normal rats, the estimated permeability coefficient of DOX was increased 17-fold (to 243 +/- 2.5 microL/min/g brain). When the ATP content recovered to a normal level by means of 30-min and 24-hr cerebral recirculation of blood, the permeability coefficient recovered to 14.0 +/- 5.0 and 18.4 +/- 2.3 microL/min/g brain (mean +/- SEM, N = 3-6), respectively, very close to the control permeability (14.3 +/- 1.5 microL/min/g brain). The uptake of DOX by primary cultured brain capillary endothelial cells expressing P-gp at the luminal membrane was increased significantly (up to 2-fold), which correlated well with the decrease of cellular ATP contents caused by treating the cells with metabolic inhibitors. Evidence for the ATP-dependent transport of DOX obtained from the present in vivo and in vitro studies strongly indicates that P-gp in the brain capillaries functions actively as an efflux pump in the physiological state, providing a major mechanism to restrict the transfer of DOX into the brain.
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PMID:In vivo and in vitro evidence for ATP-dependency of P-glycoprotein-mediated efflux of doxorubicin at the blood-brain barrier. 776 97

In the normocapnic range, middle cerebral artery mean velocity (MCA Vmean) changes approximately 3.5% per mmHg carbon-dioxide tension in arterial blood (PaCO2) and a decrease in PaCO2 will reduce the cerebral blood flow by vasoconstriction (the CO2 reactivity of the brain). When standing up MCA Vmean and the end-tidal carbon-dioxide tension (PETCO2) decrease, suggesting that PaCO2 contributes to the reduction in MCA Vmean. In a fixed body position, PETCO2 tracks changes in the PaCO2 but when assuming the upright position, cardiac output (Q) decreases and its distribution over the lung changes, while ventilation (VE) increases suggesting that PETCO2 decreases more than PaCO2. This study evaluated whether the postural reduction in PaCO2 accounts for the postural decline in MCA Vmean). From the supine to the upright position, VE, Q, PETCO2, PaCO2, MCA Vmean, and the near-infrared spectrophotometry determined cerebral tissue oxygenation (CO2Hb) were followed in seven subjects. When standing up, MCA Vmean (from 65.3+/-3.8 to 54.6+/-3.3 cm s(-1) ; mean +/- SEM; P<0.05) and cO2Hb (-7.2+/-2.2 micromol l(-1) ; P<0.05) decreased. At the same time, the VE/Q ratio increased 49+/-14% (P<0.05) with the postural reduction in PETCO2 overestimating the decline in PaCO2 (-4.8+/-0.9 mmHg vs. -3.0+/-1.1 mmHg; P<0.05). When assuming the upright position, the postural decrease in MCA Vmean seems to be explained by the reduction in PETCO2 but the small decrease in PaCO2 makes it unlikely that the postural decrease in MCA Vmean can be accounted for by the cerebral CO2 reactivity alone.
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PMID:The postural reduction in middle cerebral artery blood velocity is not explained by PaCO2. 1647 Apr 13


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