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PubMed1968

The effect of intraventricular injections of noradrenaline, 5-hydroxytryptamine, acetylcholine and tranylcypromine on the ox (Bos taurus) at different environmental temperatures.

1. Noradrenaline, 5-hydroxytryptamine (5-HT), acetylcholine and tranylcypromine were injected or infused into the lateral ventricle of the ox. The effects of these drugs on heart and respiration rates, heat production, rectal, skin and hypothalamic temperatures and skin evaporative loss were measured when the animal was exposed to environmental temperatures ranging from -1 degrees C to +30 degrees C.2. Acetylcholine (0.001-2 mg) had no detectable effect on temperature regulation at 20 degrees C.3. In small doses (0.005-0.05 mg) 5-HT had no detectable effect. Larger doses (2-5 mg) given in a cold environment (-1 degrees C) also had no effect but the same doses given in warm environments (15-30 degrees C) caused increases in skin temperatures, skin evaporative loss and respiratory rate, and decreases in rectal and hypothalamic temperatures.4. Infusion of tranylcypromine (0.107 ml./min of a 1 in 50 solution) in a warm environment (20 degrees C) also caused a decrease in rectal temperature after a delay of 1-1(1/2) hr during which no effects were apparent.5. Noradrenaline (2 mg) had no effect on temperature regulation when injected into animals in a warm environment (30 degrees C). When injected (1 mg) into animals in a cold environment (-1 degrees C) shivering stopped and heat production and rectal and hypothalamic temperatures were decreased.6. It is concluded that intraventricular 5-HT and noradrenaline both cause a decrease in body temperature, and it is unlikely that central temperature regulation in the ox is mediated only by these two substances.

Acetylcholine↗

PubMed1979

Possible involvement of brainstem norepinephrine in pentylenetetrazol convulsions in rats.

The thresholds of twitch and clonic convulsion induced by intravenous infusion of pentylenetetrazol (PTZ) were measured in rats treated with 6-hydroxydopamine (6-OHDA). In adult rats, intraventricularly applied 6-OHDA increased susceptibility to PTZ convulsions and decreased norepinephrine (NE) contents of the cortex, hypothalamus and brainstem. When 6-OHDA was applied intraventricularly at 8 days after birth, PTZ convulsion susceptibility was slightly decreased and brainstem NE content was significantly increased. However, the effects of 6-OHDA given at 20 days after birth were similar to those observed in adults. Significant decrease of cortical and hypothalamic NE contents, but no change in PTZ convulsion susceptibility, occurred following 6-OHDA injections into the dorsal and ventral NE bundles. These results suggest that the brainstem NE neurons play an inhibitory role on the development of PTZ convulsions.

Animals↗

PubMed1997

Electrophysiological effects of E 4031, a drug with selective class III properties, in man.

We studied the electrophysiological effects of E 4031, given in a dose ascending manner (1.5, 3.0, and 6.0 micrograms/kg over 5 min followed by 0.1, 0.2, and 0.4 microgram/kg per min for 60 min, respectively) to 19 volunteers. There were significant, dose related linear increase in QT and QTc intervals, in atrial functional and effective refractory periods (ERPs) at a paced cycle length of 400 ms, and in ventricular functional and ERPs at a paced cycle length of 600 ms. There was no significant change in the AH and HV intervals or QRS duration. No significant proarrhythmic or other side effects were encountered during the administration of the drug. E 4031 prolongs atrial and ventricular refractoriness without significantly affecting AV or intraventricular conduction, consistent with selective Class III properties. At the doses used in the present study, intravenous infusion of E 4031 appears to be safe and well tolerated.

Adolescent↗

PubMedDate not supplied

Effects of intraventricular locus coeruleus transplants on seizure severity in genetically epilepsy-prone rats following depletion of brain norepinephrine.

Audiogenic seizures (AGS) in genetically epilepsy-prone rats (GEPR) of the moderate-seizure substrain (GEPR-3s) were investigated to determine whether norepinephrine (NE) depletion induced by 6-hydroxydopamine (6-OHDA) microinfusion into the locus coeruleus (LC) could alter the efficacy of intraventricular NE tissue grafts in promoting reductions in seizure severity in AGS. GEPR-3s were stereotaxically infused with 6-OHDA (4 micrograms/side/rat), or vehicle into the region of the LC. Following 6-OHDA treatment all animals were subjected to 3 AGS tests. GEPR-3s seizure severities were increased in 39.5% of the animals after microinfusion of 6-OHDA into the region of the LC. Following the third AGS test, each rat was stereotaxically implanted with 17 gestational day rat fetal tissue obtained from the dorsal pons and containing the primordia of the LC or with tissue obtained from the neocortex or were sham-grafted. Subsequent to grafting, rats were subjected to 3 additional AGS tests. 53% (10/19) of 6-OHDA treated GEPRs showed a significant reduction in seizure severity following transplantation of fetal LC tissue. In contrast, only 20% (1/5) of GEPRs infused with saline rather than 6-OHDA showed a reduction of seizure severity following fetal LC transplantation. NE content in the cortex and pons/medulla was decreased by 78% and 46% respectively following 6-OHDA microinfusion into the LC. Prominent grafts with numerous TH positive neurons and neurites were present within the third ventricle of grafted animals, while cortex grafts contained no TH immunostained structures. These findings suggest that the efficacy of fetal LC tissue to promote reductions in seizure severity in GEPRs is increased following depletion of central NE by microinfusion of 6-OHDA.

Acoustic Stimulation↗

PubMed2005

Different doses of dopamine have heterogeneous effects on cerebral hemodynamics and dopamine receptors in young rabbits as measured with near infrared spectroscopy.

BACKGROUND: Fluctuations in cerebral blood volume and cerebral oxygenation may be important in the pathogenesis of intraventricular hemorrhage and hypoxic-ischemic brain injury in the neonate. The cerebral hemodynamic response to dopamine infusion in premature infants is not well established. The newborn rabbit, a rather immature species at birth, is a suitable model for monitoring the physiological changes of the cerebral circulation. METHODS: The effect of dopamine upon cerebral hemodynamics and basal ganglia dopaminergic receptors were studied using four different dopamine doses. RESULTS: No significant changes in near infrared spectroscopy (NIRS) parameters were observed in the animals that received 0.5 (n = 5) and 1 microg/kg/min (n = 4) of dopamine intravenously. In contrast, in those animals that received dopamine at 5 microg/kg/min (n = 7) and 50 microg/kg/min (n = 7), there was a significant decrease in oxygenated hemoglobin. Moreover, this was accompanied by a significant increase in deoxygenated hemoglobin soon after drug infusion. Cerebral blood volume was increased in the group that received 5 microg/kg/min, but significantly decreased in the group that received 50 microg/kg/min. In both groups NIRS parameters returned to baseline values soon after stopping dopamine infusion. CONCLUSION: Despite evidence of a physiological response, we found no difference in the distribution of dopamine receptors between experimental and control animals. We therefore speculate that dopamine has an effect on the cerebrovasculature that could be mediated by factors other than changes in the basal ganglia dopamine receptors.

Animals↗

PubMedDate not supplied

[Electrical changes in experimental diastolic and mixed overloads of the right ventricle].

The paper describes the electrical changes in 115 mongrel dogs with exposed heart and open pericardium, during the gradual development of diastolic and combined (diastolic and systolic) overloading of the right ventricle. Ventricular overload was produced by means of a constant venous infusion of saline solution: up to 12 liters in 3 hours and half. In all cases, right intraventricular conduction disturbances, of either proximal or distal type, appeared. Right blocks were classified on the base of the topography of the ventricular activation delay. They were correlated with the hemodynamic adaptation. The results of this study allow us to formulate the following main points: 1) Disturbances of the right intraventricular conduction during experimental diastolic and combined overloading of the ipsilateral ventricle, seem to be due to a distention of the ventricular specialized fibers; 2) proximal right blocks are related to a global dilatation of the ventricular chamber, secondary either to a quick overloading or to a decrease in the myocardial capacity for adaptation; 3) distal right blocks are caused more frequently by a distention of the anterolateral portions of the free right ventricular wall, where the right middle subdivision is located.

Animals↗

PubMed1980

The treatment of raised intracranial pressure following aneurysm surgery.

The effect of intravenous mannitol infusion and withdrawal of cerebrospinal fluid on the intracranial pressure and clinical state was studied in 26 patients with raised intracranial pressure after direct surgery for ruptured aneurysm. Each method decreased the mean intracranial pressure by about 60% of the pre-treatment level. The maximal decrease following mannitol occurred after 60-90 minutes and generally lasted between three and four hours. The effects of mannitol did not decrease when repeated infusions were necessary. Rebound increases in the intracranial pressure following infusion were not observed. Withdrawal of cerebrospinal fluid lowered the intracranial pressure immediately and the effect persisted for approximately 60 minutes. This could be repeated as often as necessary and was without systemic disturbance, although a patent intraventricular catheter was necessary. The two methods could be used simultaneously.

Cerebrospinal Fluid Shunts↗

PubMed1981

Intracranial hemorrhage following administration of sodium bicarbonate in rabbits.

Studies on the correlation between hyperosmolality and brain damage, especially intracranial hemorrhage, were carried out on young and newborn rabbits following infusion with 7% sodium bicarbonate. 1) All the young rabbits injected with 7% sodium bicarbonate died of hyperosmolality at over 380 mOsm/L (the mean was 462 mOsm/L) after drip infusion at the rate of 20-60 ml/kg/hr. Young rabbits under a 10% hypoxic environment died even at the 350 mOsm/L level (the mean was 392 mOsm/L) during infusion of 7% sodium bicarbonate. Half of the case of newborn rabbits injected with 7% sodium bicarbonate at 10 ml/kg, intraperitoneally, had intracranial hemorrhage at 335 mOsm/L. When the hyperosmolality reached 392 mOsm/L (50 ml/kg), intracranial hemorrhage was observed in all cases. 2) The main cause of death in young and newborn rabbits was subdural hemorrhage in the subtentorial region. Intraventricular hemorrhage was observed in about 40% of the cases of young and newborn rabbits. 3) The blood pH was elevated by the drip infusion, but when the hyperosmolality reached about 400 mOsm/L, the blood pH began to fall. At the same osmolality, pCO2 showed a marked elevation. It is likely that the decrease of the blood pH was caused by the elevation of pCO2 and the outflow of H+ from intracellular compartments resulting from the hyperosmolality. These results apparently indicate that fatal intracranial hemorrhage was induced by hyperosmolality and was enhanced by the combination of hypoxia and immaturity.

Animals↗

PubMed1991

Intraventricular insulin reduces food intake and body weight of marmots during the summer feeding period.

The study presented below describes experiments that investigate the ability of insulin to inhibit food intake in awake, active marmots during the summer season. Our results suggest that increasing intraventricular insulin concentration during the summer active feeding period will cause a decrease in food intake and body weight of marmots. When infused with insulin into their lateral ventricles (Alzet #2002 minipumps), animals had significantly lower food intake as compared to their food intake during the control period. In addition, these animals lost body weight during the period of the insulin infusion. We suggest that during the summer when marmots are not hibernating and are actively feeding, brain insulin levels may play a role in regulating food intake.

Adipose Tissue↗

PubMed1992

Favorable outcome of B-cell acute lymphoblastic leukemia in childhood: a report of three consecutive studies of the BFM group.

In 1981 the BFM group introduced a new treatment strategy for B-cell acute lymphoblastic leukemia (B-ALL). A cytoreductive prephase (prednisone/cyclophosphamide) was followed by eight 5-day courses of chemotherapy. Fractionated cyclophosphamide, methotrexate (MTX) 0.5 g/m2 (24-hour infusion), and MTX intrathecally were administered at each course and cytosine arabinoside (ARA-C)/teniposide (VM-26) was given alternately with doxorubicin. In study ALL-BFM-83, central nervous system (CNS) chemotherapy was intensified by adding dexamethasone, while MTX/ARA-C was administered intraventricularly. Therapy duration was reduced to six courses. In study ALL-BFM-86, MTX 0.5 g/m2 was replaced by high-dose (HD) MTX, 5 g/m2 (24-hour infusion), and MTX/ARA-C/prednisolone intrathecal therapy was introduced. Doses of ARA-C and VM-26 were increased and fractionated, cyclophosphamide was partially replaced by ifosfamide, and vincristine was added. CNS irradiation was 24 Gy for prevention and 30 Gy for overt disease in studies ALL-BFM-81 and -83, but was omitted in ALL-BFM-86. In all, 87 patients were enrolled, 22 (8 CNS-positive) in study All-BFM-81, 24 (7 CNS-positive) in study ALL-BFM-83, and 41 (0 CNS-positive) in study ALL-BFM-86. The estimated 5-year duration of event-free survival (EFS) was 43% in study ALL-BFM 81, 50% in study ALL-BFM-83, and 78% in study ALL-BFM-86 (minimal follow-up, 25 months). Nineteen of 24 relapses occurred while on therapy or shortly thereafter. In study ALL-BFM 81, the CNS was the most frequent site of failure. In ALL-BFM-83, there were no isolated CNS relapses, but more bone marrow (BM) relapses occurred. In ALL-BFM-86, localized manifestations were the predominant site of failure, no isolated BM relapses occurred, and only one CNS relapse was diagnosed. No single parameter exerted a consistent influence on outcome with one exception. The presence of residual disease after the first two courses was correlated with an increased risk of therapy failure. We conclude that an intensive, short-pulse therapy delivered within a 4-month period is highly effective in the treatment of B-ALL. In addition to fractionated cyclophosphamide/ifosfamide, a 24-hour infusion of HD MTX 5 g/m2 in conjunction with an i.th. therapy is an important component for prevention of both systemic and CNS relapses. CNS irradiation is not needed for CNS-negative patients.

Adolescent↗

PubMed1983

Effect of prostaglandin E1 on vasoactive intestinal polypeptide release from the hypothalamus and on prolactin secretion from the pituitary in rats.

In order to elucidate the mechanisms by which prostaglandin (PG) affects PRL secretion, the effect of PGE1 on vasoactive intestinal polypeptide (VIP) release from the rat hypothalamus was examined by determining plasma VIP levels in rat hypophysial portal blood in vivo and VIP release from the perifused hypothalamus in vitro. Intraventricular injection of PGE1 (1 and 5 micrograms/rat) caused a 2- to 3-fold increase in the concentration of plasma VIP in hypophysial portal blood in anesthetized rats. The flow rate of portal blood was slightly increased after the injection of PGE1. VIP release from the perifused rat hypothalamus was stimulated by high potassium levels (56 mM). The infusion of PGE1 (10 microM) resulted in a significant increase in VIP release from the hypothalamus in vitro. Both these responses were calcium dependent. The intraventricular injection of PGE1 (1 and 5 micrograms/rat) resulted in a dose-related increase in peripheral plasma PRL levels in the rat. These findings suggest that PGE1 plays a stimulatory role in regulating VIP release from the hypothalamus into hypophysial portal blood and causes PRL secretion from the pituitary in rats.

Alprostadil↗

PubMed1982

Failure of blood cardioplegia to protect myocardium at lower temperatures.

To assess the effect of temperature, oxygenated blood and crystalloid cardioplegic solutions (CPs) at infusion temperatures of 20 degrees C, 10 degrees C and 4 degrees C were compared. The amount of potassium in each CP was 25 mEq/l. There were six study groups with seven canine hearts in each group, all of which were subjected to 90 minutes of global ischemia at 20 degrees C, 10 degrees C or 4 degrees C, followed by 45 minutes of normothermic reperfusion. During ischemia, either blood or crystalloid CP was given every 30 minutes. With each infusion, any change in myocardial oxygen tension was recorded using mass spectrometry, and oxygen consumption (MVO2) was calculated. Left ventricular (LV) function was assessed before and after ischemia in all hearts by measuring isovolumic developed pressure using an intraventricular balloon. Injection of 20 degrees C blood CP resulted in a mean increase in intramyocardial oxygen tension (PO2) of 7 mm Hg. At 10 degrees C or 4 degrees C, blood CP infusions did not cause a significant increase in intramyocardial PO2, while with crystalloid CP, intramyocardial PO2 did not increase at any of the three infusion temperatures. The mean MVO2 with each blood CP injection, expressed as ml O2/100 g LV wet weight, was 16.5 +/- 0.8 for 20 degrees C blood, 4.1 +/- 0.3 for 10 degrees C blood and 3.5 +/- 0.4 for 4 degrees C blood (p less than 0.001, 20 degrees C blood vs 10 degrees C and 4 degrees C blood). MVO2 with each crystalloid CP injection was 0.9 +/- 0.1 for 20 degrees C CP, 0.8 +/- 0.1 for 10 degrees C CP, and 0.7 +/- 0.1 for 4 degrees C CP. Recovery of developed pressure after 45 minutes of reperfusion, expressed as a percentage of preischemic control, was 76.0 +/- 3.4% or 20 degrees C blood CP, 65.6 +/- 2.3% for 10 degrees C blood CP, and 54.0 +/- 2.7% for 4 degrees C blood CP (p less than 0.05, 20 degrees C blood CP vs 10 degrees C and 4 degrees C blood CP). Recovery of developed pressure, also expressed as a percentage of preischemic control, was 56.6 +/- 1.4% for 20 degrees C crystalloid CP, 72.9 +/- 3.0% for 10 degrees C crystalloid CP, and 72.0 +/- 2.3% for 4 degrees C crystalloid CP (p less than 0.05, 20 degrees C crystalloid CP vs 10 degrees C and 4 degrees C crystalloid CP). These data show that blood CP is most effective when infused at 20 degrees C. The use of 10 degrees C blood CP enhanced myocardial cooling, but was of no additional benefit, presumably because there was little oxygen delivery. Blood CP at 4 degrees C resulted in significantly poorer preservation of LV function. Crystalloid CP infused at either 4 degrees C or 10 degrees C was as effective as 20 degrees C blood CP, despite the absence of oxygen use by hearts treated with crystalloid CP.

Animals↗

PubMed1999

Analgesia and sedation in preterm neonates who require ventilatory support: results from the NOPAIN trial. Neonatal Outcome and Prolonged Analgesia in Neonates.

BACKGROUND: Preterm neonates are exposed to multiple painful procedures after birth and exhibit acute physiological responses to pain. Occurrence of early intraventricular hemorrhage within 24 to 72 hours after birth suggests a role of pain and stress in the multifactorial causation of severe intraventricular hemorrhage and periventricular leukomalacia. We proposed that such neurologic outcomes in preterm neonates who require ventilatory support may be reduced by morphine analgesia or midazolam sedation compared with a placebo. OBJECTIVES: To define the incidence of clinical outcomes in the target study population, to estimate the effect size and adverse effects associated with analgesia and sedation, and to calculate the sample size for a definitive test of this hypothesis. METHODS: Sixty-seven preterm neonates were randomized in a pilot clinical trial from 9 centers. Neonates of 24 to 32 weeks gestation were eligible if they had been intubated and required ventilatory support for less than 8 hours and if they were enrolled within 72 hours after birth. Exclusion criteria included major congenital anomalies, severe intrapartum asphyxia, and participation in other research studies. Severity of illness was assessed by the Clinical Risk Index for Babies, and neonates were randomized to receive continuous infusions of morphine sulfate, midazolam hydrochloride, or 10% dextrose (placebo). Masked study medications were continued as long as clinically necessary, then weaned and stopped according to predefined criteria. Levels of sedation (COMFORT scores) and responses to pain (Premature Infant Pain Profile scores) were measured before, during, and 12 hours after discontinuation of drug infusion. Cranial ultrasound examinations were performed as part of routine practice, and poor neurologic outcomes were defined as neonatal death, severe intraventricular hemorrhage (grade III or IV), or periventricular leukomalacia. RESULTS: No significant differences occurred in the demographic, clinical, and socioeconomic variables related to mothers and neonates in the 3 groups or in the severity of illness at birth as measured by Clinical Risk Index for Babies scores. Two neonates in the placebo group and 1 neonate in the midazolam group died; no deaths occurred in the morphine group. Poor neurologic outcomes occurred in 24% of neonates in the placebo group, 32% in the midazolam group, and 4% in the morphine group (likelihood ratio chi2 = 7.04, P = .03). Secondary clinical outcomes and neurobehavioral outcomes at 36 weeks' postconceptional age were similar in the 3 groups. Responses elicited by endotracheal tube suction (Premature Infant Pain Profile scores) were significantly reduced during the morphine (P<.001) and midazolam (P = .002) infusions compared with the placebo group. CONCLUSIONS: This pilot trial suggests that preemptive analgesia given by continuous low-dose morphine infusion may reduce the incidence of poor neurologic outcomes in preterm neonates who require ventilatory support. Limitations in the sample size of this pilot study suggest that these results should be confirmed in a large multicenter randomized trial.

Analgesia↗

PubMed2000

Safety and feasibility of continuous infusion of remifentanil in the neurosurgical intensive care unit.

OBJECTIVE: Remifentanil is a selective mu-opioid agonist with a context-sensitive half-time of 3 to 5 minutes, independent of dose or administration duration. Other desirable effects include decreased cerebral metabolism and intracranial pressure (ICP) with minimal cerebral perfusion pressure changes. We present six cases illustrating indications for the use of remifentanil in the neurosurgical intensive care unit. METHODS: Patients received bolus doses of remifentanil of 0.05 to 1.0 microg/kg, followed by continuous infusions of 0.03 to 0.26 microg/kg/min, titrated to effect. When infusions were discontinued for neurological examinations, another bolus dose preceded infusion reinstitution. Indications for the use of remifentanil included mean arterial pressure and cerebral perfusion pressure decreases with the use of other agents (e.g., codeine or propofol) for ICP control, elevated ICP that was refractory to propofol/mannitol treatment, agitation that was unresponsive to standard therapies, and coughing that caused ICP increases after subarachnoid hemorrhage. RESULTS: Three patients experienced spontaneous intracranial bleeding (two cases of subarachnoid hemorrhage and one case of intraventricular hemorrhage), and three patients exhibited severe traumatic subdural hemorrhage. All patients recovered from the effects of remifentanil within 3 minutes after discontinuation of infusion, which allowed frequent rapid neurological assessments. Procedures for pulmonary toilet (i.e., endotracheal suctioning, postural drainage, and bronchoscopy) were performed without deleterious ICP increases or mean arterial pressure or cerebral perfusion pressure decreases during remifentanil infusions. CONCLUSION: The ultrashort duration of action of remifentanil allowed easy performance of frequent neurological examinations in the neurosurgical intensive care unit. No patient experienced deleterious hemodynamic or neurological effects as a result of remifentanil use.

Adolescent↗

PubMed1987

Alterations in systemic haemodynamics induced by atriopeptin III.

The mechanism of the hypotensive response to the intravenous administration of atriopeptin III was investigated in rats of the Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) Okamoto strains. Cardiac performance and the systemic haemodynamic response to acute volume loading were evaluated before and during atriopeptin infusion. Cardiac output was measured by a thermo-dilution technique in conscious rats, and left ventricular pressures with differential (dP/dt) calculations were obtained in anaesthetized animals. Bolus injections followed by a 1-h continuous infusion of atriopeptin caused a progressive decrease in mean arterial pressure (MAP) and cardiac output with no significant change in heart rate. In addition there was a transient decrease, maximal at 5 min, and a subsequent increase in peripheral resistance. Atriopeptin did not alter the maximal cardiac output achieved following acute volume expansion. In the anaesthetized animals, bolus injection with a subsequent 15-min continuous infusion of atriopeptin III significantly reduced left ventricular pressures, dP/dt and mean arterial pressure. Volume expansion fully restored intraventricular pressures and dP/dt while increasing mean arterial pressure toward baseline. We conclude that the steady decrease in mean arterial pressure produced by atriopeptin III is due to a decrease in cardiac output secondary to a fall in stroke volume caused by a lowered filling pressure.

Animals↗

PubMed1989

Rapid activation of gluconeogenesis after intracerebroventricular carbachol.

Intracerebroventricular administration of carbachol (27 nmol in 5 microliters 0.15 M NaCl) produced marked hyperglycemia in 24-h fasted rats, despite the negligible amounts of preformed liver glycosyl residues. To investigate the possibility of a stimulation of gluconeogenesis, conscious unrestrained rats were continuously infused with [14C]bicarbonate (0.51 microliters, 0.18 muCi/min) and label incorporation into circulating glucose determined before and after intraventricular injection. The rate of 14C incorporation into blood glucose of fed rats was not affected by intraventricular injection of 0.15 M NaCl but increased significantly after carbachol administration. In both fed and 24-h fasted rats the hyperglycemia induced by intraventricular carbachol was accompanied by marked increases in plasma lactate. Previous adrenodemedullation prevented both the hyperglycemia and the hyperlactemia. Liver pyruvate kinase activity was reduced in carbachol-treated rats, when the enzyme was assayed with suboptimal concentrations of phosphoenolpyruvate and in the absence of fructose 1,6-biphosphate. Phosphoenolpyruvate carboxykinase activity was not affected. The data suggest that central chemical stimulation with cholinergic agents induces a rapid activation of liver gluconeogenesis, which probably results from an increased sympathetic outflow for epinephrine secretion by the adrenal medulla.

Animals↗

PubMed2000

Protective effect of a caspase inhibitor in models for cerebral ischemia in vitro and in vivo.

In primary neuronal-astrocyte cultures from mouse brain, ischemic conditions were simulated by combined oxygen-glucose deprival (OGD) for 2 hrs. This treatment resulted in near complete neuronal damage 24 hrs. later and was accompanied by DNA degradation and apoptotic nuclear morphology. Since caspases are key enzymes in the propagation and execution of programmed cell death, we evaluated the effect of the caspase inhibitor z-VAD-fmk. Damage following 2 hrs. OGD could be reduced by up to 56% with z-VAD-fmk (p<0.05). DNA-fragmentation and caspase activation has been also reported in an in vivo model of cerebral ischemia imitating human stroke. In this model the middle cerebral artery (MCA) is permanently occluded resulting in focal cerebral ischemia and subsequent infarction. Since z-VAD.fmk does not penetrate the blood-brain barrier it was applied intraventricularly as a bolus injection given 30 min. before MCA occlusion which was followed by 24 hrs. of infusion. Infarct volume was determined 48 hrs. after MCA occlusion by means of in vivo magnetic resonance imaging. Z-VAD.fmk dose dependently reduced infarct volume reaching a significant decrease of the cortical infarct by 45% when given as a 120 ng bolus followed by 40 ng/hr. infusion (p<0.05). In summary, our study supports the concept that caspase inhibitors are beneficial in brain ischemia.

Amino Acid Chloromethyl Ketones↗

PubMed1985

[Cardiovascular complications due to naftidrofuryl].

The authors report the case of a serious cardiovascular complication due to naftidrofuryl overdosage following its intravenous administration. Other similar complications have already been reported in the literature and in experimental animal studies (particularly involving the conduction system of the heart). Since naftidrofuryl belongs to the class of local anesthetics and is pharmacologically related to procainamide, certain precautions must be closely followed if it is administered intravenously: avoidance of rapid injection directly into the vein, limiting the infusion to 200 to 400 mg given over a 3 hour period using preferably a constant infusion syringe pump or an infusion pump, and using caution when associated with other medications, particularly antiarrhythmic agents which could affect atrioventricular or intraventricular conduction.

Adolescent↗