Drug effects on cerebral blood flow in the baboon model--acetazolamide and nimodipine

The sensitivity of the baboon model under anaesthesia for single photon emission computed tomography (SPECT) of the brain with 99mTc-HMPAO, as recently developed by us to study cerebral blood flow patterns, was investigated using drugs that are known to increase cerebral blood flow, e.g. acetazolamide, the carbonic anhydrase inhibitor and nimodipine, the calcium channel blocker. Increases in cerebral blood flow for both acetazolamide and nimodipine were observed that correspond well with other studies. Statistically significant regional specificity was noted for acetazolamide and nimodipine. Interestingly a combination of these drugs did not enhance cerebral blood flow but rather decreased it in comparison with the individual drug responses. The results were correlated with arterial blood pressure, heart rate, pCO2 and pO2. A blood pressure decrease was noted for both drugs, while acetazolamide had a marked influence on pO2. The results indicate that the baboon model is sensitive for evaluation of drug effects on cerebral blood flow.     

Cerebral blood flow in the diabetic patient

Asthma affects about 1 in 10 children. The condition is characterized by acute respiratory distress brought on by environmental factors. The condition is treated with medications aimed to reduce reaction to stimulants by the airway. Dental management involves attention to the status of the patient and awareness of stimulants of the reactive airway. Clinical recommendations are provided.     

Cerebral blood flow in subarachnoid hemorrhage

Myelin protein zero (MPZ, P0) is well known as the adhesion molecule responsible for the compaction of the myelin sheath of peripheral nerves. Mutations are linked to Charcot-Marie-Tooth syndrome type 1B (CMT1B) and the more severe Dejerine-Sottas syndrome (DSS). Three mutations leading to phenotypes of increasing severity (Ser34del/CMT1B, Ser34Cys/DSS, INS663GC/DSS) were expressed in S2 insect cells and resulted in a decreased adhesion capability in correlation with their respective phenotypes.     

Cerebral blood flow changes in cluster headache

Serial cerebral blood flow studies performed by the intra-carotid 133Xenon method were fortuitously determined during the course of a cluster headache in a 32 year old man. The initial study was performed about 10 min after the headache began and showed values at the upper limit of normal. Twenty min after the headache started a second procedure showed that the autoregulatory response on hyperventilation was normal. Ergotamine tartrate was given intra-muscularly 23 min after the headache began and there was partial relief. A third cerebral blood flow estimation showed abnormally high values. The probable reasons for this are discussed.     

The isolated supported canine heart: a model for the evaluation of drug effects on regional myocardial blood flow

The present investigation was designed to determine the effect of propranolol on regional myocardial blood flow and oxygen consumption (MVO2) in the isolated supported dog heart preparation perfused at a constant coronary blood flow. The transmural distribution of blood flow, determined by the radioactive microsphere technique, was expressed as the epicardial/endocardial blood flow ratio (epi/endo). Propranolol (0.5 mg/kg i.v.) produced a significant decrease in heart rate and myocardial contractile force and an increase in coronary artery perfusion pressure due to an increase in coronary vascular resistance. These hemodynamic changes were accompanied by significant decreases in epi/endo (increased endocardial perfusion) and MVO2. Reduction of perfusion pressure to control by a decrease in total coronary blood flow produced no further change in epi/endo or MVO2. However, increasing heart rate to control increased epi/endo to predrug levels. Contractile force and MVO2 remained reduced below control. Norepinephrine infusion (1 mug/min intracoronary) produced a significant increase in heart rate and contractile force and decrease in perfusion pressure. These changes were accompanied by an increase in epi/endo and MVO2. Propranolol (0.5 mg/kg i.v.) abolished the response to norepinephrine. Propranolol may produce beneficial effects in angina pectoris by a decrease in epi/endo (via a reduction in heart rate) and MVO2 and by beta adrenergic blockade of the deleterious effects of catecholamines.     

Cerebral blood flow and energy metabolism in the newborn

In normal newborn term and preterm infants CBF is relatively low corresponding to a low metabolic rate for oxygen, whereas cross-brain oxygen extraction is similar to that in adults. This provides for a considerable reserve capacity to deal with decreased CBF or decreased oxygen content in arterial blood. CBF reactivity to CO2 is normal, and the evidence is that pressure-flow autoregulation is present, even in very preterm infants. Absence of autoregulation and CBF-CO2 reactivity has been documented in severely asphyxiated infants, and in preterm infants who went on the develop severe intracranial hemorrhage. A number of methods are available to study CBF and brain metabolism in newborn infants. Several of them involve ionizing radiation, which has limited their use, even though it is unlikely that the associated risks are particularly high. Magnetic resonance spectroscopy has demonstrated a delayed disturbance of energy metabolism following severe asphyxia. Doppler ultrasound has rarely been helpful to obtain quantitative data. Near infrared spectrocopy has now been in use for more than 10 years. It has been slow to fulfill its promise as a continuous monitor of cerebral circulation and of oxygen sufficiency of neurons.     

Clinical experience with sodium valproate in children

Good control was achieved with sodium valproate (Epilim) in 44 (71%) of a sample of 62 children with severe recurrent epileptic seizures. The medication was most effective in the control of petit mal; good results, however, were also achieved in some patients with previously poorly controlled grand mal epilepsy and psychomotor and myoclonic seizures. Twenty children required no other anti-convulsant and 28 required only one other. Side-effects were infrequent and mild. Only the high cost of sodium valproate in South Africa precludes its more general use in childhood epilepsy.     

Cerebral blood flow changes in acute experimental haemorrhagic vasospasm

Subarachnoid haemorrhage was produced in 26 dogs by injecting fresh homogenous blood into the cysterna chiasmatica. Two types of vasospasm were observed, firstly segmental arterial spasm closely related to the bleeding point and secondly generalized arterial vasospasm not directly related to the bleeding point and often occurring some way from the bleeding point. Reduction in CBF occurred in 61% of cases and was always accompanied by radiological vasospasm. However, in about one quarter of the cases with vasospasm there was no alteration in CBF.     

Cerebral blood flow in single and multiple lacunar infarctions

BACKGROUND AND PURPOSE: Single and multiple lacunar infarctions may have some difference in underlying diseases and cerebral blood flows. To determine the difference, we investigated underlying diseases and cerebral blood flows in single and multiple lacunar infarctions. METHODS: Fifteen cases of lacunar infarction, 10 cases of multiple lacunar infarctions, and 16 control subjects were studied. Regional cerebral blood flow was measured within 14 days after stroke onset with the stable xenon CT method. RESULTS: The rate of association of diabetes mellitus was higher in the multiple lacunar infarctions group than in the single lacunar infarction group. The blood flow in the cerebral cortex was significantly lower in the multiple lacunar infarctions group than in the single lacunar infarction group. The blood flow change by acetazolamide in the cerebral cortex was significantly lower in the multiple lacunar infarctions group than in the single lacunar infarction group. CONCLUSIONS: There is some difference in underlying diseases and cerebral blood flows between single and multiple lacunar infarctions.     

Acidosis and hyperlactatemia in acute sodium valproate poisoning

OBJECTIVES: We searched for signs of metabolic acidosis and associated hyperlactatemia in case of sodium valproate overdose. PATIENTS AND METHODS: A retrospective study was conducted in the toxicology intensive care unit at the Fernand Widal hospital from 1990 to 1995. Patients retained for study had sodium valproate levels above the therapeutic range (> 600 mumol/l). Data collected included past history, intubation for mechanical ventilation, administration of catecholamines and infusion of bicarbonate or sodium lactate, and blood pressure. Laboratory tests included serum sodium valproate, pH, PCO2, bicarbonate, anion balance and lactate. RESULTS: The study included 22 consecutive patients. None had a history of liver disease. Thirteen patients were intubated before admission to intensive care. Two received catecholamines. None of the patients received bicarbonate or sodium lactate. Mean blood pressure was 118 +/- 16 mmHg, mean serum sodium valproate was 2668 +/- 2437 mumol/l, mean pH was 7.41 +/- 0.08, mean PO2 35.6 +/- 8.0, mean anion imbalance 23.2 +/- 6.0 mmol/l and mean lactate 5.0 +/- 2.1 mmol/l. There was a significant correlation between lactase and pH (p < 0.003). CONCLUSION: We found metabolic acidosis with major anion imbalance and high lactate levels in patients with acute sodium valproate intoxication. Hyperlactatemia could be due to the direct effect of sodium valproate or to an unknown mechanism.     

A comparative cerebral blood flow study in a baboon model with acetazolamide provocation: 99mTc-HMPAO vs 123I(IMP)

Pharmacological interactions are important when nuclear medical procedures are applied to patients under drug therapy, or drug provocation. This study compares in baboon models (regional) cerebral blood flow [(r)CBF] results from 99mTc-HMPAO and 123I-iodoamphetamine [123I(IMP)] each with and without acetazolamide, the latter a suggested drug for testing cerebrovascular reserve. Expected differences in cerebral uptake were observed between the two radio-tracers without acetazolamide. The increase in tracer uptake resulting from acetazolamide is significantly enhanced for 123I(IMP), which could have diagnostic implications.     

Increase of human plasma GABA by sodium valproate

gamma-Aminobutyric acid (GABA) was measured in the plasma of volunteers during subchronic treatment with sodium valproate (VPA). After 2 days of oral treatment with 300 mg VPA, t.i.d., the GABA concentration was increased to about 30% compared to 2 control days. This response was similar to that after 2 days of treatment with 600 mg VPA, t.i.d., whereas on the fourth day of treatment with the latter dose, a plasma GABA increase of about 90% was observed.     

Cerebral blood flow study using SPECT in patients with memory disorders

INTRODUCTION: Global amnesia (AG) is a dysfunction of memory, in which there is a sudden incapacity to remember recent events and assimilate new information. The aetiology is currently under discussion. The main hypotheses under consideration are an ischemic mechanism and an epileptic mechanism. OBJECTIVE: To study the cerebral blood flow in patients with temporary global amnesia (AGT) or permanent global amnesia (AGP) using functional neuroimaging techniques. MATERIAL AND METHODS: Four patients were studied. Two had severe alterations of fixation memory which had been present for months. The other two had a sudden loss of recent memory, although space-person orientation and immediate memory remained normal. In all cases the cerebral blood flow (FSC), was assessed by single photon emission tomography (SPECT), using Tc-HMPAO as the radio tracer. RESULTS: We describe 4 patients, 2 men and 2 women aged between 42 and 64.2 with AGT and the others with AGP. On SPECT there was temporal hypoperfusion in all 4 patients. In 2 cases there was associated parietal hypoperfusion and in 1 case there was frontal hypoperfusion. CONCLUSIONS: These findings suggest that AGT and AGP are of vascular origin and that SPECT is a useful diagnostic technique in patients with AG.     

Cerebral blood flow velocity decreases during cognitive stimulation in Huntington's disease

OBJECTIVE: To examine whether activation of cerebral blood flow velocity during cognitive stimulation, as measured by transcranial Doppler ultrasonography (TCD), is altered in patients with Huntington's Disease (HD). BACKGROUND: Previous research suggests that resting cerebral blood flow in symptomatic and asymptomatic HD patients is reduced from expected premorbid levels. The effects of cognitive activation on this relative hypoperfusion in HD has not been studied extensively. METHODS: We measured TCD flow velocity during rest and cognitive testing with the Porteus Maze Test and the Trails Test in 12 normal control subjects and 10 gene-positive HD patients. Percent change (i.e., flow during testing/resting) of flow velocity in the anterior and middle cerebral arteries were compared between groups. Correlations among percent flow velocity change, a disability rating scale, and cognitive test scores were calculated. RESULTS: In control subjects, anterior cerebral artery flow velocity and middle cerebral artery velocity increased during cognitive testing (p=0.001). HD patients showed a smaller blood flow velocity increase in the anterior cerebral arteries during the Porteus Maze Test (p < 0.001) and the Trails Test, Part B (p < 0.001). In the left anterior cerebral artery, flow velocity fell an average of 4.2% below resting baseline levels during the Porteus Maze Test, and 1.2% below resting levels during the Trails Test. The magnitude of the cerebral blood flow velocity changes in the anterior cerebral artery correlated with a number of cognitive test scores and with a rating scale of functional disability. In addition, logistic regression was able to discriminate the HD patients from the control group based on blood flow velocity changes (p=0.0025). When HD patients were divided into more (i.e., HD with chorea; n=4) and less impaired (i.e., without chorea; n=6) groups, both showed significant decreases in left anterior cerebral artery flow velocity during visual spatial executive cognition testing compared with control subjects. CONCLUSIONS: These results suggest that activation of visual spatial executive functions cause decreased flow velocity in the anterior cerebral artery, but not the middle cerebral artery, in HD patients. These changes are related to test performance and functional capabilities.     

Usefulness of fixed-dose drug combinations]

Diurnal rhythm of serum melatonin concentrations was estimated in 12 men with low back pain syndrome before and after exposure to a very low-frequency magnetic field (2.9 mT, 40 Hz, square wave, bipolar). Patients were exposed to the magnetic field for 3 weeks (20 min per day, 5 days per week) either in the morning (at 10:00 hr) or in the late afternoon (at 18:00 hr). Significant depression in nocturnal melatonin rise was observed regardless of the time of exposure. This phenomenon was characteristic for all the subjects, although the percent of inhibition of melatonin secretion varied among the studied individuals.     

Effects of the GABA mimetic drug, sodium valproate, on event-related potentials and its relation to the law of initial value

The effects of gamma-aminobutyric acid (GABA) mimetic drug sodium valproate (VPA) on event-related potentials (ERPs) were investigated in 18 healthy volunteers during an auditory odd ball task. VPA (200 or 400 mg) or an inactive placebo was administered according to a completely randomized double-blind, cross-over design. ERPs were recorded one hour after medication was given. VPA did not affect the latencies of N100, P200, N200 and P300. Although on the whole VPA had no effect on the amplitudes of the ERP components in the subjects, it increased the P300 amplitude in the low P300 amplitude subjects and decreased it in the high P300 amplitude subjects. This tendency toward a bidirectional response was also seen in the P200 and N200 amplitudes. It was concluded that the response which takes place being dependent on the difference in the initial values was recognized on the effect of a single administration of 200 or 400 mg VPA to ERPs. The results of this study are discussed, especially in relation to the law of initial value.     

Cerebral blood flow is increased throughout 12 h of hypoxaemia in the mid-gestation ovine fetus

The changes in regional cerebral blood flow (CBF) in response to prolonged hypoxaemia were measured using coloured microspheres in the 0.6-gestation ovine fetus (n = 5). Fetal hypoxaemia was induced for 12 h by reducing maternal uterine blood flow with an adjustable clamp. CBF (mL min-1 100 g-1) was increased (P < 0.05) from control values (38.7 +/- 3.5) to 105.6 +/- 5.6 at 6 h of hypoxaemia, and to 121.9 +/- 23.1 at 12 h of hypoxaemia. One hour after fetal hypoxaemia had ceased, CBF (54.0 +/- 3.3) had decreased (P < 0.05) towards control values indicating incomplete cardiovascular recovery. Cerebral vascular resistance at 6 h and 12 h of hypoxaemia was lower (P < 0.05) than control values, and returned to control values 1 h after fetal hypoxaemia had ceased. Cerebral oxygen delivery at 6 h and 12 h of hypoxaemia was not significantly different from control values, but was higher (P < 0.05) 1 h after hypoxaemia had ceased. It is concluded that CBF is sufficiently increased during prolonged hypoxaemia in the mid-gestation fetus to maintain cerebral oxygen delivery.     

Changes in red blood cells with valproate therapy

Unlabeled use of drugs in children occurs frequently and contributes to the therapeutic orphan dilemma. This situation can no longer be condoned; few acceptable reasons still exist for not evaluating potentially effective drug therapy in children. An apparent lack of research funds is not one of these reasons; only allocation of these funds to pediatric pharmacology is found wanting. Availability of clinical pharmacology programs, pediatric pharmacology manpower, sensitive analytical techniques, and acceptable ethical approaches to pediatric research reveal that drug evaluation is feasible in children. Studies readily include the required therapeutic indication for drug use in pediatrics. Efforts of academia, government and industry are now converging to show that the path for the noble mission of pediatric pharmacology--rational use of FDA approved drugs for children--is now clear for action.