Velnacrine is a centrally acting anticholinesterase which has been considered for use in the treatment of Alzheimer's disease. If proven to be of value, it will be used concurrently with other medications. Its potential to cause interaction is, therefore, important to study. The aim of this work was to investigate velnacrine as an inhibitor of hepatic oxidative enzymes. The effects of velnacrine on antipyrine metabolism in isolated rat hepatic microsomes were compared to those of cimetidine. Aliquots of 200, 250 and 300 micrograms/ml antipyrine were incubated alone, with 20 micrograms/ml cimetidine and with each of 20, 50 and 100 micrograms/ml velnacrine. The concentrations of antipyrine and of its metabolites, 3-hydroxymethylantipyrine, 4-hydroxyantipyrine and norantipyrine were assayed by reverse phase high performance liquid chromatography. Cimetidine inhibited production of all three metabolites. Velnacrine did not affect 3-hydroxymethylantipyrine production. Mean inhibition of 4-hydroxyantipyrine production of 15%, 30% and 25% (P < 0.01), and of 14%, 25% and 12% of norantipyrine production (P < 0.01) occurred. These results indicate that velnacrine may inhibit the enzymes responsible for the metabolism of antipyrine to norantipyrine and 4-hydroxyantipyrine. The clearance rate of drugs that are metabolised through the hepatic oxidase system may, therefore, be reduced in the presence of concurrent treatment with velnacrine.

Animals↗

PubMedDate not supplied

Assessment of the value of therapeutic monitoring of tacrine in Alzheimer's disease.

OBJECTIVES: The purpose of this study was to validate the lower end of the putative therapeutic range of serum tacrine concentrations of 7-20 ng ml(-1) in the treatment of Alzheimer's disease. METHODS: The relationship between dose, steady-state serum tacrine concentrations and change in MMSE score (a measure of cognitive function) was examined in 106 Alzheimer's disease patients who had been treated with the drug for 12 weeks. RESULTS: In all, 72% of patients showed some response, but there was no relationship between dose and the chance of a favourable outcome. The proportion of patients with serum concentrations above 7 ng x ml(-1) who improved (79%) was significantly greater than that of those with serum concentrations below this level (47%) (P < 0.02). Also, a significantly greater proportion of patients with serum concentrations above both 5 ng x ml(-1) and 9 ng x ml(-1) showed improvement in comparison to those with concentrations below these levels. CONCLUSIONS: This study indicates that therapeutic monitoring of serum tacrine concentrations might increase the possibility of responding to tacrine by some 68%. This represents an important contribution to the management of Alzheimer's disease patients with this drug, and may also be relevant to the use of the newer generation of cholinesterase inhibitors.

Aged↗

PubMedDate not supplied

Chemoradiotherapy in the management of localized tumors of the pancreas.

In western countries, carcinoma of the pancreas remains the most lethal of the common malignancies. Even the favorable "organ-confined" tumors present a considerable challenge. The lack of anatomic barriers to local infiltration and the biological propensity for early lymphatic, perineural, and vascular invasion are nearly insurmountable obstacles to complete surgical eradication of this malignancy. Various combinations of chemotherapy and radiotherapy (RT) have been used with marginal but measurable success. Earlier trials conducted by the Gastrointestinal Tumor Study Group established roles for 5-fluorouracil chemotherapy and RT in the treatment of patients with resectable or locally advanced pancreatic cancer. More recently, computed tomography-guided conformal RT and a variety of intraoperative RT techniques have enabled more reliable sterilization of the local surgical field and escalation of doses to potentially curative levels (7000 cGy) for unresectable lesions. Chemotherapy dose intensification through the use of portable programmable pumps for protracted venous infusions and the development of active systemic agents in addition to 5-fluorouracil suggest that an effective combination chemotherapeutic regimen might soon be developed. This report reviews the current standards of practice and integrates recent developments to construct a modern algorithm for the use of chemoradiotherapy in the management of localized (nonmetastatic) pancreatic cancer. The likely directions of future investigations are also discussed.

Algorithms↗

PubMedDate not supplied

ERPs to stimuli requiring response production and inhibition: effects of age, probability and visual noise.

Sixty-six normal adults ranging in age from 20 to 85 years were presented with stimuli containing explicit instructions to initiate or to inhibit a motor response (the words 'push' or 'wait'). In one task, the effect of stimulus probability was investigated by varying probability between 0.25 and 0.75 for both Go and No-go stimuli. In another task, the effect of visual noise was investigated by degrading the stimuli with ampersands on half of the trials. Regression analysis was used to examine the effects of age on P3 amplitude and latency for each stimulus type. The effects of stimulus variables on P3, independent of age, were examined by standardizing each subject's data to those expected for a 20 year old. P3 latency to all stimuli and RT to Go stimuli increased with age. The latency of P3s to No-go stimuli was less sensitive to age than Go stimuli. P3 amplitude at Cz and Pz (but not Fz) diminished with age. P3s to Go stimuli were maximal at Pz and earlier than P3s to No-go stimuli. P3s to No-go stimuli were maximal at Cz. These differences between Go and No-go stimuli remained true under visual noise and probability manipulations. Visual noise prolonged the latency of Go and No-go P3. Less probable Go and No-go stimuli elicited larger and later P3s than more probable stimuli. Decreasing the probability of the No-go stimulus enhanced its central distribution.

Adult↗

PubMedDate not supplied

Late event-related potential changes in alcoholics.

The P3 component of the event-related potential (ERP) was recorded during a Go/No-Go task from 42 alcoholic subjects, abstinent for 11-63 days, and 66 normal adult volunteers. In two different tasks, ERPs were elicited by visually presented words which provided explicit response instructions to Go (PUSH) or No-Go (WAIT). In the Noise Task, half of both Go and No-Go stimuli were degraded with ampersands (&P&U&S&H&, &W&A&I&T&). In the Probability Task, the probability of the Go stimulus was 25% and No-Go 75% on one run and the proportion reversed on another run. For both tasks, the amplitude of alcoholics' P3 was smaller than that of controls to the Go but not to the No-Go stimulus. There was a similar, but less pronounced trend for P3 latency to be delayed in alcoholic subjects for the Go, but not No-Go stimuli for the Noise Task. The P3 changes in alcoholics are consistent with those seen in several disease states which produce cognitive impairment.

Adult↗

PubMedDate not supplied

Automatic and effortful processing in aging and dementia: event-related brain potentials.

Automatic and effortful processes were investigated using event-related brain potentials (ERPs) recorded from moderately impaired subjects with probable Alzheimer's Disease (AD), normal elderly, and normal young controls. The effects of effortful attention on ERPs to loud noises and the effects of stimulus intrusiveness on effortfully elicited ERPs were studied. First, ERPs to task relevant and irrelevant startling noises were compared. Second, ERPs to startling noises and moderate tones were compared when both were targets. The effects of age (young vs. elderly controls) and effects of dementing disease (AD subjects vs. elderly controls) were also assessed. Effortful attention augmented noise-elicited P300 amplitude in elderly subjects, but not in young. Intrusiveness augmented task-relevant P300 amplitude in young subjects, but not in elderly. Neither variable affected P300 amplitude in AD subjects. Thus, effects of age and disease depended on how P300 was elicited: when effortfully elicited, P300 amplitude was affected by disease but not age; when automatically elicited, P300 amplitude was affected by age but not disease. N1 effects differed from P300 effects.

Acoustic Stimulation↗

PubMedDate not supplied

Prophylactic granulocyte transfusions: results of a randomized controlled trial in patients with acute myelogenous leukemia.

A prospective randomized and controlled clinical trial of prophylactic granulocyte transfusions was conducted in an attempt to reduce the mortality from infection in newly diagnosed adults with acute myelogenous leukemia. Granulocytes were harvested from normal donors by cytapheresis, and transfused patients received a median of 1.45 x 10(10) granulocytes (range 0.28--3.45 x 10(10)) on alternate days during marrow aplasia caused by initial induction chemotherapy. Transfusion were started if the absolute peripheral granulocyte count was less than 500 microliters. Thirteen patients received from one to 12 granulocyte transfusions, and 11 control patients received no granulocytes. No significant advantage was demonstrated in the transfused patients compared with controls with regard to the following: 1) deaths due to infection, 2) reduction in the frequency of febrile episodes, 3) delay in the onset of fever, 4) reduction in the length of febrile episodes, or 5) reduction in the frequency of proven infection.

Adolescent↗

PubMedDate not supplied

Combined granulocyte and platelet transfusions. Development of alloimmunization as reflected by decreasing cell recovery values.

Twenty-three patients undergoing induction therapy for acute myelogenous leukemia (AML) received a total of 191 combined prophylactic granulocyte (PMN) and platelet (PLT) concentrates on alternate days (median 8, range 3-12 per patient). Each transfusion was assessed by monitoring the patient for reactions and by estimating the recovery of PMN in the circulation at 1 hour and of PLT at 1 and 20 hours. Seventeen patients developed alloimmunization to PLT from at least one donor, defined as either a PLT recovery of less than 15 percent at 1 hour and/or less than 10 percent at 20 hours. In this group there was a progressive reduction in PMN and PLT recovery with increasing transfusion number, strongly suggesting alloimmunization to both cells. Thirty-four transfusions were accompanied by transfusion reactions, thirty-two of which occurred in ten patients who had PMN recoveries of less than 5 percent after at least one transfusion (median 2.5, range 1-6 transfusions per patient). Actuarial calculations predicted that 70 percent of patients would become alloimmunized to PLT from at least two individuals after receiving 11 transfusions. These results suggest that combined PMN and PLT transfusion are associated with the rapid development of alloimmunization.

Cell Survival↗