Frontal degenerative dementia and neuroimaging.
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Aged↗
Biomedical subjects
J W Russell
Publications and source records attributed to J W Russell.
Role of nerve growth factor in suramin neurotoxicity studied in vitro.
We determined whether suramin neurotoxicity can be prevented by nerve growth factor (NGF) and if this interaction occurs at the level of the NGF receptor. Neurite outgrowth from rat dorsal root ganglia in vitro was measured serially in the presence of suramin (100-600 microM) alone or with beta-NGF (50-1,000 ng/ml). Competitive NGF receptor-binding studies were done with 125I-labeled NGF in the presence or absence of suramin. Neurite growth was inhibited in a dose-dependent manner, but at usual neurotoxic levels this inhibition could be overcome completely by increasing the concentration of NGF. Receptor-binding assays showed similar dose-dependent inhibition of 125I-labeled NGF binding. In the presence of suramin, the dissociation constant for high-affinity binding was decreased from 1.2 x 10(-11) to 3.9 x 10(-10) and low-affinity binding from 2.7 x 10(-9) to 1.2 x 10(-8). Increasing doses of suramin inhibited 125I-labeled NGF specific binding in a dose-dependent fashion, and doses of suramin > or = 1,000 microM were able to completely inhibit 125I-labeled NGF specific binding. Suramin-induced dorsal root ganglia damage can be ameliorated by high-dose NGF. This effect is most likely due to competition between suramin and NGF at the high-affinity NGF receptor.
Animals↗
Prodrugs of 2',3'-didehydro-3'-deoxythymidine (D4T): synthesis, antiviral activity, and rapid pharmacokinetic evaluation.
A series of 5'-derivatives and modified pyrimidine analogues of 2',3'-didehydro-3'-deoxythymidine (d4T, stavudine, 1) were synthesized to determine their potential as oral prodrugs of d4T. Utilizing a screen developed for the rapid evaluation of a variety of prodrugs in mice, it was determined that 5'-acetate 2 provided comparable plasma levels of d4T after oral administration of the prodrug to that when d4T was administered alone. The relative oral bioavailability of methoxy acetate 3 and cyclohexyl carbonate 5 was 79 and 41%, respectively. Dihydropyridine ester 6 did not provide detectable levels of d4T up to 1 h after oral administration of 6. Thiopyrimidines 8 and 9, as well as aminopyrimidine 10 also failed to provide measurable levels of d4T after oral administration. 5'-Derivatives 3, 5, and 6 showed similar activity to that of d4T against HIV and MuLV, as did 5'-benzoyl-4-thio derivative 8. However, the corresponding 4-thio 5'-alcohol 9 was inactive.
Animals↗
Pharmacokinetics and antiviral activity of a novel isonucleoside, BMS-181165, against simian varicella virus infection in African green monkeys.
A novel nucleoside analog BMS-181165 with potent activity against varicella-zoster virus was tested for efficacy in a simian varicella virus infection in African green monkeys. BMS-181165 was effective in preventing the development of a rash, decreasing the development of viremia and preventing death in infected monkeys when administered orally at 4, 16 or 64 mg/kg/day. The compound is well orally absorbed in monkeys, between 44 to 50% oral bioavailability, and may prove of value in therapy of varicella-zoster infections in humans.
Administration, Oral↗
The effect of nerve growth factor, ciliary neurotrophic factor, and ACTH analogs on cisplatin neurotoxicity in vitro.
Cisplatin, used to treat ovarian, bladder, and testicular cancers, causes a sensory dose-limiting neuropathy. Preliminary observations in humans and animals suggest that nerve damage may be prevented by ACTH analogs, particularly those belonging to the melanocortin class, and by nerve growth factor (NGF). We established a rat embryo dorsal root ganglion model to study cisplatin neurotoxicity. The drug reproducibly inhibited axonal growth at concentrations similar to that known to produce toxicity in neurons. The inhibition was prevented in a dose-dependent fashion by simultaneous exposure to alpha-melanocyte stimulating hormone (alpha-MSH) or ACTH but not by excess NGF or ciliary neurotrophic factor (CNTF). The ACTH peptides were not effective in preventing suramin-induced neurotoxicity in the same model. Drug interaction and dose-response studies showed that ACTH and alpha-MSH do not act by potentiation of NGF action. ACTH analogs appear to protect against cisplatin-induced neurotoxicity directly at the cellular level.
Adrenocorticotropic Hormone↗
Brachial and lumbar neuropathies.
Sporadic acute brachial plexus neuropathy occurs in approximately 1.64/100,000 population, but may present in epidemic form. Sporadic lumbosacral plexus neuropathy is far less common and has to be distinguished from more common disorders affecting the plexus and roots such as diabetes. Early this century, when serum therapy became popular to treat or prevent prevalent infectious diseases, it became apparent that a plexopathy could follow treatment. It has thus been assumed that many of the cases are due to an autoimmune or inflammatory lesion of the plexus. A wide variety of vaccines, infections and medications seem able to precipitate the disorder. Recent work has shown that cultured lymphocytes from affected patients, but not controls, are able to mount a blastogenic response to components of cadaver brachial plexus. This response seems to be selective not only to the brachial plexus, but also to discrete components of the plexus. The recovery rate in brachial plexus neuropathy is good, being almost 90% at 3 years. Recovery with lumbosacral disease is less satisfactory. Histological material and descriptions of acute brachial plexus neuropathy are rare. There is some evidence that an inflammatory process is present, but the role of demyelination and axonal atrophy in producing the observed clinical signs, is still uncertain. Virtually nothing is known about the histological changes in lumbosacral plexus neuropathy. Treatment is mainly supportive, but important in limiting disability. Steroids may help relieve pain in the acute stages, but do not seem to alter the prognosis.
Biopsy↗
Inhibitors of blood platelet cAMP phosphodiesterase. 4. Structural variation of the side-chain terminus of water-soluble 1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one derivatives.
1-(Cyclohexylmethyl)-4-[4-[(2,3-dihydro-2-oxo-1H-imidazo[4,5-b] quinolin-7-yl)oxy]-1-oxobutyl]piperazine (2) was previously identified as a potent, water-soluble inhibitor of human blood platelet cAMP phosphodiesterase and of induced aggregation in vitro that demonstrated effective antithrombotic activity in animal models of thrombosis. Although 2 exhibited 25% oral bioavailability in rats, pharmacokinetic studies conducted in monkeys revealed that the parent compound was less than 5% bioavailable, the result of extensive first-pass biotransformation in the liver. In an effort to identify potent platelet aggregation inhibitors with enhanced metabolic stability, the side-chain amide moiety of 2 was replaced with chemically more stable urea (6a-s), sulfonamide (13a-m), sulfone (19a-r), and tetrazole (23a-s) moieties. Many representatives from each of these structural types effectively combined potent inhibition of ADP-induced human platelet aggregation in vitro with excellent aqueous solubility, and several are superior to 2. Within each series, the N-(cyclohexylmethyl)-, N-(2-ethylbutyl)-, N-benzyl-, and N-(4-fluorobenzyl)-substituted derivatives were evaluated for in vitro metabolic stability by incubating with the S-9 fraction of monkey liver for 2 h, and the extent of biotransformation was compared with that of the prototype 2. The sulfone 19e and the tetrazoles 23e, 23g, 23j, and 23q were significantly more stable than 2 under these conditions, and 19e and 23e were selected for evaluation in vivo. Tetrazole 23e exhibited 72% bioavailability following ip administration to rats compared with 35% bioavailability for 2 and 19e under the same conditions. However, the oral bioavailability of 19e and 23e in the rat was estimated to be only 3%, suggesting that 19e and 23e are less readily absorbed from the gastrointestinal tract than 2.
3',5'-Cyclic-AMP Phosphodiesterases↗
Predictive value of electromyography in diagnosis and prognosis of the hypotonic infant.
To investigate the diagnostic validity of electromyography in the hypotonic infant, 79 children aged 0 to 12 months, seen over a 20-year period, were studied retrospectively. The diagnoses using clinical, muscle biopsy, and laboratory characteristics were: 25 central hypotonia, 20 spinal muscular atrophy, 20 myopathy, four myotonic dystrophy, four benign congenital hypotonia, two congenital muscular dystrophy, two myasthenia gravis, one infantile inflammatory myopathy, and one arthrogryposis multiplex congenita. Using strict criteria, electromyography accurately predicted the final diagnosis in 65% of infants with spinal muscular atrophy and was consistent with the diagnosis in another 25%. In contrast, electromyography accurately predicted the final diagnosis in only 10% of infants with myopathy and was normal in 88% of infants with central hypotonia. In infants with spinal muscular atrophy, there was no difference in the predictive value of electromyography when performed in the newborn compared to older infants. Normal distal nerve conduction velocities in infants with spinal muscular atrophy may predict prognosis, since these infants had a longer survival. Electromyography thus has a high predictive value for infantile spinal muscular atrophy but not for myopathy.
Biopsy↗
Determination of 9-[(2-phosphonylmethoxy)ethyl]adenine in rat urine by high-performance liquid chromatography with fluorescence detection.
A high-performance liquid chromatographic (HPLC) method for the determination of 9-[(2-phosphonylmethoxy)ethyl]adenine (PMEA) in urine is described. The procedure includes treatment of the urine sample with chloroacetaldehyde to form the fluorescent 1,N6-ethenoadenosine derivative, which was analyzed by reversed-phase HPLC with fluorometric detection. Validation of the method showed good sensitivity, precision and reproducibility. The method is useful for the study of urinary excretion of PMEA in the rat.
Adenine↗
Ischemic cerebrovascular complications and risk factors in idiopathic hypertrophic subaortic stenosis.
To determine the risk and time to cerebrovascular complications with idiopathic hypertrophic subaortic stenosis, we studied 119 patients (66 men and 53 women) with evidence of this disease based on strict echocardiographic criteria and followed them up for a mean +/- SEM of 6.5 +/- 0.6 years. Cerebral ischemic events occurred in 26 patients (22%), and in five patients stroke was the initial presenting event. Men had cardiac symptoms at a younger age than women, but there was no significant difference in age at the time of stroke. Cardioembolic cerebrovascular events were associated with atrial fibrillation and left atrial enlargement, whereas atheroembolic events were associated with hypertension. An increased risk of stroke was associated with female sex, mitral anulus calcification, hypertension, and atrioventricular conduction delay. Unlike most previous series, this study shows that patients with idiopathic hypertrophic subaortic stenosis may present with stroke.
Adult↗
Comparative pharmacokinetics of new anti-HIV agents: 2',3'-dideoxyadenosine and 2',3'-dideoxyinosine.
A number of 2',3'-dideoxynucleosides have been shown to inhibit the in vitro infectivity and cytopathic effect of the human immunodeficiency virus (HIV). These compounds, as their 5'-triphosphates, inhibit viral reverse transcriptase by competing with the natural substrate at the same binding site on the enzyme. Dideoxynucleoside triphosphates can also be incorporated into growing DNA chains which then blocks further DNA elongation because they lack the 3'-hydroxyl group required for further polymerization. Among these nucleosides, 2', 3'-dideoxyadenosine 2',3'-dideoxyadenosine (ddA) and 2',3'-dideoxyinosine (ddI) show promising in vitro activity. Because adenosine is rapidly converted to inosine by adenosine deaminase, the in vivo conversion of ddA to ddI was studied to determine suitability of measuring plasma levels of ddI and to assess the bioavailability and pharmacokinetics of ddA. This report describes and compares the pharmacokinetics of ddA and ddI in the mouse.
Animals↗
Psychiatric screening in the premenstrual syndrome.
Prospective daily ratings of premenstrual symptomatology were obtained from 40 women for one full menstrual cycle. Nineteen of these women were complaining of suffering from a premenstrual syndrome. The General Health Questionnaire (GHQ) was administered in the mid-follicular and late luteal phases of the cycle. Women who were complaining of the premenstrual syndrome showed significant premenstrual increases in premenstrual symptoms, of a magnitude that was significantly greater than those of control subjects. The GHQ scores of the women who were complaining of premenstrual syndrome were significantly higher than those of the control subjects in both the follicular and luteal phases of the cycle. The mean GHQ score of the group with premenstrual syndrome was significantly elevated above the published normal value. Fifty-six per cent of those who complained of premenstrual syndrome had follicular GHQ scores which were higher than the recommended threshold for clinical psychiatric disturbance. Only 10.5% of the control group were above this threshold. General Health Questionnaire scores were stable across phases of the cycle and were correlated to the severity of symptoms of premenstrual syndrome. Premenstrual Moos Menstrual Distress Questionnaire (MDQ) scores were related strongly to follicular MDQ scores. A high proportion of women who complain of premenstrual syndrome show evidence of a more general psychiatric problem which should be evaluated before therapy.
Adult↗
Determination of anagrelide in plasma by capillary gas chromatography-mass spectrometry.
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Fibrinolytic Agents↗
Assessment of premenstrual symptomatology: a re-evaluation of the predictive validity of self-report.
The predictive validity of subjects' self-reports of the severity of four groups of symptoms associated with the premenstrual syndrome (PMS) was assessed by canonical correlation of retrospective self-reports of usual symptom severities with prospectively obtained symptom severity scores from the next two cycles. Prospective scores from the second cycle were then correlated with retrospective recall scores obtained after the end of that cycle. A measure of inter-cycle variability was obtained by correlation between two consecutive sets of prospective scores. The symptoms studied were tension, depression, cognitive and physical ('water retention') symptoms. It was found that subjects' recall of a particular cycle predicted 72% of the variance in that cycle's prospective severity scores, indicating that the subjects correctly interpreted the severity of premenstrual symptoms and distinguished them from symptoms present in the follicular part of the cycle. Retrospective reports of usual PMS symptomatology predicted 21% of the variance in symptom scores in the next menstrual cycle and 12% of the variance in the following one. Despite this decrease, averaging the scores from the two prospective cycles improved the prediction to 23%. Prospective scores from one cycle predicted only 14% of the variance in prospective scores from the next, suggesting a high degree of inter-cycle variability. Women's self-reports of their usual PMS symptomatology reflect their experience more accurately than has been thought. The finding of marked inter-cycle variability suggests that arguments for the use of a single cycle of prospective data in PMS evaluation are fallacious and that retrospective self-report may be clinically useful and relatively valid.
Adult↗
Evaluation of the premenstrual syndrome.
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Adult↗
A prospective comparison study of premenstrual symptoms.
A study in which two groups of women were compared prospectively has been carried out. One group (n = 31) complained of premenstrual syndrome (PMS) whereas the other group (n = 12) denied suffering from PMS. It was found that premenstrual symptoms increased significantly in women who complained of PMS although some symptoms (irritability, abdominal swelling) increased significantly in the other group as well. The group that complained of PMS showed significantly greater premenstrual increases in some symptoms than did the comparison group, but not in anxiety, irritability, tension or breast tenderness. In the late follicular phase statistically significant baseline differences occurred between the two groups in depression, anxiety, tension and irritability. Significant correlations between baseline and premenstrual scores in the PMS group were found for most of the symptoms that were studied, particularly for tension, anxiety, sleeplessness and depression. These results suggest that women who complain of premenstrual syndrome may require therapy for their generally higher levels of anxiety and depression throughout the entire menstrual cycle rather than for the premenstrual exacerbation alone.
Adult↗
Gas chromatographic-mass spectrometric method for trazodone and a deuterated analogue in plasma.
A plasma assay method for trazodone and a 2H4 analogue is described which uses gas chromatography--electron-impact selected-ion monitoring mass spectrometry. Etoperidone is used as an internal standard. The analytes are extracted from basic medium into n-butyl chloride, then back extracted into aqueous 0.1 M hydrochloric acid. The aqueous layer is made basic and re-extracted with n-butyl chloride. The solvent is reduced under nitrogen at 35 degrees C and the residue is redissolved in toluene for gas chromatographic--mass spectrometric analysis. The ions monitored are m/z 231, 235, and 225 for trazodone, [2H4] trazodone and etoperidone, respectively. Quantitation is in the range 40-1000 ng/ml with acceptable precision and accuracy. The method is suitable for biopharmaceutical studies.
Biological Availability↗
Effects of acute food and/or water deprivation on muricide.
The present experiment was designed to test certain predictions derived from models of interactions between muricide and appetitive behaviors proposed earlier by Russell and Singer [8,9]. One of the major features of the models centered on whether the two types of behavior are inevitably related. The general design of the present experiment involved testing for muricide either (a) after deprivation of food and/or water or (b) at times during the normal diurnal cycle when the two consummatory responses were at their minima and maxima. Deprivation and testing for muricide were limited to a single episode in order to eliminate confounding effects of repeated deprivations and of repeated exposures to prey. Periods of acute deprivation ranging from 5.5 to 22.0 hr did not induce significant quantitative changes in muricidal behavior. However, muricide and the appetitive behaviors did co-vary under conditions associated with the normal diurnal cycle. Comparing the present results with findings from experiments using repeated deprivation leads to the suggestion that covariation of appetitive and muricidal behaviors is not an innate characteristic, but rather is acquired through processes of learning. Present results further suggest that each of the two types of behavior has its own physiological substrate which can be modified independently, but also may be activated concomitantly by a common set of antecedent conditions.
Aggression↗