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R D Schwarz

Publications and source records attributed to R D Schwarz.

17 recordsLinked to original sources
PubMed1992

Structure-activity studies on benzhydrol-containing nipecotic acid and guvacine derivatives as potent, orally-active inhibitors of GABA uptake.

The introduction of lipophilic groups onto the ring nitrogen of nipecotic acid and guvacine, two known GABA uptake inhibitors, afforded potent, orally-active anticonvulsant drugs. A series of compounds is reported which explores the structure-activity relationships (SAR) in this series. Among the areas explored: side-chain SAR (aromatic-, heterocyclic-, and tricyclic-containing side chains) and modifications to the tetrahydropyridine ring. The benzhydrol ether-containing side chains afforded the most potent compounds with several exhibiting in vitro IC50 values for GABA uptake of < 1 microM (including 5, Table I; 37, 43, Table IV; and 44, Table V). Compound 44 was selected for extensive evaluation and subsequently progressed to Phase 1 clinical trials with severe adverse effects seen after single dose administration to humans.

Administration, Oral↗
PubMed1992

Cholinergic agents: effect of methyl substitution in a series of arecoline derivatives on binding to muscarinic acetylcholine receptors.

Arecoline, arecaidine, and a series of derivatives, differing by the presence or absence of methyl groups at positions on the periphery of the molecule, were prepared, and their binding to muscarinic acetylcholine receptors was tested. On the basis of this study, muscarinic agonism for arecoline series is governed by strict structure-activity relationships, as previously observed for other agonist series. Only minor changes in nitrogen substitution were tolerated in the present series of arecoline derivatives.

Animals↗
PubMed1991

A silica gel plate-based qualitative assay for acetylcholinesterase activity: a mass method to screen for potential inhibitors.

A procedure for the qualitative assessment of inhibitory activity towards acetylcholinesterase for a given compound is described. Solutions of the compounds of interest are spotted on silica gel TLC plates in a matrix pattern. The silica gel plate is sprayed with a solution of acetylthiocholine iodide and 5,5-dithiobis(2-nitrobenzoic acid) followed by a solution of acetylcholinesterase. The enzyme reaction produces a yellow background color with inhibitor compounds exposed as white zones where color has failed to develop. The results for a test set of compounds were compared to those obtained using the standard Ellman assay procedure and found to agree for virtually all of these compounds. The conditions of silica gel plate thickness, reagent concentration, and enzyme source under which this procedure is suitable were investigated. This represents an extremely rapid method to screen large numbers of compounds to uncover new inhibitors of acetylcholinesterase and potentially other enzymes as well.

Acetylcholinesterase↗
PubMed1990

Loss of muscarinic M1 receptors with aging in the cerebral cortex of Fisher 344 rats.

Age-related changes in central cholinergic muscarinic receptors were measured in young (3-6 month), middle-aged (15-17 month), and aged (22-26 month) male Fisher 344 rats by receptor binding techniques. Using [3H]-quinuclidinyl benzilate as the ligand, a significant decrease (14-19%) in the number of muscarinic cortical receptors was measured in aged rats compared to both young and middle-aged rats. With the selective M1 antagonist, [3H]-pirenzepine, a 17% decrease in receptor density was observed in the cortex of aged animals compared to young rats. For both ligands no differences were observed in the striatum or hippocampus between any age group and there was no change in affinity (Kd) in any of the three brain regions for the three age groups. Additionally, there was no difference in choline acetyltransferase activity measured in cortex, hippocampus, or striatum of young and aged rats. Thus, there is a loss of M1 muscarinic receptors in the cerebral cortex of aged male Fisher 344 rats.

Aging↗
PubMed1989

Acute scrotal pain in children: prospective study of diagnosis and management.

Forty-eight boys were assessed for an acutely painful scrotum. Thirty-six (75%) of them underwent radionuclide scanning of the scrotum; the average age of this group was 11 years. The scan revealed epididymitis in 19 cases, spermatic cord torsion in 9, appendix testis torsion in 7 and acute hernia-hydrocele in 1. The diagnosis was confirmed at operation in all nine cases of spermatic cord torsion. Boys who had epididymitis received antibiotics only; all were available for short-term follow-up, and 16 were also assessed at a mean of 6 months after infection. Only one boy had testicular atrophy; he had undergone repair of an inguinal hernia, which could not be ruled out as a cause. Bacteriuric epididymitis occurred in three boys; two had known predisposing genitourinary anomalies, the third had no abnormalities. Boys who had nonbacteriuric epididymitis were investigated by renal and pelvic ultrasonography or voiding cystourethrography; no important abnormalities were detected. This prospective study indicates that radionuclide scanning can reliably differentiate spermatic cord torsion from other acute scrotal disease.

Acute Disease↗
PubMed1983

An in-vivo method for testing drugs that influence striatal dopaminergic functions.

A procedure is described for evaluating the effects of drugs on dopaminergic function in the striatum of mice. Mice, anesthetized with chloral hydrate are injected with 6-hydroxydopamine into one striatum to destroy dopamine nerve terminals at this site. Several days later, the mice are anesthetized with halothane, and test drugs or saline are injected into the intact striatum either before or after the systemic administration of amphetamine. The effect of these drugs on amphetamine-induced circling behavior is evaluated. Using this model, we have found that pilocarpine and muscimol can inhibit amphetamine-induced circling and their effects are blocked by the systemic administration of scopolamine and picrotoxin, respectively. In addition, ethyleneglycol-bis-(beta-amino-ethyl ether) N,N'-tetraacetic acid (EGTA), a calcium chelating agent, inhibited amphetamine-induced circling behavior and this effect is prevented by adding calcium to the EGTA solution. Finally, the intrastriatal administration of prostaglandin E2 but not its metabolite, 13,14-dihydro-15-keto-prostaglandin E2 inhibited amphetamine-induced circling suggesting a selective effect of the active prostaglandin. These results suggest that this procedure could be used for evaluating both the mechanism of action of drugs in the striatum as well as screening drugs for their therapeutic potential.

Animals↗
PubMed1982

Acute renal failure secondary to bilateral ureteric obstruction: review of 50 cases.

The records of 50 patients with acute renal failure secondary to bilateral ureteric obstruction were reviewed. An underlying malignant disorder was the cause of the obstruction in 38 of the patients and had not previously been diagnosed in almost half of them. Carcinomas of the cervix and prostate were the most frequent malignant disorders, and aggressive management resulted in good survival rates. Similarly, the outcome for patients with benign bilateral ureteric obstruction, usually caused by retroperitoneal fibrosis, was good with proper management.

Acute Kidney Injury↗
PubMed1982

Prostaglandin inhibition of amphetamine-induced circling in mice.

The effect of prostaglandins (PG) on amphetamine(AMPH)-induced circling was examined in mice unilaterally lesioned with 6-hydroxy-dopamine. At doses of 0.03-1.0 nmol/g, intraventricularly injected PGD2, PGE2, and PGF2 alpha all inhibited AMP-induced circling, while thromboxane-B2 (TxB2) was inactive at 1.0 nmol/g. The inhibition of circling was not due to alterations in body temperature as measured by rectal temperature changes. When injected intrastriatally, the same major PG inhibited AMP-induced circling at the lower doses of 0.01-0.1 nmol/g, while the PGE2 metabolite 13, 14-dihydro-15-keto-PGE2 was inactive at 0.1 nmol/g. PG administered alone did not procude circling. For both routes of administration, the order of potency was PGE2 greater than PGD2 greater than PGF2 alpha. These results suggest that PG can alter motor function governed by central dopaminergic pathways.

Amphetamine↗
PubMed1982

Prostaglandin inhibition of apomorphine-induced circling in mice.

The effect of prostaglandins (PGs) on apomorphine (apo)-induced circling was examined in unilaterally lesioned mice. Intraventricularly injected PGD2, PGE2, and PGF2 alpha at a dose of 1.0 nmole/g all inhibited apo-induced circling. When injected directly into the striatum, these same PGs also inhibited circling in a dose range of 0.01-0.1 nmole/g, while the PGE2 metabolite, 13,14-dihydro-15-keto-PGE2, was inactive at 0.1 nmole/g. For both routes of administration, PGF2 alpha appeared to be the most potent of the PGs tested. PGs administered alone by either route to unilaterally lesioned mice did not produce circling. Pretreatment with the PG synthetase inhibitor, indomethacin, caused the apo treated mice to circle at significantly higher rates than control animals. These results are the first report suggesting that within dopamine (DA)-mediated pathways PGs act at sites postsynaptic to the dopaminergic synapse.

Animals↗
PubMed1981

The pathogenesis of renal dysplasia. I. Quantification of hypoplasia and dysplasia.

In order to assess the relative effects of abnormal ureteric orifice position and abnormal urodynamics on the morphogenesis of hypoplasia and dysplasia in kidneys obtained from infants, we devised a method of quantifying the renal structures. The method was based on radial glomerular counts which ranged from zero to normal (seven to nine), a score for dysplastic structures, and the ratio of normal to abnormal tissues present. These three values, when plotted against each other, correlated closely. The glomerular count, with occasional minor adjustment for inconsistencies, was the best parameter of hypodysplasia. Severe to moderate grades of hypodysplasias fell in the low and middle ranges and hypoplasia through to normal in the highest range. By grading kidneys in this way, we were able to compare the effects of ureteral ectopy and abnormal urinary dynamics on the developing kidney.

Histological Techniques↗
PubMed1981

The pathogenesis of renal dysplasia. III. Complete and incomplete urinary obstruction.

We graded obstructed kidneys of infants on the hypodysplasia scale to assess the influence of complete and partial obstruction on the pathogenesis of hypodysplasia. Kidneys with complete obstruction exhibited severe grades; those with partial ureteral obstruction had near normal grades. Those kidneys subjected to partial urethral obstruction ranged from mild to severe grades which correlated with degrees of lateral ectopy of the urethral office. Renal parenchymal development was impaired by complete obstruction but was tolerant to incomplete obstruction. Abnormal orifice positions associated with urethral obstructions were considered to be manifestations of ectopic ureteric buds and the hypodysplasia to be evidence of abnormal induction of abnormal renal blastema.

Humans↗
PubMed1980

The relationship between the stimulation of dopamine synthesis and release produced by amphetamine and high potassium in striatal slices.

The effects of amphetamine (amph) and high K+ on the synthesis and release of dopamine (DA) were compared in striatal slices. Both agents stimulated DA synthesis as well as release. For both agents, Ca2+ was required for the initiation of synthesis stimulation as well as for the maintenance of this stimulation. The addition of EGTA to medium containing slices that were already stimulated by 1.0 microM-amph or 55 mM-K+ markedly reduced the stimulation of DA synthesis. Although it has been reported that high K+ activates soluble tyrosine hydroxylase (TH), neither high K+ nor amph appeared to increase the affinity of the synthetic cofactor, 6-MPH4, or decrease the affinity of the catechol, DA, for TH. This finding was supported by the observation that the inhibitory effect of L-DOPA on DA synthesis in slices, in which synthesis was stimulated by either agent, was not decreased. Although both 1.0 microM-amph and 55 mM-K+ stimulated the release of [3H]DA from striatal slices, the release produced by K+ was Ca2+-dependent, whereas release produced by amph did not occur at any concentration tested. Studies on pH requirements for both synthesis and release also confirmed a similarity between amph and K+ in stimulating synthesis but not in stimulating release. These results suggest that depolarizing agents, such as high K+, couple synthesis and release of DA by a Ca2+-dependent mechanism. In contrast, the simultaneous stimulation of synthesis and release by amph is not regulated by Ca2+.

Amphetamine↗
PubMed1976

The assessment of sphincteric activity in patients following trans-sphincteric urethral reconstruction.

12 patients who had previously undergone trans-sphincteric urethral reconstruction were studied with regard to their sphincter mechanisms. The method of study was by urethral pressure profile and urethral voluntary sphincteric pressure increment. This study showed that patients may undergo trans-sphincteric urethral reconstruction with preservation of normal profiles and voluntary pressure increases indicating preservation of the "external" sphincter mechanism.

Adult↗
PubMedDate not supplied

Cognition activators.

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Alzheimer Disease↗