Biomedical subjects
Publications and source records attributed to R L Smith.
The cutaneous penetration of acyclovir can be significantly increased from a propylene glycol base vehicle by adding small amounts of a polar lipid such as oleic acid. These results are consistent with those found for salicylic acid, and the large increases in acyclovir penetration could potentially lead to better topical treatment of herpes simplex.
Single-cell recordings from the anesthetized gerbil revealed that neurons in the ventral cochlear nucleus, the most peripheral nucleus of the central auditory system, differentially encode a functionally relevant acoustic feature--amplitude modulation. Onset units show the strongest phase--locked responses to amplitude-modulated sounds, followed in order by chopper, primarylike-with-notch and primarylike units. All these neurons show enhanced responses relative to auditory-nerve fibers which provide their ascending inputs. This enhancement occurs over a 90 dB range of sound levels.
Although beta-blockers are structurally closely related, there are marked differences in the extent of metabolism, related mainly to relative lipophilicity. Lipophilic beta-blockers are metabolized by C-oxidative pathways and glucuronidation. Metabolism of lipophilic beta-blockers is important in determining pharmacokinetics, formation of active metabolites, stereoselectivity and isomer preference, and interphenotypic variation. The oxidative clearance of metoprolol, timolol and bufuralol is regulated/influenced by the debrisoquine hydroxylation gene locus. The metabolism of these lipophilic beta-blockers thus exhibits polymorphic characteristics, there being significant interphenotype differences in pharmacokinetics (bioavailability, peak plasma level, plasma terminal t1/2) between the poor and extensive metabolizers of debrisoquine. There are similar interphenotype differences in beta-blocker pharmacodynamics in terms of beta-blockade. A number of adverse effects of lipophilic beta-blockers have been hypothesized to predominate in the poor metabolizer phenotype including unacceptable bradycardia, loss of cardioselectivity, greater CNS side-effects, and interactions with drugs metabolized by the same polymorphic systems. However, objective evidence for this is lacking.
Three complex inhibitory responses, tonic immobility, the dorsal immobility response, and lordosis, were studied in the intact female rat during estrus and diestrus and in ovariectomized rats with estrogen-progesterone treatment or controls. In each condition, the effects of vaginal-cervical stimulation were also studied. The results of two experiments indicate that estrus and estrogen-progesterone treatment significantly potentiate lordosis and the dorsal immobility response with or without vaginal-cervical stimulation. Tonic immobility was also potentiated by estrus and estrogen-progesterone treatment, but only if vaginal-cervical stimulation was applied. Vaginal-cervical stimulation potentiated both tonic immobility and the dorsal immobility response, but not lordosis, which was already at a high level.
Adult male Wistar rats treated with morphine sulfate (0.5, 5.0, and 10.0 mg/kg, SC) showed a dose-dependent potentiation of tonic immobility (TI) and dorsal immobility response (DIR) durations. Naloxone (4.0 mg/kg, SC) did not affect the DIR durations but reversed the potentiated morphine effects on both TI and DIR. These results suggest that although opiate receptors may be involved, mu-opiate receptor function is not essential for modulating various complex immobility responses.
The effects of ovariectomy, sham ovariectomy, and estradiol benzoate replacement on unilateral intrastriatal dopamine-induced postural deviation were studied in rats. Animals were tested prior to surgery, and at both two and seven days after surgery. Relative to the pre-surgery test, ovariectomized rats greatly increased this behavioral response two days after surgery while sham ovariectomy resulted in no significant change. Estradiol benzoate treatment in ovariectomized animals not only prevented this increase but significantly suppressed it at both two and seven days after surgery relative to pre-surgery levels. Thus, removal of endogenous estrogen in female rats resulted in an acute increase in a striatal DA-mediated behavior which could be prevented by hormone replacement. These results are consistent with the hypothesis that estrogen suppresses some striatal DA-mediated behaviors.
When a tone burst is presented to the ear, the firing rate of single auditory nerve fibers is initially high, then rapidly declines toward a smaller value. The rate of this decline in gerbil is a complex function of stimulus frequency and intensity, and fiber characteristic frequency.
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A series of 5-substituted 3,5-dihydroxypentanoic acids and their derivatives have been prepared and tested for inhibition of HMG-CoA reductase in vitro. In general, unless a carboxylate anion can be formed and the hydroxy groups remain unsubstituted in an erythro relationship, inhibitory activity is greatly reduced. Furthermore, only one enantiomer of the ring-opened form of lactone 6a(+/-) possesses the activity displayed by the racemate. Insertion of a bridging unit other than ethyl or (E)-ethenyl between the 5-carbinol moiety and an appropriate lipophilic moiety (e.g., 2,4-dichlorophenyl) attenuates activity.
The ability to oxidize sparteine to form 2- and 5-dehydrosparteine was studied in 154 healthy Ghanaians. Although the urinary metabolic sparteine/dehydrosparteines ratio varied widely (from 0.14 to 12.5), in contrast to observations in several Caucasian population groups the ratios were not bimodally distributed and no phenotypically poor oxidizers of sparteine were found. The ability of these same subjects to oxidize debrisoquin and phenformin was also studied in 141 and 143 subjects. Of the 141 subjects dosed with debrisoquin, 10 proved to be poor oxidizers, and of the 143 subjects dosed with phenformin, 11 were poor oxidizers. All the poor oxidizers of debrisoquin were also poor oxidizers of phenformin. The 10 confirmed poor metabolizers of debrisoquin, who had debrisoquin metabolic ratios ranging from 14.4 to 52.0, had sparteine metabolic ratios ranging only from 0.15 to 12.5. Whereas Caucasian poor metabolizers of sparteine excrete less than 2.0% of a dose as dehydrosparteines, the mean excretion of dehydrosparteines in our 10 subjects was 20.6% +/- 13.2%. The overall rank correlation between the sparteine and debrisoquin metabolic ratios was low (rs = 0.47), while the coefficient of determination for linear regression (r2) was only 0.17. Our data show that the ability of Ghanaians to oxidize sparteine is largely independent of their capacity for debrisoquin oxidation and is indicative of a major interethnic difference in the genetic control of these reactions.
Adaptation of auditory-nerve responses was investigated by applying increments and decrements in intensity to an ongoing tonal background. The change in firing rate produced by a change in intensity was obtained as a function of the time delay from the onset of the background to the onset of the change in intensity. The initial change in firing rate was measured using both small (1 ms) and large (10 ms) time intervals in order to evaluate properties of rapid and short-term adaptation, respectively. Consistent with previous results, the incremental and decremental responses measured with large windows were independent of time delay and the amount of prior adaptation. A similar additivity was observed for the incremental response measured with a small time window. In contrast, the decremental response measured with a small window decreased with increasing time delay and in proportion to the decrease in firing rate produced by the background. A similar decrease was observed in the response modulation produced by sinusoidal amplitude modulation. It was concluded that sensitivity to decrements in intensity decreases during adaptation, so that this response component does not reflect the additivity inherent in other aspects of adaptation.
Metabolically active heterocysts isolated from wild-type Anabaena sp. strain CA showed high rates of light-dependent acetylene reduction and hydrogen evolution. These rates were similar to those previously reported in heterocysts isolated from the mutant Anabaena sp. strain CA-V possessing fragile vegetative cell walls. Hydrogen production was observed with isolated heterocysts. The ratio of C2H4 to H2 produced ranged from 0.9 to 1.2, and H2 production exhibited unique biphasic kinetics consisting of a 1 to 2-min burst of hydrogen evolution followed by a lower, steady-state rate of hydrogen production. This burst was found to be dependent upon the length of the dark period immediately preceding illumination and may be related to dark-to-light ATP transients. The presence of 100 nM NiCl2 in the growth medium exerted an effect on both acetylene reduction and hydrogen evolution in the isolated heterocysts from strain CA. H2-stimulated acetylene reduction was increased from 2.0 to 3.2 mumol of C2H4 per mg (dry weight) per h, and net hydrogen production was abolished. A phenotypic Hup- mutant (N9AR) of Anabaena sp. strain CA was isolated which did not respond to nickel. In isolated heterocysts from N9AR, ethylene production rates were the same under both 10% C2H2-90% Ar and 10% C2H2-90% H2 with or without added nickel, and net hydrogen evolution was not affected by the presence of 100 nM Ni2+. Isolated heterocysts from strain CA were shown to have a persistent oxygen uptake of 0.7 mumol of O2 per mg (dry weight) per h, 35% of the rate of whole filaments, at air saturating O2 levels, indicating that O2 impermeability is not a requirement for active heterocysts.
Previously published results of phenformin 4-hydroxylation in 195 unrelated white British volunteers and 87 family members of 27 randomly selected probands have been subjected to genetic analysis. The results clearly show that about 9% of this population has a genetically determined defect in carrying out this oxidation reaction. The character for the defect is inherited in a Mendelian autosomal recessive fashion. The polymorphism shows a substantial degree of dominance.
Recent studies have found that the hyperphagia and obesity resulting from lesions of the ventromedial hypothalamus (VMH) are both reversed and prevented by complete adrenalectomy. Several previous experiments, however, reported little or no suppression of VMH weight gain in hypophysectomized (HYPOX) rats. This study directly compared the effects of hypophysectomy and adrenalectomy on hypothalamic obesity in adult female rats. Complete adrenalectomy (i.e, stress-induced plasma corticosterone less than 1.0 micrograms/dl) totally suppressed abnormal weight gain in the first 20 days after VMH lesions but did not affect intracranial self-stimulation. Hypophysectomy also resulted in suppression of weight gain, but the HYPOX-VMH rats nevertheless gained significantly more weight than HYPOX rats with sham lesions. However, the HYPOX-VMH animals had very low levels of plasma corticosterone and adrenocorticotropin (ACTH) (from residual pituitary tissue or of diencephalic origin), and incompletely adrenalectomized rats with similar low levels of plasma corticosterone gained an equal amount of weight after VMH lesions. It was concluded that adrenal glucocorticoid hormones play a largely permissive role in the VMH syndrome, with only very small levels required for the manifestation of obesity.
In order to obtain a phenotypically stable cell population of chondrocytes, high density primary monolayer cultures of bovine articular chondrocytes were established. Using these cultures, a specific insulin-like growth factor-I/somatomedin-C (IGF-I/SM-C) receptor was demonstrated and characterized. At 15 degrees C steady-state binding was attained by 5 h, and averaged 25% per 2.2 X 10(6) cells. Fifty per cent displacement of 125I-labelled IGF-I/SM-C by unlabelled IGF-I/SM-C occurred at concentrations of only 2.3 ng/ml, whereas IGF-II and porcine insulin were approximately 15- and 1000-fold less potent respectively. Scatchard analysis gave a linear plot, with a calculated association constant of 2.26 X 10(9) l/mol and a receptor number of 15 400 sites per cell. Preincubation of chondrocyte monolayers with either IGF-I SM-C or porcine insulin at 37 degrees C for 20 h resulted in reduction of 125I-labelled IGF-I/SM-C binding in a dose-dependent manner, although higher concentrations were required with insulin. More than 40% down-regulation of the receptor occurred with IGF-I/SM-C at concentrations of 10 nmol/l and nearly 70% reduction at 50 nmol/l. Interestingly, after preincubation with either human (h) or bovine (b) GH, 40% down-regulation of 125I-labelled IGF-I/SM-C binding was observed at concentrations of 10 mumol/l. Local production of IGF-I/SM-C by chondrocytes in response to GH stimulation may have occurred, but, because only 120 pmol IGF-I/SM-C and less than 30 pmol IGF-I/SM-C per litre were recovered from serum-free conditioned media preincubated with bGH and hGH respectively, this was not established.(ABSTRACT TRUNCATED AT 250 WORDS)
One-hundred-and-twenty volunteers and three families were investigated for possible association between the sulphoxidation of S-carboxymethyl-L-cysteine and the debrisoquine hydroxylation polymorphism. The observed individual variations in these two metabolic reactions were shown not to be concordant (rs = 0.068) and any heritable factors controlling the major aspects of these phenomena do not co-segregate.
Using the N-oxide derivative of niaprazine, a nicotinamide-based drug, as substrate, the possibility of a 1,2-oxygen shift from N to adjacent C occurring in vivo has been investigated. By comparison of the percentage of the 6-pyridone derivative formed after administration of 14C-niaprazine to rats with that obtained after giving 14C-niaprazine N-oxide, it has been shown that a 1,2-oxygen shift might contribute to the formation of 6-pyridone derivatives as metabolites of nicotinamide-related drugs in vivo.
L-645,151 [(2-sulfamoyl-6-benzothiazolyl)-2,2-dimethylpropionate] is the O-pivaloyl ester of L-643,799 (6-hydroxybenzothiazole-2-sulfonamide), topically administered L-645,151 being a substrate for ocular esterases with the resultant liberation of the active moiety, L-643,799, during penetration of the ocular surface. The minimum concentrations of topically administered suspensions (1 drop of 50 microliters into both eyes) of L-645,151, L-643,799, dichlorphenamide and methazolamide significantly lowering the elevated intraocular pressure (IOP) of the alpha-chymotrypsinized rabbit eye were 0.25, 2, 10 and 5%, respectively. IOP was not significantly decreased by 10% suspensions of acetazolamide or ethoxzolamide. The IOP lowering action of L-645,151 was local as the unilateral instillation of L-645,151 (0.25%) into the contralateral eye was devoid of effect in alpha-chymotrypsinized rabbits. L-645,151 (2%) decreased aqueous humor inflow in both the conscious rabbit and the anesthetized dog. Outflow facility in the conscious rabbit was unaltered by a 10% suspension of L-645,151. Low peak levels (0.52 microgram/g) of L-643,799 were present in rabbit renal cortex after the instillation of L-645,151 (2%) into both eyes; this treatment did not induce diuresis in the conscious rabbit. The corresponding maximum concentration in the iris + ciliary body was 4.01 micrograms/g. These preclinical studies reveal that L-645,151 is the most potent, topically effective ocular hypotensive carbonic anhydrase inhibitor described to date.