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Biomedical subjects

R D Smyth

Publications and source records attributed to R D Smyth.

At least 37 records · Page 2Linked to original sources
PubMed1980

Human perinatal distribution of butorphanol.

The perinatal distribution of butorphanol was demonstrated in relation to maternal-neonatal transfer and colostrum/milk excretion in obstetric patients. Parenteral butorphanol passed the placental barrier and was found in neonatal cord serum. The mean neonatal serum concentration of butorphanol was not different from the mean maternal serum concentration of butorphanol, following a 1 or 2 mg intramuscular dose. Butorphanol was detected in the milk of lactating women following oral and intramuscular administration. Serum and milk concentrations appeared to be parallel with time. This observation was confirmed by the constancy of the mean milk-to-serum concentration ratio (0.7 intramuscular, 1.9 oral). We calculated that 4 micrograms would be the maximum amount of butorphanol, which would be expected to be present in the full daily milk output (1 L) following administration four times a day of 2 mg intramuscular or of 8 mg oral doses. An oral dose of 4 micrograms to an infant weighing 4 kg corresponds to the negligible oral dose of 0.7 mg to a 70 kg adult. The demonstrated safety and efficacy of butorphanol as an obstetric analgesic and the characteristics of the maternal-neonatal transfer and milk excretion are indicative of the potential excellence of this agent for obstetric use.

Anesthesia, Obstetrical↗
PubMed1980

Serum levels of butorphanol by radioimmunoassay.

A radioimmunassay was developed for the analysis of butorphanol in human serum. The procedure involves extraction of serum with hexane containing 2% isoamyl alcohol, followed by evaporative solvent removal and radioimmunoassay of the reconstituted residue. The antibody significantly cross-reacts with unidentified butorphanol metabolites but not with two known metabolites, hydroxybutorphanol and norbutorphanol. Extraction eliminated interference from the butorphanol metabolites normally present in serum. The antibody also cross-reacts with pentazocine and cyclazocine but not with morphine, hydromorphone, oxymorphine, codeine, methadone, and meperidine. Butorphanol tartrate was administered intravenously (2 mg) to normal male volunteers. Serum butorphanol levels declined biexponentially with an average terminal half-life of 2.7 hr. Enzymatic serum hydrolysis prior to extraction yielded additional butorphanol, indicating the presence of butorphanol conjugates. The specificity of the assay for butorphanol was confirmed by GLC--mass fragmentography.

Adult↗
PubMed1980

Pharmacokinetics of subcutaneous and intramuscular butorphanol in dogs.

Butorphanol tartrate was administered intramuscularly and subcutaneously to adult male and female dogs at a dose of 0.25 mg/kg. No significant absorption lag time and no significant difference bwtween peak intramuscular and subcutaneous serum concentrations were observed. The mean peak serum concentration was 29 ng/ml at mean times of 28 min after subcutaneous administration and 40 min after intramuscular administration. There were no significant differences in the pharmacokinetics of butorphanol in dogs with either route. The serum half-life was 1.62 hr, and the serum clearance was 3.45 liters/kg/hr. The apparent volume of distribution of butorphanol was 7.96 liters/kg. Although considerable inter- and intraanimal variation in Cmax and AUC was observed, there was no significant difference in the area under the serum concentration versus time curves, and the two administration routes were considered bioequivalent.

Animals↗
PubMed1980

Comparative pharmacokinetics of ceforanide (BL-S786R) and cefazolin in laboratory animals and humans.

Ceforanide (BL-S786R) is a new, broad-spectrum, parenteral cephalosporin. Pharmacokinetic properties were determined in rats (100 mg/kg), rabbits (30 mg/kg), dogs (25 mg/kg), and humans (2 g or 30 mg/kg) and compared with equivalent single doses of cefazolin. Plasma half-lives for ceforanide and cefazolin were 1.1 and 0.5 h in the rat, 5 and 0.3 h in the rabbit, 1 and 0.8 h in the dog, and 2.6 and 2 h in humans, respectively. The slower elimination of ceforanide, as reflected by longer plasma half-life, larger area under the curve, and peak plasma concentrations, was due to slower body and renal clearances. The apparent volumes of distribution of ceforanide and cefazolin were comparable. Rats, dogs, and humans excreted 80 to 100% of the ceforanide dose in the 0- to 24-h urine; rabbits excreted only 50%. Tubular secretion constituted 50% of ceforanide renal excretion in rabbits, dogs, and humans and 90% in rats; the remainder was excreted by glomerular filtration. There was no apparent correlation between the extent of tubular secretion and degree of plasma protein binding in different species. There was no significant pharmacokinetic interaction between ceforanide and amikacin in the rat. The slower elimination kinetics of ceforanide are indicative of the potential for a longer dosing interval and more effective antibiotic therapy as compared with available cephalosporins.

Adult↗
PubMed1980

Bioavailability and metabolism of potassium phosphanilate in laboratory animals and humans.

Phosphanilic acid is an antibacterial agent with a mode of action and antibacterial spectrum similar to those of sulfamethoxazole, with the exception that it has potent antipseudomonal activity. Bioavailability studies in rats (50, 300, and 600 mg/kg, oral and subcutaneous), dogs (50, 150, and 450 mg/kg, oral and intravenous infusion), and humans (400 and 800 mg, oral) showed that the extent of oral absorption of potassium phosphanilate was low. The bioavailability, calculated by comparing the oral values for area under the plasma concentration curve with those for the respective parenteral doses, was 10% for rats and 45 (50 and 150 mg/kg) and 19% (450 mg/kg) for dogs. The 24-h urinary recovery also confirmed the low oral bioavailability, i.e., rat, 13 (oral) and 75% (subcutaneous); dog, 15 to 29 (oral) and 87% (intravenous) of the dose. Plasma levels and urinary recovery (4%, oral) were low and variable in humans. The poor absorption of oral doses may be due to drug precipitation in the stomach, low permeability of the soluble species due to extensive in situ ionization (pK(a), 1.8 to 2) in the intestine, or first-pass metabolism to N-acetylphosphanilic acid. The plasma t((1/2)) values after parenteral administration were 0.3 h in rats and 1.3 h in dogs. Although the lack of adequate blood levels of phosphanilic acid after oral administration in humans precludes the use of this compound for treatment of systemic infections, the sustained urinary concentration at levels severalfold higher than the minimal inhibitory concentration (1 mug/ml) for at least 10 h postdose was indicative of the therapeutic usefulness in urinary tract infections.

Adolescent↗
PubMed1980

The relationship between serum gastrin, gastric ulceration and basal acid output in the polyarthritic rat.

The relation between the incidence of gastric ulceration, basal acid output and serum gastrin concentration was studied in the pyloric-ligated normal rat and the rat with established adjuvant disease (polyarthritis). Although there was no significant difference in either gastric secretions or basal acid output, serum gastrin was significantly higher in the adjuvant rat than in the normal rat, independent of the nutritional state of the animal. The incidence of the gastric lesions was eight times greater in adjuvant rats compared to controls in a 6-hour pyloric-ligation period. When the period of pyloric ligation was increased from 6 to 17 hr, there was 91% increase in gastric lesions in polyarthritic rats. Histopathology of the lesions in the polyarthritic rat showed diffuse and focal submucosal edema with polymorphonuclear inflammatory cell infiltration in the submucosa of the fundic and antral areas of the stomach. The increased susceptibility of the polyarthritic rat to gastric ulceration could be related to a combination of experimental stress and hypergastrinemia. Since similar elevations in serum gastrin have been reported in the rheumatoid arthritis in man, it is herein proposed that the polyarthritic rat could be used as a screening model for the evaluation of the ulcerogenicity potential of nonsteroidal anti-inflammatory drugs.

Animals↗
PubMed1980

Placental transfer and other physiologic studies with intravenous butorphanol in the anesthetized pregnant ewe.

In clinical evaluation, butorphanol has been used in labor pain with analgesia and newborn outcome comparable to meperidine. Only limited placental transfer studies have been done in the human. The placental transfer and effect of intravenous butorphanol (2 mg) on avrious cardiovascular parameters were determined in anesthetized sheep. Serum butorphanol was determined by a specific radioimmunoassay. Butorphanol 2 mg intravenously did not affect the measured cardiovascular parameters in either ewe or fetus. Butorphanol could be demonstrated in the fetal circulation within one minute of administration and appeared to reach equilibrium in the maternal circulation rapidly and to remain in equilibrium thereafter. A biexponential decline of butorphanol was observed in the maternal serum with a terminal elimination half-life of 50 minutes. The data suggest butorphanol distribution in the pregment ewe can be conceptualized by the two compartment model, with the fetus as part of the peripheral compartment. These studies support the clinical finding from other studies that butorphanol appears to be a safe analgesic for use in labor pain.

Anesthesia↗
PubMed1979

Clinical pharmacokinetics and safety of high doses of ceforanide (BL-S786R) and cefazolin.

The pharmacokinetics and safety of ceforanide and cefazolin were compared in normal subjects after 30-min intravenous infusions of 2-, 3-, and 4-g single doses and 4-g twice-daily doses for 10 days. No significant differences were observed in plasma-renal pharmacokinetic parameters between single and multiple doses of ceforanide. Half-life (t((1/2)), 2.8 h), plasma clearance (Cl(p), 48 ml/min per 1.73 m(2)), and renal clearance (Cl(0-12h) (r), 47 ml/min per 1.73 m(2); tubular secretion, 44%, and glomerular filtration, 56%) did not change with increased dose or on multiple dosing. No significant change was observed in t((1/2)) (1.9 h), area under the plasma concentration-time curve, Cl(r) (60 ml/min per 1.73 m(2); tubular secretion, 80%, and glomerular filtration, 20%), or Cl(p) (75 ml/min per 1.73 m(2)) for 4-g single doses compared with twice-daily administration of cefazolin. A small increase in cefazolin clearance was observed when plasma concentrations were greater than 100 mug/ml, when the single dose was increased from 2 to 4 g; this was a result of the decrease in percentage of plasma protein binding and increased renal clearance due to increased glomerular filtration. The increase in renal clearance resulted in a lack of linear proportionality of the plasma area under the curve with dose over a range of 2 to 4 for both cephalosporins, although this effect was much less marked with ceforanide. Both compounds were well tolerated both locally and systemically. There was no evidence of any change in renal function based on clearances of drug, p-aminohippuric acid, or creatinine, and other standard clinical parameters.

Adult↗
PubMed1979

Physiological disposition and subcellular localization of 14C-fenclorac in the rat.

The physiologic disposition and subcellular tissue localization of 14C-fenclorac was studied in rats receiving single and multiple oral doses of the drug. The drug was primarily excreted via renal and fecal routes. The 24-hour urinary and fecal elimination rates were 41 and 17% respectively, of the administered dose. The daily elimination rates of drug/drug metabolites were not altered when the treatment period was extended to seven days, suggesting that the processes for the renal and fecal clearance of drug were not affected by this treatment schedule. Studies on the distribution of 14C-fenclorac in slected tissues revealed that hepatic, renal and splenic tissue to plasma ratio of the label twenty-four hours after a single dose was 1.53, 3.88 and 0.11, respectively. Similar results were observed in rats receiving multiple doses of 14C-fenclorac. The 14C-label was distributed throughout the subcellular organelles with the highest concentration in the cytosol and lower levels in the mitochondria and microsomes. Furthermore, these experiments demonstrated that both metabolic (hepatic) and excretory (kidney) organs do not accumulate fenclorac in animals receiving the drug up to seven days.

Animals↗
PubMed1978

GLC assay of fenclorac in human plasma.

A simple, sensitive GLC assay for fenclorac is described. Plasma proteins were precipitated with methanol, and the methanolic extract was refluxed with hydrochloric acid to form the methyl esters of fenclorac and the internal standard. The esters were purified by partitioning into benzene. Aliquots of 1 microliter of the concentrated benzene phase were injected into the gas chromatograph and quantitated by a 63Ni-electron-capture detector. Recovery of fenclorac from plasma averaged 82 +/- 1.6%.

Adult↗
PubMed1977

Quantitative determination of fenclorac in serum.

A spectrophotometric method for the analysis of fenclorac and its metabolite, 3-chloro-4-cyclohexylbenzeneglycolic acid, in human serum was developed. The parent compound represented at least 90% of the total species present in blood; the metabolite was present to the extent of about 10%, primarily in the elimination phase. The basic procedure consists of extraction of both compounds from serum, further extraction to remove interfering substances, alkaline conversion of fenclorac to the alpha-hydroxy acid metabolite, oxidation of this metabolite to the corresponding benzaldehyde derivative, and spectrophotometric measurement of the absorbance of the aldehyde at 252 nm. A comparison of serum concentrations obtained by this method with concentrations calculated from 14C-data following oral administration of 1-14C-fenclorac to eight normal adult volunteers indicated a 90% correlation between methodologies over a range of 1.4-25.5 microgram of fenclorac/ml of serum.

Adult↗