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Biomedical subjects

R D Miller

Publications and source records attributed to R D Miller.

At least 361 records · Page 20Linked to original sources

High performance liquid chromatography of natural products. II. Direct biological correlation of components in the fermentation broth.

A portion of the eluent, during liquid chromatography of a fermentation broth, is applied directly to a paper strip at the same rate as the recording of the U. V. absorption. The paper is then placed on the agar inoculated with an appropriate test organism. This procedure permits direct correlation of biological activity with corresponding peaks in the U. V.

Anti-Bacterial Agents↗

FDA seeks tighter controls over research with human subjects.

The Food and Drug Administration and other federal agencies have proposed or adopted regulations for institutions involved in research with human subjects. As a consequence, institutional review boards (IRBs) are becoming a necessity in many hospitals that did not previously need them. Unfortunately, the various requirements, especially those proposed by the FDA, imposed upon IRBs often make compliance for hospitals a complex undertaking.

Ethics Committees, Clinical↗

Hypotensive anesthesia for total hip arthroplasty: a study of blood loss and organ function (brain, heart, liver, and kidney).

The authors attempted to determine whether hypotensive anesthesia or the method of inducing hypotension has any effect on postoperative brain, liver, or kidney function and myocardial status following total hip arthroplasty. Thirty patients were anesthestized with halothane-nitrous oxide for total hip arthroplasty and randomly assigned to one of three groups. In two groups mean arterial blood pressure was decreased to 50 torr by high inspired concentrations of halothane (n = 90) or sodium nitroprusside (n = 12). In the third group (n = 9) mean blood pressure was maintained within 20% of control. Intraoperative blood losses decreased from 1,183 +/- 172 ml in the normotensive group to 406 +/- 102 ml and 326 +/- 41 ml in the halothane and nitroprusside hypotensive groups, respectively. Neither method of inducing hypotension nor hypertensive technique affected the results of postoperative tests of cerebral, hepatic, or renal function and myocardial status. These tests were performed before anesthesia and operation and at intervals in the postoperative course. In this small group of patients, deliberate hypotension for total hip arthroplasty added no morbidity and significantly shortened operating time, decreased blood loss, and decreased the number of blood transfusions needed.

Aged↗

Hypothermia and the pharmacokinetics and pharmacodynamics of pancuronium in the cat.

We tested the effect of hypothermia on the pharmacokinetics and pharmacodynamics of pancuronium in the cat. In 14 cats given pancuronium, 120 microgram/kg i.v., we found that neuromuscular block lasted between 2.5 and 3.0 times longer at 29 degrees C (N = 5) than at 34 degrees C (N = 5) or 39 degrees C (N = 4). The apparent plasma elimination half-life was 46 +/- 7 min (S.E.) at 29 degrees C as compared to 21 +/- 2 and 25 +/- 6 min at 34 and 39 degrees C, respectively. The volume of distribution of the central compartment and total volume of distribution at steady state were less at 29 and 34 dgrees C than at 39 degrees C. Total plasma clearance was 4.3 +/- 0.4 ml/kg/min at 29 degrees C and 10.7 +/- 0.9 and 10.9 +/- 1.5 ml/kg/min at 34 and 39 degrees C, respectively. The reduced plasma clearance resulted at least in part from a markedly reduced biliary and urinary excretion of pancuronium at 29 degrees C as compared to 34 and 39 degrees C. In four other cats, the plasma concentration of pancuronium was correlated with depression of twitch tension under steady-state conditions. The ED50 of pancuronium (plasma concentration required for a 50% depression of twitch tension) was 0.035 and 0.073 microgram/ml at 29 and 38 degrees C, respectively. We conclude that a pancuronium neuromuscular block is prolonged at 29 degrees C because of an increased sensitivity of the neuromuscular junction to pancuronium and delayed biliary and urinary excretion.

Animals↗

The comparative potency and pharmacokinetics of pancuronium and its metabolites in anesthetized man.

To determine the potency of pancuronium and its metabolites, 3-OH-, 17-OH- and 3,17-OH-pancuronium, cumulative dose-response curves were determined in five anesthetized patients with each drug. Pancuronium (ED50 = 0.041 mg/kg) was 2 times more potent than 3-OH-pancuronium (ED50 = 0.082 mg/kg), 50 times more potent than 17-OH-pancuronium (ED50 = 2.0 mg/kg) and 54 times more potent than 3,17-OH--pancuronium (ED50 = 2.15 mg/kg). In 21 other patients, one equipotent dose of either pancuronium or one of its metabolites was given as an i.v. bolus. Onset time and duration of neuromuscular blockade from 3-OH- and 3,17-OH-pancuronium did not differ significantly from that of pancuronium; 17-OH-pancuronium had a shorter duration of action than did pancuronium. Although pancuronium tended to have a slightly longer elimination half-life, the pharmacokinetics of the four drugs did not differ significantly. The elimination half-lifes were 110, 68, 73 and 71 min for pancuronium and its 3-OH, 17-OH and 3,17-OH derivatives, respectively. We conclude that although pancuronium is more potent than its 3-OH, 17-OH and 3,17-OH metabolites, the pharmacokinetics of these three metabolites do not differ from each other and from that of pancuronium.

Dose-Response Relationship, Drug↗

Pancuronium-induced neuromuscular blockade, and its antagonism by neostigmine, at 29, 37, and 41 c.

To determine the effects of variations in temperature on the neuromuscular blockade produced by pancuronium, the drug was infused intravenously into 18 cats anesthetized with chloralose and urethane at a constant continuous rate to produce and maintain 90 per cent depression of twitch tension of the anterior tibial muscle following supramaximal stimulation of the peroneal nerve. The mean (+/-SE) infusion rates of pancuronium needed were 0.44 +/- 0.05, 0.99 +/- 0.11, and 1.05 +/- 0.09 microng/kg/min (r = 0.73) at 29, 37, and 41 C, respectively. In contrast, the doses of neostigmine necessary for 50 per cent antagonism of the pancuronium-induced depression of twitch tension were not significantly different at the three temperatures. The time required to achieve peak neostigmine effect was longer at the lowest temperature. The durations of neostigmine action were longer at 29 and 37 than at 41 C. It is concluded that hypothermia augments neuromuscular blockade produced by pancuronium and prolongs the time to peak effect, and possibly the duration of action, but not the dose of neostigmine needed to antagonize the blockade.

Anesthesia, Intravenous↗

Ligated renal pedicles and duration of action of neostigmine and pyridostigmine.

1. The duration of neostigmine or pyridostigmine antagonism of a (+)-tubocurarine (Tc) neuromuscular blockade was determined in the cat anterior tibialis-peroneal nerve preparation with and without ligated renal pedicles. 2. The infusion rate of Tc required to maintain a 90% depression of twitch tension was reduced from 8.8 +/- 1.4 (s.e.) to 3.4 +/- 0.6 mugkg-1 min-1 by renal pedicle ligation. 3. Renal pedicle ligation resulted in an increased duration of antagonism of Tc by both neostigmine and pyridostigmine.

Animals↗

Binding of progesterone to Neisseria gonorrhoeae and other gram-negative bacteria.

The binding of [1,2-(3)H]progesterone to progesterone-sensitive Neisseria gonorrhoeae CS-7 and the progesterone-insensitive Neisseria mucosa, Pseudomonas aeruginosa, and Salmonella typhimurium (rough and smooth strains) was investigated. The kinetics of binding to N. gonorrhoeae CS-7 demonstrated that the majority of the progesterone binding occurred and equilibrium was reached within the first 30 min. Despite the rapid binding of progesterone, only about 20% of the added steroid was bound at the cell concentration used throughout this study. Whole cells of progesterone-insensitive bacteria bound progesterone less efficiently than the progesterone-sensitive N. gonorrhoeae CS-7. N. mucosa bound low amounts of this steroid (20% of that bound by N. gonorrhoeae CS-7) whereas the other gram-negative bacteria exhibited little progesterone binding (<3% of that bound by N. gonorrhoeae CS-7). The outer membrane permeability of N. gonorrhoeae CS-7, as measured by crystal violet uptake and inhibition, was similar to the deep rough mutant of S. typhimurium TA 1535. The latter organism neither bound nor was inhibited by progesterone. However, isolated cell envelopes of N. gonorrhoeae and progesterone-insensitive bacteria all bound progesterone equally well. Cortisone and cholesterol, althouh structurally similar to progesterone, were not inhibitory to N. gonorrhoeae and did not bind to whole cells as well as progesterone. The major site of progesterone binding appeared to be the cytoplasmic membrane, which bound four times more progesterone than the outer membrane. In addition, isolated cytoplasmic membrane proteins bound more than three times more progesterone per milligram of protein than the intact membrane.

Cell Membrane↗

Inhibitory action of fatty acids on the growth of Neisseria gonorrhoeae.

Fatty acids of various chain lengths (C(1) to C(24)) were examined for their effects on growth, oxygen consumption, and in vitro reduced nicotinamide adenine dinucleotide oxidase activity of Neisseria gonorrhoeae CS-7. The growth inhibition caused by saturated fatty acids increased with increasing chain length to a maximum with palmitic acid (C(16)). Stearic acid (C(18)) and longer saturated fatty acids showed little inhibition of growth. However, unsaturated fatty acids of chain length C(16) to C(20) were inhibitory. Similar inhibition was observed with Bacillus subtilis and a deep rough mutant of Salmonella typhimurium. Wildtype S. typhimurium and Pseudomonas aeruginosa were more resistant to medium-chain (C(7) to C(10)) fatty acids and completely resistant to long-chain (C(12) to C(18)) fatty acids. Thus, sensitivity of N. gonorrhoeae to long-chain fatty acids appears to be related to the permeability of the outer membrane. Growth inhibition by short-chain (C(1) to C(6)) fatty acids was pH dependent; inhibition of growth increased with decreasing pH. Saturated fatty acids inhibited oxygen consumption by log-phase cells of N. gonorrhoeae. This inhibition increased with increasing chain length to a maximum observed with myristic acid (C(14)). Whereas stearic acid (C(18)) had little effect upon oxygen consumption, unsaturated C(18) fatty acids were inhibitory. An in vitro inhibition of reduced nicotinamide adenine dinucleotide oxidase activity by saturated (C(1) to C(12)) and unsaturated (C(16) to C(20)) fatty acids was also observed. Although the inhibitory concentrations were generally higher than those required to inhibit growth or oxygen consumption, an inhibition of electron transport may be partially responsible for the observed growth inhibition.

Bacteria↗

The excretion of enterotoxin B from nongrowing cells of Staphylococcus aureus 4916.

The physiological conditions for the excretion of staphylococcal enterotoxin B (SEB) by nongrowing cells have been determined. In general, SEB excretion appears to be best when amino acids serve as sources of carbon, nitrogen, and energy. Little toxin was produced in a nitrogen-free medium with glucose as the sole carbon source. Inhibitor studies have shown that most of the toxin excreted by nongrowing cells was the result of de novo protein synthesis. Optimum toxin excretion was also obtained under conditions of aeration, and at or near optimum growth temperature, those conditions at which the cells are metabolically and biosynthetically most active. Levels of cell-associated SEB decreased during toxin excretion. However, these levels of toxin could not account for the high levels of toxin released during excretion. Glucose and several other rapidly fermentable carbohydrates inhibited toxin excretion by as much as 80% under conditions of uncontrolled decrease in pH: however, when the pH was kept at either 6.2 or 7.5 a stimulation of toxin excretion was observed. Protoplast studies have suggested that SEB production does not take place in the absence of an intact cell wall.

Air↗

The pharmacokinetics of d-tubocurarine in man with and without renal failure.

Plasma and urine concentrations of d-tubocurarine (d-TC) were determined and twitch tension was monitored before and after the intravenous administration of d-TC, 0.5 mg/kg in patients anethetized with halothane and nitrous oxide with (N=5) and without (N=5) renal failure. Terminal half lives of d-TC of 231 and 330 minutes predicted from other studies for patients with and without renal function were consistent with plasma concentrations measured. In patients with normal renal function, 38% of unchanged d-TC was eliminated in urine in 25 hours as opposed to 13% in those patients with a newly transplanted kidney. However, we still conclude that a newly transplanted kidney can eliminate d-TC effectively since the kidney was inserted 3.5 hours after administration of d-TC. Absence of renal function significantly prolonged the duration of neuromuscular blockade but did not alter the plasma concentrations of d-TC required for neuromuscular blockade. Thus, prolonged neuromuscular blockade from d-TC in patients with renal failure is due to decreased elimination rate of the drug as a consequence of lack of renal function rather than increased sensitivity.

Adult↗

Measurement of IgD by a double antibody radioimmunoassay: demonstration of an apparent trimodal distribution of IgD levels in normal human sera.

A double antibody radioimmunoassay (RIA) was developed to measure IgD in serum and secretions. One IgD myeloma protein was used as radiolabeled antigen and standard with antiserum to a second IgD myeloma protein. The IgD standard and normal sera yielded parallel inhibition curves in the RIA and inhibition was produced by IgD and not by any of the other immunoglobulins. The assay had a lower limit of sensitivity of 0.01 International Unit (I.U.)/ml and modifications increased the sensitivity to 0.0008 I.U./ml. Measurable IgD levels were found in all 112 normal adult sera assayed (geometric mean 13.0 I.U./ml, arithmetic mean 30.1 I.U./ml, median 14.8 I.U./ml, range 0.10 to 202 I.U./ml, 95% of values between 0.19 and 156 I.U./ml. The distribution of IgD in the 112 normal sera appeared trimodal with modes at approximately 0.25 I.U./ml, 5I.U./ml, and 35 I.U./ml. IgD was measurable in nasal and bronchial washes and human milk, but could not be detected in parotid fluid.

Antigens↗

Renal failure and postoperative respiratory failure: recurarization?

The occurrence of acute postoperative respiratory failure in three patients with renal failure is presented. The most likely cause was the return of muscle paralysis after the apparent antagonism of tubocurarine by neostigmine (recurarization). In addition to reducing the dose of tubocurarine, the authors recommend that pyridostigmine be used as an antagonist instead of neostigmine because the former has a longer duration of action.

Adult↗

Duration of halothane anesthesia and neuromuscular blockade with d-tubocurarine.

Cumulative d-tubocurarine dose-response curves were determined in 35 unpremedicated adult surgical patients. In five awake patients with and five awake patients without ulnar nerve block the median effective doses of d-tubocurarine necessary for 50 per cent depression of twitch tension (ED50) were 8.3 and 9.1 mg/m2, respectively. The presence of an ulnar nerve block did not significantly alter ED50, which suggests that the central nervous system has little influence on the d-tubocurarine dose-response curve. The ED50's of d-tubocurarine were 4.8, 4.5, 2.5, 3.2, and 3.8 mg/m2 in patients anesthetized with 1.0 to 1.3 per cent alveolar concentrations of halothane for 10, 20, 40, 80, and 160 minutes, respectively. It is concluded that duration of anesthesia has no effect on neuromuscular blockade by d-tubocurarine.

Adult↗

Biphasic respiratory depression after fentanyldroperidol or fentanyl alone used to supplement nitrous oxide anesthesia.

Either fentanyl or Innovar (fentanyl, 0.05 mg/ml, and droperidol 2.5 mg/ml) was administered to supplement nitrous oxide anesthesia for operations on 29 patients. Both fentanyl and Innovar depressed the slope of the rebreathing CO2 response curve during operation to 42 per cent +/- 6 (mean of all intraoperative values, +/- SE) of the awake control value. Following the last injection of drug but with continuation of operation, the slope increased such that it was 77 per cent +/- 8 of control on the patients' arrival in the recovery room. The slope continued to increase to a peak of 103 per cent +/- 9 of control. Soon therafter respiratory depression recurred, as indicated by a decline in the slope to 55 per cent +/- 5 of control, with a subsequent gradual return to 85 per cent +/- 8 of control 230 minutes after the last injection. This biphasic response occurred in 90 per cent (26 of 29) of the patients treated either with fentanyl alone or with Innovar. Full recovery appeared to be more rapid with Innovar than with fentanyl alone. Droperidol did not augment and may have attenuated fentanyl-induced respiratory-depression.

Adult↗