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Biomedical subjects

S A Forman

Publications and source records attributed to S A Forman.

At least 55 records · Page 3Linked to original sources
PubMed1989

Molecular sites of anesthetic action in postsynaptic nicotinic membranes.

Theories of general anesthesia have traditionally been based on correlations between potency and the properties of simple models such as apolar solvents, lipid bilayers and soluble proteins. However, mechanisms can now be determined directly by studying excitable proteins in their membrane environment. Stuart Forman and Keith Miller describe the physiological, biophysical and molecular biological evidence pointing to the location of a discrete allosteric site on the nicotinic acetylcholine receptor at which local anesthetics act. General anesthetics, while superficially resembling local anesthetics in their actions on the receptor, do not appear to act upon such a site.

Anesthetics↗
PubMed1989

Actions of pentobarbital enantiomers on nicotinic cholinergic receptors.

The enantiomers of pentobarbital had four different actions on the nicotinic receptor-rich membranes from Torpedo electroplaques. (i) Both inhibited cholinergically stimulated cation flux through the receptor's channel, with IC50 values of approximately 25 microM and extremely weak stereoselectivity. (ii) (R)-(+)-[14C]Pentobarbital bound to a saturable site with an apparent dissociation constant of 100 microM, a Hill coefficient of 1.2, and a stoichiometry of 1:1 with the acetylcholine binding sites. (S)-(-)-Pentobarbital also displaced (+)-[14C]pentobarbital but its IC50 was 4-fold higher than that of the (+)-enantiomer under the same conditions. (iii) Both enantiomers caused a stereoselective allosteric inhibition of [3H]acetylcholine binding, which occurred over the same concentration range and with the same stereoselectivity as barbiturate binding. (iv) Above 1 mM, pentobarbital caused an unexpected and sudden increase in [3H]acetylcholine binding, which lacked significant stereoselectivity. These results are consistent with a model where low concentrations of pentobarbital act on the receptor by binding to allosteric sites that have higher affinity but lower stereoselectivity for the open channel conformation than for the resting conformation, whereas the highest concentrations of pentobarbital act by nonspecific mechanisms mediated by general membrane perturbations.

Acetylcholine↗
PubMed1988

A review of propylene glycol dinitrate toxicology and epidemiology.

Propylene glycol dinitrate (PGDN) is a rapidly metabolized, nitrated ester explosive propellant with acute cardiovascular effects at lower levels of exposure and methemoglobinemia and vascular collapse at higher ones. Exposure can be by dermal or inhalation routes. Toxicology has played an important role in setting workplace permissible exposure limits, which have been limited by vascular headaches and subtle, transient decrements in central nervous system performance. Less well characterized is the etiology of excess, long-term cardiac morbidity in PGDN-exposed workers. Human central nervous system degeneration and links to infectious diseases are unsubstantiated concerns.

Animals↗
PubMed1988

High acetylcholine concentrations cause rapid inactivation before fast desensitization in nicotinic acetylcholine receptors from Torpedo.

By using both a 3 to 4 ms quenched-86Rb+ flux assay and native acetylcholine receptor (AChR) rich electroplaque vesicles on which 50-60% of acetylcholine activation sites were blocked with alpha-BTX, we determined apparent rates of agonist-induced inactivation in AChR from Torpedo under conditions where measured flux response was directly proportional to initial 86Rb+ influx rate. Inactivation kinetics with acetylcholine in both the activating range (10 microM-10 mM) and the self-inhibiting range (15-100 mM) were measured at 4 degrees C. In the presence of 10 microM-1 mM acetylcholine, inactivation is characterized by a single exponential rate constant, kd (fast desensitization). Plots of kd vs. acetylcholine concentration display maximum kds [kd(max)] of 6.6-8.0 s-1, half-maximal kd at 102 +/- 16 microM, and a Hill coefficient of 1.6 +/- 0.3, closely paralleling the initial ion flux response of AChR. Thus, fast desensitization probably occurs from a doubly-liganded preopen state or the open channel state. In the self-inhibiting acetylcholine concentration range, inactivation is biphasic. A "rapid inactivation" phase is complete within 30 ms, followed by fast desensitization at a rate close to kd(max). Both the rate and extent of rapid inactivation increase with acetylcholine concentration, indicating that acetylcholine binds to its self-inhibition site with apparent kon approximately equal to 10(3) M-1s-1 and koff approximately equal to 40 s-1. This slow kon suggests either hindered access to the inhibitory allosteric site or that a fast binding step is followed by a slower conformational change leading to channel inhibition. Overall, our data suggest that acetylcholine binds preferentially to its inhibitory site when the receptor is in the open-channel conformation and that fast desensitization can occur from all multiple-liganded states.

Acetylcholine↗
PubMed1988

'B-readers' and asbestos medical surveillance.

"B-readers" certified in International Labor Office methodology interpret large numbers of randomly distributed asbestos medical surveillance roentgenograms of US Navy employees. Analysis of 23 participating observers, interpreting more than 105,000 radiographs, demonstrated a 300-fold prevalence range of perceived "definite" pulmonary parenchymal abnormalities. There was an evident geographic component to interpretation habits, with East and West Coast observers more likely to interpret films as abnormal than observers from the midcontinent. The most expert observers, a group who instruct the course leading to National Institute for Occupational Safety and Health certification in International Labor Office methodology, also perceived fewer abnormalities than other readers or coastal observers. Instructors still exhibited a sevenfold prevalence range of positive interpretation. Under usual surveillance conditions, the habits of B-readers appear to have a major impact upon the diagnosis of asbestosis from roentgenograms. Certification in B-reading should not be the only quality assurance for radiographic surveillance programs, medical decision-making, epidemiologic comparisons, nor related legal activities.

Asbestosis↗
PubMed1988

US Navy shipyard occupational medicine through World War II.

For more than 60 years the US Navy has maintained occupational health programs for its civil service workers in shipyards, arsenals, and aircraft repair facilities. The early history of the organization, people, and professional activities dedicated to the health of this large federal industrial workforce is examined. Early efforts were stimulated by increasingly complex naval technology and worker compensation law. During World War II training, clinical, and preventive programs were pursued vigorously. Navy occupational health paralleled and at times led the development of occupational medicine and industrial hygiene in America.

Asbestosis↗
PubMed1987

Is agonist self-inhibition at the nicotinic acetylcholine receptor a nonspecific action?

Agonist concentration-response relationships at nicotinic postsynaptic receptors were established by measuring 86Rb+ efflux from acetylcholine receptor rich native Torpedo membrane vesicles under three different conditions: integrated net ion efflux (in 10 s) from untreated vesicles, integrated net efflux from vesicles in which most acetylcholine sites were irreversibly blocked with alpha-bungarotoxin, and initial rates of efflux (5-100 ms) from vesicles that were partially blocked with alpha-bungarotoxin. Exposure to acetylcholine, carbamylcholine, suberyldicholine, phenyltrimethylammonium, or (-)-nicotine over 10(8)-fold concentration ranges results in bell-shaped ion flux response curves due to stimulation of acetylcholine receptor channel opening at low concentrations and inhibition of channel function at 60-2000 times higher concentrations. Concentrations of agonists that inhibit their own maximum 86Rb+ efflux by 50% (KB values) are 110, 211, 3.0, 39, and 8.9 mM, respectively, for the agonists listed above. For acetylcholine and carbamylcholine, KB values determined from both 10-s and 15-ms efflux measurements are the same, indicating that the rate of agonist-induced desensitization increases to maximum at concentrations lower than those causing self-inhibition. For all partial and full agonists studied, Hill coefficients for self-inhibition are close to 1.0. Concentrations of agonists up to 8 times KB did not change the order parameter reported by a spin-labeled fatty acid incorporated in Torpedo membranes. We conclude that agonist self-inhibition cannot be attributed to a general nonspecific membrane perturbation. Instead, these results are consistent with a saturable site of action either at the lipid-protein interface or on the acetylcholine receptor protein itself.

Acetylcholine↗
PubMed1987

Patient recruitment experience in the Thrombolysis in Myocardial Infarction Trial.

Patient recruitment for a small randomized study and several unrandomized studies conducted by the Thrombolysis in Myocardial Infarction investigators during 1984, 1985, and early 1986 will be reviewed. These studies, with patient numbers ranging from 48 to 316, were conducted to obtain information for planning a large-scale trial of thrombolytic therapy. Recruitment success of the 13 clinics was measured by comparing actual recruitment with the expectation of one patient per week and by comparing actual recruitment with the clinic directors' projections. Both methods indicated that four clinics had recruitment above expectation and five clinics had recruitment below expectation. Clinic staff members were requested to maintain logs of patients entering the coronary care unit and to complete screening forms on patients who met certain criteria but were ineligible. Considerable variation was noted in the number of patients screened and the number eligible.

Clinical Trials as Topic↗
PubMed1987

Thrombolysis in myocardial infarction (TIMI): comparative studies of coronary reperfusion and systemic fibrinogenolysis with two forms of recombinant tissue-type plasminogen activator.

Coronary recanalization rates and changes in plasma proteins of the fibrinolytic system were evaluated with two preparations of recombinant tissue-type plasminogen activator (rt-PA): the early formulation in liquid excipient ("old" rt-PA) and the later lyophilized form ("new" rt-PA). The dose dependency of coronary recanalization and of effects on plasma proteins was evaluated for the new rt-PA. Four groups of patients were studied: Study 1, 80 mg old rt-PA infused intravenously over 3 hours (n = 113); Study A, 80 mg new rt-PA over 3 hours (n = 47); Study B, 100 mg new rt-PA over 3 hours (n = 83); and Study C, 150 mg new rt-PA over 6 hours (n = 62). With equal doses of 80 mg, coronary recanalization rates at 90 minutes of infusion, determined angiographically, averaged 62% (Study 1) and 45% (Study A) with no overlap of 95% confidence limits. Increasing the dose of the new rt-PA to 100 mg, recanalization rates at 90 minutes averaged 71% (Study B), similar to those observed in Study 1. An increase to 150 mg resulted in higher recanalization rates at 30 minutes of infusion, 42% compared with 24% in Study 1 with no overlap of 95% confidence limits, and comparable rates at 90 minutes, 76 versus 62%. A linear trend test indicated a significant relation (p less than 0.01) between the dose of the new rt-PA and the rate of coronary recanalization at 30, 60 and 90 minutes of infusion. The new rt-PA affected plasma proteins of the fibrinolytic system less than the old form. There was a dose-dependent relation (p less than 0.001) in the effect of the new rt-PA on the plasma proteins. The frequency of bleeding complications was similar in the four study groups. These results indicate that the new rt-PA is less potent than the old rt-PA, in relation to both coronary reperfusion and systemic fibrinogenolysis. A higher and longer dosage regimen caused more rapid recanalization with similar effects on fibrinogenolysis.

Aged↗
PubMed1987

Cardiac morbidity and mortality associated with occupational exposure to 1,2 propylene glycol dinitrate.

Myocardial infarction and angina pectoris are conditions long associated with occupational exposure to nitroglycerin and related explosives. Cardiac sentinel events in selected munitions workers exposed to the related nitrated ester 1,2 propylene glycol dinitrate were identified and studied. Potentially exposed workers experienced significantly increased relative morbidity compared with control groups. There was no difference in hospitalizations for cardiac arrhythmias. The only cardiovascular mortality occurred in the control groups. The total number of cases was small. Possible sources of bias and causal speculations are discussed.

Adult↗
PubMed1985

n-Alkanols and halothane inhibit red cell anion transport and increase band 3 conformational change rate.

The effects of halothane and n-alkanols on band 3, the anion-exchange protein of the red cell membrane, have been characterized by radioactive sulfate exchange and equilibrium and kinetic binding of a fluorescent anion transport inhibitor, 4,4'-dibenzamido-2,2'-stilbenedisulfonic acid (DBDS), with fluorescence and stopped-flow techniques. Ethanol, butanol, hexanol, heptanol, octanol, and decanol inhibit radioactive sulfate efflux from red blood cells in a dose-dependent manner with an average Hill coefficient of 1.3 +/- 0.1. Over a 10(4)-fold range of buffer concentrations, the calculated membrane alkanol concentrations at which anion transport rates are reduced by 50% are 100-200 mM. At 100-300 mM membrane concentrations, halothane and the n-alkanols increase the apparent rate of DBDS binding to band 3 2-3-fold. Analysis of kinetic and equilibrium DBDS binding data shows that these drugs increase the rate of the DBDS-induced conformational change in the DBDS-band 3 complex. Equilibrium DBDS binding studies reveal differences between the actions of short-chain alkanols (ethanol and butanol) and those of long-chain alkanols (hexanol and longer). Short-chain alkanols reduce the equilibrium affinity of DBDS for band 3, while long-chain alkanols have no effect on equilibrium DBDS binding. The results for halothane and long-chain alkanols suggest a nonspecific, lipid-mediated mechanism of anesthetic action, which may be coupled to protein inactivation by an increase in the rate of protein conformational changes resulting in nonfunctional states. The results for short-chain alkanols indicate that they have the same nonspecific actions as the long-chain alkanols but also have specific effects on the stilbene binding site of band 3.

Alcohols↗
PubMed1983

Secondary prevention of myocardial infarction with drugs.

Clinical trials in the field of secondary prevention of myocardial infarctions are reviewed, with emphasis on those studies that were randomized and included at least 100 patients. Standardized total mortality data, when available, are provided. Five groups of drugs are reviewed: 1) antiarrhythmic drugs, including studies of phenytoin, tocainide, mexiletine and aprindine. Important, commonly used drugs in this group, which apparently have not been submitted to clinical trials, include procainamide and lidocaine; 2) lipid-lowering drugs, including estradiol, conjugated equine estrogen, dextrothyroxine, clofibrate and nicotinic acid; 3) anticoagulant drugs, the oldest and most controversial preventive drug measure. In this group, only the oral drug derivatives of indandione or coumarin have been tested, and no appropriate studies of parenteral heparin were found; 4) platelet-active drugs--six studies dealing with aspirin alone, one combining aspirin and dipyridamole, and one study of sulfinpyrazone are reviewed; and 5) beta-adrenergic blocking drugs, including practolol and timolol.

Adrenergic beta-Antagonists↗