Bradycardia after infusion of atrial natriuretic factor.
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Adult↗
Biomedical subjects
P Somani
Publications and source records attributed to P Somani.
Sodium regulation of alpha 2-adrenoreceptors of human platelets: inactivation by 4,4'-diisothiocyano-2,2'-stilbene disulfonic acid (DIDS).
In the present study, we investigated the effect of DIDS on Na+ regulation of alpha 2-adrenoreceptors in human platelets. Pretreatment of platelet membranes at 23 degrees C for 60 min with DIDS produced a reduction in the affinity of the receptors for both antagonist and agonist in a concentration related manner; however, there was a marked difference in the degree of reduction in the affinity of the receptors for antagonist and agonist. Thus, at 1 mM concentration of DIDS, the affinity of the receptors for antagonist was reduced by 2-fold while the affinity of the receptors for agonist was reduced by 14-fold. Furthermore, this concentration of DIDS abolished the ability of Na+ in reducing the affinity of the receptors for agonist. We suggest that the effect of DIDS is via Na+ binding component of the alpha 2-adrenoreceptor-adenylate cyclase complex.
4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
Effect of proteases and phospholipases on [3H]yohimbine binding to human platelet membranes.
Trypsin and chymotrypsin inactivated specific [3H]yohimbine binding sites in the partially purified human platelet membranes in a concentration- and time-dependent fashion. The maximal inactivation (70-80% of control) was incomplete regardless of the concentrations of the proteases used or the incubation time. Scatchard analysis of the binding data showed that the total number of binding sites was reduced, but the affinity of the receptor to the ligand remained unaffected. Pretreatment of the membranes with unlabeled yohimbine or epinephrine produced a 20-30% increase in the specific [3H]yohimbine binding; however, this treatment offered only a slight protection (10-15%) against trypsin-induced inactivation of [3H]yohimbine binding. Pretreatment with phospholipase A2 produced a complete inhibition, while pretreatment with phospholipase C resulted in only a partial (70-80% of control) reduction in [3H]yohimbine binding. The inhibitory effects were not reversed when the specific binding of [3H]yohimbine was carried out with membranes treated with phospholipases and subsequently washed with defatted bovine serum albumin, suggesting that products released from phospholipolysis were not involved in the inhibition of [3H]yohimbine binding. These results suggest that the integrity of the receptor proteins and phospholipids is necessary for the specific binding of the ligand to the alpha 2-adrenoreceptor proteins of the human platelet membranes.
Blood Platelets↗
Amiodarone-associated changes in human neutrophils.
Amiodarone and its major metabolite, desethylamiodarone, were measured in the plasma, white blood cells (WBCs) and red blood cells (RBCs) of 14 patients receiving chronic amiodarone therapy. The mean plasma concentrations (+/- standard error of the mean) of amiodarone and desethylamiodarone were 2.4 +/- 0.6 and 1.6 +/- 0.4 microgram/ml, respectively. The drug level in the WBCs was 62 +/- 12 micrograms/g protein during the early loading phase and 106 +/- 33 micrograms/g protein during maintenance phase of amiodarone therapy. Desethylamiodarone concentration in the WBCs was 42 +/- 18 and 190 +/- 33 micrograms/g protein during the loading and maintenance phases, respectively. Although a trend in WBC to plasma concentration was seen, there was no linear correlation between these levels. In 1 patient with severe neuropathy, biopsy of the nerve and muscle showed high concentrations of both amiodarone and desethylamiodarone. Although there was a decrease in tissue drug levels, proportionately high tissue:plasma drug levels were detected at the time of necropsy approximately 6.5 months after amiodarone was discontinued in this patient. Neutrophils from all patients receiving chronic amiodarone therapy showed multiple myelin-like polymorphic inclusion bodies (onionoid bodies) upon electron microscopic examination. Our observations suggest that WBC drug concentrations and electron microscopic changes may provide a means of correlating tissue concentrations and of following patients receiving chronic amiodarone therapy.
Amiodarone↗
Possible role of collagen in transverse myelitis and chymopapain-induced paraplegia.
We studied the effect of nucleus pulposus (NP) on platelet aggregation. Our in vitro experiments showed that NP extract produced platelet aggregation and the addition of collagenase to the NP extract abolished this response. It was further shown that chymopapain did not affect the activity of the extract. We assume that collagen is the active platelet aggregant in the NP extract. Intravascular release of collagen may cause platelet aggregation, vascular obstruction, ischemia, and cord necrosis in a patient with acute transverse myelitis. Intradiskal chymopapain is known to cause transverse myelitis and it is possible that collagen released during the action of the enzyme initiates a similar chain of events.
Cartilage↗
Electropharmacology of amiodarone: absence of relationship to serum, myocardial, and cardiac sarcolemmal membrane drug concentrations.
Plasma concentrations are often of major consideration in the evaluation of therapeutic efficacy of cardiovascular drugs. This approach is based on the assumptions that the concentration of the drug in the cardiac muscle is in equilibrium with the plasma drug level and that pharmacologic efficacy is proportional to the myocardial drug concentration. The more pronounced pharmacologic efficacy of amiodarone following chronic administration, despite low plasma drug concentrations, and the lesser effects of the drug after acute intravenous administration, when drug levels are maximum, has not been explained on the basis of the pharmacokinetic behavior of the drug. Data obtained from the transmembrane action potential recordings from rabbit ventricular myocardium were therefore correlated with drug concentrations in the serum, myocardium, and myocardial sarcolemma following acute intravenous administration and after 4 weeks of oral administration of 20 mg/kg/day of amiodarone. Following 15 minutes of acute drug administration, when amiodarone concentrations were maximal in the serum (4.72 +/- 1.23 micrograms/ml), cardiac muscle (34.5 +/- 7.6 micrograms/gm), and sarcolemma (1.94 mg/gm protein), the electrophysiologic changes were insignificant. However, following chronic treatment, when levels of amiodarone were low in the serum (0.05 +/- 0.01 micrograms/ml amiodarone, 0.25 +/- 0.08 micrograms/ml desethylamiodarone), cardiac muscle (1.91 +/- 0.9 micrograms/gm amiodarone, 1.35 +/- 1.33 micrograms/gm desethylamiodarone), and myocardial membranes (0.043 mg/gm protein [amiodarone], 0.097 mg/gm protein [desethylamiodarone], there was a 54.3% increase in action potential duration at 90% repolarization (p less than 0.01) and 65% increase in the effective refractory period (p less than 0.01) of rabbit ventricular myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)
Amiodarone↗
Amiodarone-induced ultrastructural changes in canine myocardial fibers.
Chronic clinical toxicity with amiodarone, a unique antiarrhythmic drug, is associated with intracellular myelinoid inclusion bodies in skin, cornea, lung, liver and lymph nodes. The present study was designed to develop a canine animal model to study amiodarone concentration and onset of formation of myelinoid inclusion bodies in the cardiac tissue. Amiodarone was given intravenously in a single dose (40 mg/kg body weight) or multiple doses (40 mg/kg IV + 10 mg/kg IV X 7 days). Amiodarone concentration in the heart was high after a single dose but electron microscopic examination showed a normal ultrastructure. Numerous myelinoid inclusion bodies were found in the myofibrils of the left atria and right and left ventricles after only 7 days of amiodarone treatment. Myelinoid inclusion bodies were identified in several subcellular locations including intercalated disc but most were in close proximity of the mitochondria, sometimes touching and indenting the mitochondrial membrane. The antiarrhythmic effect of the schedule of intravenous amiodarone for 7 days used in this study was minimal, and this correlated with unexpectedly low myocardial levels of the drug and its metabolite. The results are consistent with our previous data of an antiarrhythmic effect with a single intravenous dose of 40 mg/kg body weight associated with high myocardial levels of amiodarone. We conclude that a single large dose of amiodarone with high tissue level may not cause myelinoid inclusion bodies, but they can be readily identified in all heart chambers after only 1 week of amiodarone treatment. This model would be useful to study amiodarone-induced ultrastructural changes in the heart.
Amiodarone↗
[3H]Yohimbine binding to human platelet membranes: evidence for high and low affinity binding sites with negative cooperativity.
Evidence is presented that [3H]yohimbine binding to human platelet membranes does not follow the simple mass action kinetics. Although [3H]yohimbine binding was saturable and stereospecific, Scatchard analysis of the equilibrium binding data produced a curvilinear plot. Competitive displacement of [3H]yohimbine from the binding sites by unlabeled yohimbine and other alpha 2-antagonists produced shallow inhibition curves. Further, the apparent Hill coefficients of equilibrium binding and competitive displacement data were found to be less than unity. Factors such as binding to nonreceptor sites or to alpha1-adrenoceptors, dopamine receptors, or 5-HT receptors that may explain the curvilinear curve were excluded. The rank order for inhibiting [3H]yohimbine was rauwolscine greater than yohimbine greater than phentolamine greater than clonidine much greater than prazosin, suggesting that the binding sites had the characteristics of alpha2-adrenoreceptors. The affinity of the alpha2-antagonist for the receptor was enhanced by Na+ but not by guanine nucleotide, suggesting that the binding of the antagonist is modulated only by Na+. Graphic analysis of the specific binding data resulted in two components: one with high affinity and low capacity sites, and second with low affinity and high capacity sites. The experiments on dissociation kinetics, however, suggest that the observed deviation of [3H]yohimbine binding from the simple mass action kinetics is most likely due to negative cooperative interactions among alpha2-adrenoceptor sites.
Adrenergic alpha-Antagonists↗
Clinical indications for calcium channel blockers.
Ca2+ channel blocking agents have proven to be one of the most exciting groups of drugs for management of many cardiovascular diseases and as potentially first-line agents for treatment of angina pectoris and hypertension. Unlike beta blockers, they can directly relax coronary and peripheral arteries and, therefore, reduce total peripheral resistance and improve tissue perfusion. Ca2+ channel blockers are drugs of choice for patients with Prinzmetal's angina and should be first-line drugs for mixed angina, and can be used alone or with beta blockers for classic angina. These drugs as a group have many potential clinical indications, especially in diseases in which vascular or smooth muscle spasm seems to cause the disease. Although all three Ca2+ channel blockers have a common mechanism of action, their cardiac and hemodynamic effects are different, nifedipine being the least depressant to cardiac function. In choosing the right agent, careful consideration should be given to the patient's characteristics in order to derive maximum benefit with minimal risks.
Adrenergic beta-Antagonists↗
Pharmacokinetics, antiarrhythmic effects, and tissue concentrations of amiodarone and desethylamiodarone in dogs with acute coronary artery occlusion.
A single bolus of 5 or 40 mg/Kg of amiodarone was injected 24 hours after inducing coronary artery occlusion in the closed-chest dog preparation. Plasma pharmacokinetic profile was determined and the calculated t1/2 beta of 3.5 +/- 2.8 and 3.2 +/- 0.6 hour after 5 or 40 mg/Kg dose, respectively, were obtained. The major metabolite, desethylamiodarone, was detected within 15 minutes of the single bolus of amiodarone. At 6 hours after amiodarone administration, the animals were killed and tissue concentrations of amiodarone and desethylamiodarone were measured. Two additional peaks in the HPLC chromatograms were observed in plasma and tissue samples of most dogs given 40 mg/Kg I.V. amiodarone and these most likely are due to unidentified metabolites of the drug. The highest drug concentration was found in the lungs. Tissue to plasma drug rations suggested that accumulation of amiodarone and perhaps desethylamiodarone was different for different tissues. Ventricular arrhythmias were not abolished by either of the two doses of amiodarone; however, there was a gradual and statistically significant decrease in the number of ventricular premature beats and ventricular tachycardia beats over the six-hour period after a single 40 mg/Kg I.V. bolus. At the time of reduction in the arrhythmia frequency, tissue levels of both amiodarone and desethylamiodarone in the border and infarct zone of the myocardium were approximately 50% as high as in the normal zone. Plasma drug levels did not correlate well with tissue concentrations. However, there was an excellent correlation between drug levels in WBCs and various tissues except the lung. It is concluded that amiodarone is rapidly metabolized into desethylamiodarone and at least two other unidentified compounds; a large dose of amiodarone is necessary to produce some decrease in ventricular arrhythmias associated with acute coronary artery occlusion; tissue concentrations may be better correlated with drug levels in WBCs than in plasma, and coronary artery occlusion does not affect acute pharmacokinetic profile of the drug.
Amiodarone↗
Hyponatremia in patients treated with lorcainide, a new antiarrhythmic drug.
The effects of lorcainide, a new antiarrhythmic drug, on serum electrolytes and osmolality are described in a series of 33 patients with organic heart disease and complex ventricular arrhythmias treated with lorcainide. In eight patients, a mean decrease in serum Na+ of 8.25 +/- 3.2 mEq/L was observed after a single 200 mg intravenous dose of lorcainide. Sixteen of 33 patients developed significant hyponatremia and hypoosmolality during oral treatment with lorcainide. In all except two patients, serum Na+ returned to normal values within 3 to 12 months of continued lorcainide therapy. Low serum Na+ and hypoosmolality in the absence of volume depletion, clinically manifest edema, and unaltered renal, adrenal, cardiac, or thyroid function suggest that this antiarrhythmic drug produced the syndrome of inappropriate antidiuretic hormone secretion (SIADH). SIADH appeared to be transient and asymptomatic in our patients. One patient developed severe hyponatremia with serum Na+ of 108 mEq/L when hydrochlorothiazide was given to control hypertension. It is concluded that SIADH is an important side effect of lorcainide therapy. We recommend that serum Na+ be carefully monitored in patients started on lorcainide therapy, and extreme caution should be exercised in prescribing diuretics to patients with persistent hyponatremia.
Adult↗
The effect of inhaled verapamil on resting bronchial tone and airway contractions induced by histamine and acetylcholine in normal and asthmatic subjects.
In man, the influence of calcium entry blockers (CEB) on nonspecific bronchial sensitivity and resting bronchial tone is controversial. In 10 asthmatic and 8 normal subjects we recorded specific airway conductance (Gaw/VL) and flow volume loops before, 30, 60, and 90 min after the inhalation of saline, 10 (V10) and 20 mg (V20) of verapamil. The dose of inhaled histamine and acetylcholine producing Gaw/VL of -40% (PD40H and PD40ACH, respectively) with and without pretreatment with saline, V10, and, in 15 subjects, V20 was also determined. We measured plasma verapamil concentrations immediately after the end of nebulization of V10 and V20, and 30 and 60 min later. In normal subjects, V10 and V20 produced a maximal % delta Gaw/VL of 22.30 (+/- 19.50) and 33.00 (+/- 15.82), respectively (p less than 0.05). In asthmatics, V10 and V20 produced comparable % delta Gaw/VL of 22.00 (+/- 22.50) and 38.60 (+/- 38.60), respectively. This bronchodilating effect involved predominantly the large airways, persisted for 60 to 90 min, was reproducible, affected only some subjects (11 of 18), and was independent of the resting Gaw/VL, degree of bronchial sensitivity to H and ACH, and the time course of plasma verapamil concentration. The latter reached a maximum of 24.3 +/- 7.1 ng/ml after V20. In both normal and asthmatic subjects, saline or V10 did not significantly alter PD40H and PD40ACH. In normal subjects, pretreatment with V20 increased PD40H 5.3 times and PD40ACH 3.22 times (p less than 0.05). Except in 2 asthmatics, in whom V20 decreased PD40 and PD40ACH, it increased significantly PD40ACH (dose ratio: 3.15, p less than 0.05) but not PD40H.(ABSTRACT TRUNCATED AT 250 WORDS)
Acetylcholine↗
Ventilatory drive in normal man during semistarvation.
The effects of reduced caloric intake on ventilatory drive were investigated in normal volunteers. During a ten-day semistarvation period, six subjects (group 1) received parenterally an amino acid solution providing 550 kcal/d sufficient to prevent a negative nitrogen balance. Six subjects (group 2) received in addition a safflower oil solution providing a total caloric intake of 1,100 kcal/d. Hypoxic ventilatory drive was estimated by an index (parameter A) of the relation between minute ventilation (VE) and hypoxia. In group 1, mean values (+/- SEM) of A decreased significantly from 161.5 (+/- 42.0) to 48.9 (+/- 12.0) by day 10 (p less than 0.05), indicating a severe depression of hypoxic drive despite a positive nitrogen balance. In group 2, A did not change significantly (p greater than 0.05) from control values indicating a preserved hypoxic ventilatory drive. In both groups, the slopes of the line relating VE to arterial PCO2 (delta VE/delta PaCO2) did not change significantly during the ten-day semistarvation period consistent with preservation of the hypercapnic ventilatory drive. These data indicate that during periods of starvation, parenteral administration of aminoacids in an amount sufficient to maintain nitrogen balance is inadequate to prevent depression of respiratory control mechanisms unless a minimum daily caloric intake is achieved.
Adult↗
A comparison of glucose polymer and dextrose containing dialysate in CAPD patients.
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Creatinine↗
Lorcainide kinetics and protein binding in patients with end-stage renal disease.
Lorcainide is a new antiarrhythmic drug undergoing clinical investigation for management of patients with ventricular arrhythmias. In this study we investigated the kinetic profile of lorcainide in nine patients with end-stage renal disease. A single intravenous bolus of 100 mg of the drug was injected while the patients were undergoing hemodialysis or during the off-dialysis period. Renal disease did not alter the kinetic properties of lorcainide; the elimination t1/2 beta during hemodialysis was 8.61 +/- 6.35 h, not significantly different from 7.04 +/- 4.12 h off-dialysis. Serum protein binding of lorcainide was investigated in vitro, and the percent binding of lorcainide to serum proteins of normal volunteers and renal or cardiac patients was not significantly different. These data suggest that renal disease should not alter either the dose or the dosing interval of lorcainide.
Adult↗
Clinical and electrophysiologic effects of chronic lorcainide therapy in refractory ventricular tachycardia.
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Adult↗
Ceftizoxime elimination kinetics in continuous ambulatory peritoneal dialysis.
We investigated the kinetics of ceftizoxime, a beta-lactamase stable cephalosporin, in eight subjects undergoing continuous ambulatory peritoneal dialysis (CAPD). A single 500-mg or 1-gm dose was injected IV, or a 500-mg dose was given intraperitoneally in the CAPD fluid during a 6-hr dwell time. The ceftizoxime (500 mg) serum kinetic parameters were as follows: peak concentrations, 21 to 46 mg/l; volume of distribution, 0.27 l/kg; elimination rate constant, 0.0784 hr-1; plasma clearance, 1.66 l/kg hr-1; and t1/2, 10.2 hr. The t1/2 after 1 gm was 12 hr. Dialysate ceftizoxime concentrations rose rapidly between 0.25 and 2 hr and slowly over the next 4 hr, but only 4.04 +/- 1.8 and 7.4 +/- 2.9 mg ceftizoxime/hr was eliminated by the peritoneal route over a 6-hr dwell time after 500 mg or 1 gm IV. This represents only 4% to 5% of the dose. After intraperitoneal instillation, the antibiotic appeared in the serum within 15 min in all four subjects, and the peak serum concentrations ranged from 12 to 19.8 mg/l (mean +/- SD = 16.4 +/- 3.3) between 5 and 6 hr. Approximately 78% of ceftizoxime was absorbed from the peritoneal dialysis fluid during a single 6-hr dwell time. Rate constant for absorption, ka, was 0.3959 hr-1 and absorption t1/2 was 1.75 hr (as calculated by the residual equation). These data suggest that ceftizoxime has bidirectional exchange characteristics through the peritoneal membrane. Instillation of ceftizoxime in CAPD fluid alone may permit rapid absorption to reach therapeutic serum concentrations.
Absorption↗
The effects of mezlocillin, ticarcillin and placebo on blood coagulation and bleeding time in normal volunteers.
Bleeding time, coagulation tests and platelet aggregation response to adenosine diphosphate (ADP), epinephrine, arachidonic acid, ristocetin and collagen were determined in 18 normal male volunteers in a randomized, double-blind, placebo-controlled parallel study. Six subjects each received either placebo or 4.0 g of either mezlocillin or ticarcillin every 6 h for 7 days. In the placebo-treated or mezlocillin-treated groups no changes in plasma coagulation tests or bleeding time were observed. Randomly scattered decreases in platelet aggregation responses to ADP, epinephrine or arachidonic acid were noted in some subjects in both the placebo and mezlocillin groups. In contrast to these observations, in the ticarcillin treated group the bleeding time was abnormally prolonged to more than 18 min in three of six volunteers. In two of these subjects, bleeding time was prolonged after only seven ticarcillin doses (28.0 g) and in the third subject after a total of 21 doses (84.0 g). A significant decrease in platelet aggregation (P less than 0.005) induced by ADP was found in these volunteers. Although platelet aggregation response to arachidonic acid and epinephrine also appeared to be reduced in this group, correlation between increased bleeding time and abnormal platelet function was not possible because of the small number of subjects. No changes in other coagulation function were observed. The results suggest that the risk of bleeding disorder is very high with therapeutic doses of ticarcillin but not with comparable doses of mezlocillin.
Adolescent↗