Myocardial distribution of coronary blood flow in the isolated supported heart preparation.

The regional distribution of myocardial blood flow was studied by use of radioactive microspheres (15 micro-meters [mum]) under control conditions and during an intracoronary infusion of norepinephrine (2mug/min). In control experiments endocardial blood flow was generally greater than epicardial flow; during administration of norepinephrine the endocardium received significantly less blood flow. It is proposed that normally the endocardium is well perfused, but under conditions of stress, eg, norepinephrine infusion in the presence of a constant coronary blood flow, decreased endocardial blood flow results.

Antiarrhythmic effects of flecainide.

A new class I antiarrhythmic, flecainide, was investigated in 10 patients to assess short-term efficacy and safety. All patients were hospitalized for 3 days; no antiarrhythmics were given on days 1 and 3. On day 2 flecainide 1 mg/kg was given intravenously over 5 min. If the predrug arrhythmia(s) was not completely suppressed, additional boluses of 0.5 mg/kg were injected at 30- to 60-min intervals to a maximum of 5 mg/kg. Seven patients received 2 mg/kg, and 3 patients received 1 mg/kg. Before drug 5 patients had premature ventricular contractions (PVCs) (more than 4 per min); 2 patients had atrial fibrillation (AF) with PVCs; 1 patient had both PVCs and premature atrial contractions (PACs); and 2 patients had only PACs. One patient with PVCs failed to respond to flecainide; he was unresponsive to all available antiarrhythmic drugs. In the other 7 patients PVCs were suppressed for an average of 13 hr (range 6 to 24 hr), AF was not affected, and PACs were suppressed. Flecainide did not induce significant changes in P-R, QRS, or Q-T intervals. Side effects were negligible and included a tingling sensation and feeling of skin warmth for 15 min after drug in one patient.

Unidirectional absorption of gentamicin from the peritoneum during continuous ambulatory peritoneal dialysis.

Gentamicin kinetics were determined after intravenous or intraperitoneal injection in five patients undergoing continuous ambulatory peritoneal dialysis (CAPD). Our objective was to determine rate of absorption of gentamicin from the peritoneum into the systemic circulation and vice versa. After intraperitoneal instillation of 1 mg/kg in the CAPD fluid during a 6-hr dwell time, the antibiotic appeared in the serum within 15 min in four of five patients. Peak serum concentrations ranged between 1.6 and 7.2 mg/l(mean +/- SD = 3.52 +/- 2.22) in all five patients and the time to reach peak concentration was 3.8 +/- 1.5 hr. Peritoneal gentamicin clearance was 13 ml/min. Percent extraction of gentamicin from the PD fluid within the 6 hr of intraperitoneal exposure ranged from 65% to 100% (mean +/- SD = 86.8 +/- 13.2). The fraction of the intraperitoneal dose absorbed into systemic circulation was found to be 0.84 independently by calculating the ratio of AUCip and AUCiv. When the same dose of gentamicin was injected intravenously (1 mg/kg), no gentamicin could be detected in the peritoneal fluid in three of five patients and only a very small amount of the drug was present for a brief period of time in the remaining two. The kinetic parameters of intravenous gentamicin were: volume of distribution, 0.3 l/kg; elimination rate constant, 0.028 hr(-1), plasma clearance 0.009 l/kg . min(-1), and half-life 27.4 hr. In two patients with acute peritonitis treated with intraperitoneal gentamicin, peak serum concentrations were found to range between 3.5 and 4.5 mg/l. These data suggest that gentamicin is rapidly absorbed from the peritoneal fluid into the blood compartment, but that occurrence of the reverse exchange is negligible. Thus, CAPD would not be expected to alter the elimination characteristics of intravenous gentamicin. Instillation of gentamicin in CAPD fluid may allow rapid absorption to reach therapeutic serum concentrations.

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.

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.

Drugs derived from cannabinoids. 2. Basic esters of nitrogen and carbocyclic analogs.

Various basic esters of nitrogen (2) and carbocyclic (3 and 4) analogs of cannabinoids were synthesized using dicyclohexylcarbodiimide in methylene chloride. The compounds in the three series werw studied in selected pharmacological tests in mice, rats, dogs, and cats. It was shown that making the basic ester from the phenol retains biological activity and can lead to a greater selectivity of action, particularly the antinociceptive activity. The most interesting esters were 5, 6, 10, and 14 in the nitrogen analogs series and 19 and 20 in the carbocyclic series. Compound 5 was more potent than codeine in the writhing, hot-plate, and tail-flick tests and is at present undergoing clinical testing. Compound 20 was very potent in the mouse audiogenic seizure test and is of interest as an anticovulsant agent.

Pharmacokinetics of lorcainide, a new antiarrhythmic drug, in patients with cardiac rhythm disorders.

Lorcainide, a new class I antiarrhythmic drug, was administered intravenously to 10 patients with a documented history of ventricular arrhythmias. Three patients had arrhythmias resistant to all conventional antiarrhythmic drugs; in all other patients except one, previous antiarrhythmic drug therapy had to be discontinued because of poor efficacy or unacceptable adverse effects. Lorcainide was injected in incremental doses of 25 mg every 15 minutes and a dose of 182.4 +/- 26.5 mg (mean +/- standard deviation) of the drug was given. Lorcainide reduced the frequency of premature ventricular complexes in a dose-dependent manner. Plasma samples were analyzed for the drug concentrations which ranged from 0.31 to 1.14 mg/liter during the loading phase. Distribution and elimination of lorcainide follow a biexponential pattern and a fourfold intersubject variability in the pharmacokinetics of the drug was observed in these patients. The plasma half-life ranged from 6.2 to 23.1 hours (mean 13.1 +/- 5.0). Three patients are currently being treated orally with lorcainide. These data suggest that lorcainide is an effective antiarrhythmic drug with desirable pharmacokinetic properties, and long-term definitive studies are recommended.

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.

Study on some selective beta-adrenoreceptor blocking effects of 1-(4-nitrophenyl)-1-hydroxy-2-methyl isoproylaminoethane (alpha-methyl INPEA).

1. The effect of methyl substitution in the alpha-carbon position of the ethanolamine side chain of INPEA was investigated on its beta-adrenoreceptor blocking activity in the isolated turtle heart and anaesthetized cats.2. In the turtle heart preparation, the pA(2) value for erythro-alpha-methyl INPEA was 5.3, as compared with 6.9 for INPEA, while threo-alpha-methyl INPEA was extremely weak and its pA(2) value could not be determined.3. In the intact cat experiments, alpha-methyl INPEA produced a competitive blockade of the peripheral vasodilator effect of isoprenaline in doses ranging from 5 to 20 mg/kg. However, this agent had a minimal effect on the cardiac stimulant effect of the catecholamine.4. These results are consistent with the hypothesis that the beta-adrenoreceptors comprise a family of nonhomogeneous receptors and a selective blockade of only some, but not all, responses mediated through their activation can be achieved by specific molecular modification of the beta-adrenoreceptor blocking agents.

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.

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.

Resistant ventricular arrhythmias treated with lorcainide, a new antiarrhythmic drug.

A 68-year-old patient developed increasingly frequent episodes of ventricular and supraventricular arrhythmias over the past five years. During the last 12 months, he was admitted to the hospital on several occasions with complex arrhythmias including multifocal PVCs, bigeminy, trigeminy, ventricular tachycardia, and atrial flutter and fibrillation. Large and frequent doses of quinidine, procainamide, disopyramide, propranolol, and digoxin failed to suppress his arrhythmias. He had no previous history of myocardial infarction or other heart diseases. Coronary arteriography revealed no obstruction of any major arteries or their branches. A new antiarrhythmic drug, lorcainide, was given intravenously and it suppressed all PVCs, including bigeminy and ventricular tachycardia. All his arrhythmias have been completely suppressed by oral regimens of lorcainide, 100 mg four times daily, for the past four months. This is the first case of oral treatment of ventricular arrhythmias with lorcainide in this country.

Effect of atrial natriuretic peptide (8-33-Met ANP) in patients with hypertension.

In this pilot study we investigated the effects of a 4-h infusion of atrial natriuretic peptide (8-33 Met ANP) on hemodynamic, renal, and hormonal parameters in 12 patients with hypertension. Either 8-33 ANP in 5% mannitol (0.7 microgram/min [eight patients] and 1.05 micrograms/min [four patients]) or placebo (5% mannitol) was infused for 4 h on 2 consecutive days in a randomized double-blind crossover design. The plasma levels of ANP were not significantly different between the two doses of ANP and therefore the results from the two doses were combined. Plasma ANP increased from 61 +/- 24 pg/mL to 291 +/- 55 pg/mL after 2 h and to 288 +/- 40 pg/mL after 4 h. ANP caused a significant lowering of systolic blood pressure after 2 h of infusion from 148 +/- 5 mm Hg to 142 +/- 5 mm Hg (P less than .05) and to 128 +/- 6 after 4 h (P less than .01). Two hours after discontinuation of the infusion, systolic blood pressure was 126 +/- 6 and 135 +/- 7 mm Hg 4 h after the end of the infusion. Diastolic blood pressure did not change. Heart rate increased from 69 +/- 3 beats/min to 74 +/- 3 beats/min after 4 h and to 78 +/- 4 beats/min 2 h after termination of the infusion. Cardiac output did not change significantly. Urinary sodium and chloride increased significantly but creatinine clearance did not change. Plasma aldosterone decreased after 2 h of ANP infusion from 9.8 +/- 1.7 ng/dL to 6.7 +/- 0.9 ng/dL (P less than .01) and to 6.5 +/- 1.2 ng/dL after 4 h (P less than .05). Plasma renin activity decreased from 0.81 +/- 0.1 ng angiotensin I/mL/h to 0.57 +/- 0.1 after 2 h of infusion (P less than .05). There were no significant changes in plasma catecholamines or arginine vasopressin. Two patients developed severe hypotension and bradycardia and one of them had a sinus pause of 7.4 sec associated with loss of consciousness. Neither of these two patients had a significant increase in plasma catecholamines in response to the severe hypotension, suggesting that ANP may have inhibited their sympathetic response and increased their sensitivity to vagal cardioinhibitory reflexes. In conclusion, infusion of ANP in hypertensive patients causes prolonged lowering of systolic blood pressure with no change in diastolic pressure and cardiac output.(ABSTRACT TRUNCATED AT 400 WORDS)

Cardiovascular effects of nucleoside analogs.

Short-chain aliphatic esters and amides of adenosine-5'-carboxylic acid caused marked increases in coronary sinus oxygen tension (PO2) in the dog; the amides were generally more potent, causing additionally marked hypotension and tachycardia. The hypotensive effect was observed also in the spontaneously hypertensive rat. That the increase in coronary sinus PO2 paralleled an increase in coronary flow was verified with ethyl adenosine-5'-carboxylate hydrochloride. This compound also increased the reactive hyperemic response. Aminophylline blocked the increase in coronary flow. A representative amide and ester were very poor substrates for adenosine and adenylate deaminase in vitro; the amide exhibited a weak inhibitor effect on the enzymic activities while the ester was inactive. The observations that the compounds (1) cause marked pharmacological effects within seconds after intravenous administration, (2) are blocked by aminophylline like adenosine, (3) are not deaminated significantly in vitro by either adenosine or adenylate deaminase, and (4) cannot be phosphorylated at the 5' terminus because the 5'-OH has been removed chemically, support the hypothesis that they are acting directly on an "adenosine receptor" and have a prolonged duration of action because they are not metabolized significantly by the normal physiological pathways of adenosine degradation.

Streptozotocin-induced diabetes in the spontaneously hypertensive rat.

Spontaneously hypertensive rats (SHR) were more sensitive to the diabetogenic effects of streptozotocin than normotensive Wistar-Kyoto (WKY) rats. Thus, 10 days after intravenous administration of 25 mg/kg streptozotocin in SHR, mean pancreatic insulin content was decreased by 42% (p less than 0.05), and mean plasma glucose concentration was increased from 85 to 215 mg/dl (p less than 0.001), whereas between 37.5 and 50 mg/kg of streptozotocin was required to produce similar effects in normotensive WKY rats. Also, there was a progressive decrease in blood pressure in SHR injected with 25, 35.7, or 50 mg/kg of streptozotocin, whereas blood pressure was progressively increased after streptozotocin in normotensive WKY rats. The opposite effects of streptozotocin-induced diabetes on blood pressure in SHR and WKY rats could be observed at similar degrees of hyperglycemia and are presently unexplained.

Basic and clinical pharmacology of amiodarone: relationship of antiarrhythmic effects, dose and drug concentrations to intracellular inclusion bodies.

Amiodarone is a unique class III antiarrhythmic drug with several unusual pharmacokinetic, pharmacodynamic, and toxicological actions which are quite distinct from those of the standard antiarrhythmic drugs. Extensive animal and clinical studies have demonstrated that amiodarone and its major metabolite, desethylamiodarone, both produce a marked increase in the duration of transmembrane action potential, which may be related to their antiarrhythmic as well as clinical electrophysiological activity. Unlike most other cardiovascular drugs, it has been recognized for more than 20 years that optimal antiarrhythmic effects may take several days to weeks after onset of oral therapy. Amiodarone is highly lipid soluble and exhibits at least three separate compartments of drug distribution, with a long elimination half-life of 14-120 days after chronic therapy. The pharmacokinetic profile of desethylamiodarone is qualitatively similar to that of amiodarone, but its elimination half-life is even longer and its tissue distribution may be slightly different. Although there may not be any correlation between serum drug levels and clinical toxicity of amiodarone during long-term therapy, recent animal as well as clinical data suggest that multilamellar intracellular inclusions can be dissociated from cell death or clinical toxicity. Thus, it is possible that amiodarone toxicity can be minimized with low doses or low serum drug concentrations. The metabolite(s) of amiodarone may play a major role in its pharmacological and toxicological actions.

Pharmacokinetic implications of lorcainide therapy in patients with normal and depressed cardiac function.

The influence of cardiac function as measured by the left ventricular ejection fraction on the pharmacokinetic variables of a new antiarrhythmic drug, lorcainide, was investigated in 20 cardiac patients. Patients were divided into two groups: those with normal (ejection fraction greater than .40) or depressed (ejection fraction less than .40) left ventricular function. The elimination half-life, plasma clearance rates, or volume of distribution of lorcainide were not significantly different in patients with either normal or depressed cardiac function. A decrease in arrhythmia frequency could be correlated to plasma lorcainide concentration in the majority of patients, and it was noted that at least 0.1 mg/L of lorcainide was required for the presence of an antiarrhythmic effect. Three unusual cases are presented to illustrate the importance of measuring plasma drug concentrations and calculating the drug pharmacokinetics and to correlate these to the antiarrhythmic response in order to minimize the risk of plasma drug accumulation and side effects. A review of published data shows a three- to sixfold interpatient variation in the elimination half-life of lorcainide with practical implications in its use as an antiarrhythmic drug.

Inhibition of platelet aggregation by moxalactam and free N-methylthiotetrazole.

The effects of moxalactam and free N-methylthiotetrazole (N-MTT) in vitro on platelet aggregation induced by adenosine diphosphate (ADP), arachidonic acid, collagen, epinephrine, or ristocetin were determined. Moxalactam at concentrations of 1.9 mM and 5.7 mM inhibited platelet aggregation induced by ADP, arachidonic acid, epinephrine, and ristocetin. Although the aggregatory activity of collagen was not inhibited with 1.9 mM moxalactam, an increase in the concentration of moxalactam to 5.7 mM significantly inhibited collagen-induced platelet aggregation. Inhibition of platelet aggregation by free N-MTT was also concentration dependent. The lowest concentration of N-MTT used in this study, 5.7 mM, inhibited platelet aggregation induced by both arachidonic acid and ristocetin. At a concentration of 28 mM, N-MTT inhibited aggregation induced by ADP, collagen, epinephrine, and ristocetin, but not by arachidonic acid. At 57 mM N-MTT, almost complete inhibition of platelet aggregation occurred for all five agonists tested.