The acute and subchronic toxic effects of GLG-V-13 (3-[4-(1H-imidazol-1-yl)benzoyl]-7-isopropyl-3,7-diazabicyclo[3.3.1]nonane dihydroperchlorate. CAS 155029-33-7), a novel class III with some class Ib antiarrhythmic activity, were investigated in mice. The estimated LD50 for GLG-V-13 given orally were 419 mg/kg for male mice and 383 mg/kg for female mice, respectively. The acute toxic signs appeared to be of the central nervous system in origin. Four groups of mice (15 per sex, group and dose) were fed daily with diets containing GLG-V-13 for 90 consecutive days. The equivalent daily doses were 0, 22, 50 and 121 mg/kg/day and 0, 27, 60 and 136 mg/kg/day for male and female mice, respectively. All of the mice survived. Food consumption was decreased. However. mean body weight and body weight gain were not significantly changed. Gross pathological changes, especially in the lungs and liver, were found in the middle and high dose groups. Consistent increased mean corpuscular hemoglobin concentration and decreased mean corpuscular hemoglobin were observed in all dose groups. Hepalocellular necrosis was found in both male and female mice treated with the drug and was dose-dependent. Marked vacuolation of the X zone in the adrenal gland with mild to moderate deposition of ceroid pigments (brown degeneration) was observed in female mice. Lesions in the kidneys and adrenal glands may be a possible reason for changes in serum sodium and potassium ions concentrations leading to an increase in water intake. A significant reduction in cholesterol in the high dose group may be a favorable pharmacological effect of GLG-V-13. The data from the 90-day subchronic toxicity studies indicate that GLG-V-13 appears to have limited systemic toxicity potential.

The acute and subchronic toxic effects of BRB-I-28 (7-benzyl-3-thia-7-azabicyclo[3.3.1]nonane HCl), a novel class Ib antiarrhythmic agent, were investigated in male and female mice. The estimated oral LD(50) for BRB-I-28 was 128 mg/kg (male mice) and 131 mg/kg (female mice). In subchronic oral studies, four groups of mice (15/sex/group/dose) were fed daily with diets containing BRB-I-28 for 90 consecutive days. The equivalent daily doses were approximately 0, 16, 32, 76 (male) and 0, 18, 37, 89 mg/kg (female). All mice survived. Food consumption per day was decreased, but water consumption per day was increased (in a non-dose-dependent manner). However, both mean body weight and mean body weight gain were not significantly changed as were true for hematological and clinical chemistry profiles, except for serum Na(+) concentration (male) and serum K(+) concentration in male and female mice (high dose levels). Hepatocellular necrosis occurred in male and female mice (in a dose-dependent fashion). Renal cortical vacuoles and myocardial necrosis with low numbers of lymphocytic infiltrations were present in female mice (middle and high doses). Lesions in the liver, kidney and heart were mild with (very small) changes in serum biochemical values. These data suggest that BRB-I-28 has limited toxic potential, and coupled with low proarrhythmic and other desirable cardiovascular effects, makes BRB-I-28 worthy of further development.

Several 3,7-diheterabicyclo[3.3.1]nonanes (DHBCNs) were prepared and screened in the Harris dog model for their ability to abolish pace-induced and sustained ventricular tachycardia (SVT) or prevent induction of ventricular tachycardia. In addition, an electrophysiological examination was made in the infarcted hearts of each animal to determine if more than one class activity was present. The examples exhibited predominately class III antiarrhythmic activity via a prolongation of the ventricular effective refractory period (VERP) in the models, although there may well be an underlying class Ib action present as exemplified by the ability of several of the agents to slow conduction in the myocardial infarcted dog hearts. 3-[4-(1H-Imidazol-1-yl)benzoyl]-7-isopropyl-3,7-diazabicyclo[3.3.1]nonan e dihydroperchlorate displayed powerful class III activity in the model systems while several other DHBCNs exhibited various degrees of class III action. An X-ray diffraction analysis revealed that this compound has a 3,7-diazabicyclo[3.3.1]nonane bicyclic unit in a chair-chair conformation.

The intravenous, intramuscular and oral pharmacokinetics of ibuprofen in broiler chickens were investigated. In a preliminary study, plasma ibuprofen concentration-time profiles, following i.v. (25 mg/kg) dosing were best described by a 2-compartment model. After intravenous administration, the volume of distribution at steady-state (Vd(ss)), the total systemic clearance (ClB), the elimination half-life (t1/2 beta) and the MRT were 0.303 L/kg, 482.3 ml/h.kg, 2.71 h and 1.02 h, respectively. After intramuscular administration of ibuprofen, the tmax and Cmax were 0.37 h, and 42.2 micrograms/mL, respectively, with an estimated bioavailability of 46.7%. After oral administration of ibuprofen, the tmax and Cmax were 0.31 h and 23.91 micrograms/mL, respectively, with an estimated bioavailability of 24.2%. This is a preliminary study, examining the use of ibuprofen in broiler chickens, and should be followed by tissue residue and efficacy studies in different disease states.

GLG-V-13 (3-[4-(1H-imidazol-1-yl)benzoyl]-7-isopropyl-3,7-diazabicyclo [3.3.1] nonane dihydroperchlorate, CAS 155029-33-7) has been shown to be a potent class III antiarrhythmic agent. The oral and intravenous pharmacokinetics and plasma protein binding of GLG-V-13 in dogs and in rabbits have now been investigated. Plasma GLG-V-13 concentration-time profiles, following an i.v. bolus dose of 6 mg/kg, were fitted to a 2-compartment model. The volume of distribution at steady state (Vd(ss)), the total systemic (ClB), and the elimination half-life (t1/2 beta) were 4.441 l/kg, 1.113 l/h/kg, and 2.485 h in dogs and 3.723 l/kg, 1.548 l/h/kg, and 1.401 h in rabbits. Following i.v. dosing, approximately 9.38% of the parent compound was excreted in dogs urine (0-72 h). Changes in plasma GLG-V-13 concentrations, after oral administration of GLG-V-13 (6 mg/kg), were best described by the 1-compartment pharmacokinetic model. The tmax and Cmax were 1.69 h, 0.54 mg/l in dogs and 1.44 h, 0.35 mg/l in rabbits. On oral administration, GLG-V-13 was moderately eliminated (t1/2kel' 1.867 h-1 in dogs and 3.961 h-1 in rabbits, respectively). Oral bioavailability was estimated to be 53.2% +/- 11.3% in dogs and 66.7% +/- 7.7% in rabbits. About 8.74% of the oral dose (6 mg/kg) was excreted via the dog urine (0-72 h). In vitro binding of GLG-V-13 to dog plasma protein was 29.4 +/- 9.90% (from 0.5 to 4 mg/l). Ex vivo binding of GLG-V-13 to dog plasma protein was 10.4 +/- 7.20%.(ABSTRACT TRUNCATED AT 250 WORDS)

The metabolism of BRB-I-28 (7-benzyl-3-thia-7-azabicyclo[3.3.1]nonane), a novel class Ib antiarrhythmic agent, was characterized in vivo in dogs and rats and in vitro with rat liver microsomal preparations containing a NADPH-generating system. In dogs, rats and the in vitro hepatic microsomal oxidation system, BRB-I-28 was extensively metabolized to form 7-benzyl-3-thia-7-azabicyclo [3.3.1]nonane-3-oxide (I), a major metabolite. The metabolite I was produced via S-oxidation, presumably by the hepatic P-450 system. Formation of a minor metabolite, 7-benzoyl-3-thia-7-azabicyclo[3.3.1]nonane (II) via the oxidation of the benzylic site was also identified in rats. Following intravenous and oral administration of BRB-I-28 to dogs, the plasma concentration of major metabolite I could be best described by a 1-compartmental model. The plasma AUC of metabolite I was 20% (i.v.) and 179.4% (oral) of that of the parent BRB-1-28, respectively, suggesting that BRB-I-28 was metabolized significantly by the first pass effect following oral administration. Extensive metabolism of BRB-I-28 to form metabolites I and II, which have demonstrated much lower antiarrhythmic activities, further supports previously observed pharmacodynamic and pharmacokinetic findings.

Na+,K(+)-ATPase, Mg(2+)-activated ATPase, and Na(+)-ATPase activities of brain, heart, kidney, and small and large intestinal mucosa of broiler chickens exposed to heat stress (41 degrees C, 65% relative humidity for 6 h) and thermoneutral (25 degrees C, 65% relative humidity) conditions were determined. Brain and kidneys were found to have significantly higher Na+,K(+)-ATPase activities than those of heart and intestinal mucosa. Mg(2+)-activated ATPase and Na(+)-ATPase activities in the intestinal mucosa were higher than those of brain, kidneys, and heart under thermoneutral conditions. While there was a significant inhibition of total ATPase, Na+,K(+)-ATPase, Mg(2+)-activated ATPase, and Na(+)-ATPase activity of small and large intestinal mucosa of broiler chickens exposed to heat stress, the inhibitory effect was limited to total ATPase and Na+,K(+)-ATPase enzymes in kidneys. Heat stress produced a significant increase only in Mg(2+)-activated ATPase activity of the heart, without a remarkable change in all forms of ATPase activity in the brain. Heat stress significantly decreased the ratio of Na+,K(+)-ATPase to Mg(2+)-ATPase in the heart, kidneys, and small and large intestinal mucosa. The percentage of Na(+)-ATPase in Na+,K(+)-ATPase of brain, heart, and kidneys did not significantly change during heat stress, but the ratio in small and large intestinal mucosa increased significantly during heat stress. The severe disturbances in both serum electrolytes and acid-base balance observed in previous heat stress studies could partly be mediated by direct or indirect effects of heat stress on Na+,K(+)-ATPase, Mg(2+)-activated ATPase, and Na(+)-ATPase activities of kidneys, and small and large intestinal mucosa of broiler chickens.

A HPLC method was developed for the simultaneous determination of the concentrations of 7-benzyl-3-thia-7-azabicyclo[3.3.1]nonane (I) as the hydrochloride and the corresponding sulfoxide (II), the major metabolite, in dog plasma and urine. Plasma and urine samples were alkalinized and extracted with chloroform. An aliquot was injected on to a HPLC system with a C6 reversed-phase column and an UV detector. Acetonitrile-methanol-37.5 mM phosphate buffer, pH 6.8 (28:28:44 v/v) containing 4.0 mM triethylamine was used as a mobile phase. The compounds I and II were detected at 261 nm. The extraction recovery for I and II was 85% and 94% from plasma and 89% and 91% from urine, respectively. Good linearity (r>0.994) was observed throughout the range of 0.1-10.0 mu g/ml for I and 0.04-10 mu g/ml for II in plasma and in urine. Intra- and inter-assay variabilities were less than 8%. The accuracy of this method was > 95% for both compounds, and the limits of quantitation were 0.08 mu g/ml for I and 0.03 mu g/ml for II in plasma, and in urine, respectively. This method was applied to determine plasma and urine concentrations of I and II simultaneously in a dog treated with I.

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A sensitive reversed-phase HPLC technique with UV detection has been developed to determine the concentration of GLG-V-13 (3-[4-)1H-imidazol-1-yl)benzoyl]-7-isopropyl-3,7-diazabicyclo[3.3.1] nonane dihydroperchlorate) (I), a novel combined class I and class III antiarrhythmic agent, in dog plasma and urine. Alkalinized plasma and urine samples were extracted with chloroform, and the extracts were reconstituted in methanol. An aliquot was injected on to a Waters HPLC system with a 250 x 4.6 mm Ultramex 5 C-6 analytical column (5 mu m) and 30 x 4.6 mm Ultramex 5 C-6 guard column (5 mu m). The elute was detected by a UV detector at 256 nm. Acetonitrile-methanol-37.5 mM phosphate buffer, pH6.8 (27:27:46 v/v) containing 3.6 mM triethylamine was used as the mobile phase. The average extraction recovery was 89% from plasma and 93% from urine. Good lineary (r > 0.999) was observed throughout the range of 8 - 8000 ng/ml in plasma and in urine with the quantitation limit of 8 ng/ml. Intra- and inter-assay variabilities were less than 4%. HPLC analysis of plasma and urine samples from a dog treated with I has demonstrated that the method was accurate and reproducible. Preliminary pharmacokinetic results showed that the plasma concentration-time curves fitted a two compartment open model with slow elimination (t(1/2 beta) 3.0827 h(-1)); wide distribution (V-c 2.389 L/kg and V-d(ss) 3.6808 L/h.kg); and longer mean residual time (MRT 4.7632 h), respectively. It seems that there is a difference in disposition of this compound in pathological dogs compared to normal one.

The effects of BRB-I-28 and its derivatives (GLG-V-13, SAZ-VII-22 and SAZ-VII-23), a novel group of antiarrhythmic agents, were investigated on the rat heart mitochondrial respiratory chain. The results indicate that BRB-I-28 and its derivatives have concentration-dependent inhibitory effects on NADH oxidase and NADH-CoQ reductase (complex I), but they have no significant effects on succinate oxidase, succinate dehydrogenase (complex II), CoQ-cytochrome c reductase (complex III), cytochrome c oxidase (complex IV), and NADH-K3Fe(CN)6 reductase. The site of inhibition of BRB-I-28 and its derivatives on the respiratory chain was localized between flavoprotein n (FPn) and CoQ, which is similar to the effect of rotenone and several other antiarrhythmic drugs such as amiodarone, propranolol, etc. BRB-I-28 and its derivatives also have significant inhibitory effects on mitochondrial ATPase activity as reported for other antiarrhythmic drugs such as amiodarone, propranolol, quinidine, and lidocaine. However, BRB-I-28 and its derivatives have no direct effects on sarcoplasmic reticulum Ca(2+)-ATPase activity. The inhibitory effects of BRB-I-28 and its derivatives on mitochondrial oxidative phosphorylation may result in the depletion of ATP. This effect, in combination with their effects on Na+,K(+)-ATPase, could possibly produce an increase in Ca2+ concentration in cytosol. This may be another mechanism by which these DHBCN derivatives produce an increase in systemic arterial blood pressure and contractile force of isolated cardiac muscle. On the other hand, inhibition on mitochondrial respiration may account for some of the potential toxic effects of these diheterabicyclo[3.3.1]nonane derivatives.

The pharmacokinetics and plasma protein binding of BRB-I-28, a novel antiarrhythmic agent, were investigated in dogs. The plasma concentration-time profile of BRB-I-28, following an intravenous bolus dose of 10 mg/kg, can be adequately described by a 2-compartment open model. The mean volume of distribution at steady-state (Vdss) was 8.759 L/kg, the mean total systemic clearance (CL) was 1.289 ml/h/kg, and the mean elimination half-life (t½β) was 4.645 hours. Following intravenous administration, approximately 1.85% of the dose was excreted in the urine (0 to 48 hours) as parent drug. Changes in plasma concentrations, after oral administration of BRB-I-28 20 mg/kg, were best described by a 1-compartment open model. BRB-I-28 was rapidly absorbed (tmax = 1.22 hours and Cmax =1.59 mg/L) with a rapid elimination rate (t½kel = 1.583 hours). Oral bioavailability was estimated to be 44.5%. Only 2.56% of the 20 mg/kg oral dose was excreted via the urine (0 to 48 hours). In vitro binding of BRB-I-28 to plasma protein was 29.7 ± 10.3% at concentrations of 4 to 16 mg/L. In vivo binding of BRB-I-28 to plasma protein was 24.0 ± 8.7%. Extensive distribution of BRB-I-28 may be due to its low binding to plasma protein. Low oral bioavailability and limited elimination of free parent BRB-I-28 in urine indicates that BRB-I-28 may undergo extensive metabolism, which may be the reason for its short duration of pharmacological effects.

We compared the electrophysiological effects and quantified the antiarrhythmic/proarrhythmic potential of the 3,7-diheterobicyclo[3.3.1]nonane-derivative, BRB-I-28 and lidocaine in 15 consecutive postinfarction dogs. Electrophysiologic studies were performed in anesthetized animals, 1-4 days (mean +/- SE = 2.47 +/- 0.36) after the two-stage ligation of the left anterior descending coronary artery. Inducibility of sustained monomorphic ventricular tachycardia (SMVT) was compared in the pre-drug state, and after i.v. lidocaine (3 and 6 mg/kg) and BRB-I-28 (3 and 6 mg/kg) administration. During the control state, SMVT was inducible in 6/15 dogs (40%). After the administration of lidocaine, the rate of the inducible SMVT slowed (353 +/- 91 to 272 +/- 96 beat/min; p < 0.01), but due to the proarrhythmic action of the drug, SMVT became inducible in 13/15 dogs (87%). Sustained reentry was induced after 3 mg/kg lidocaine in 3 dogs and after 6 mg/kg in 4. The mean aortic blood pressure in these SMVTs was 36 +/- 8 mm Hg. After administration of BRB-I-28 (6 mg/kg) SMVT was not inducible in 2/6 and in 4 the SMVT rate was slowed (380 +/- 104 to 208 +/- 105 beat/min; p < 0.005) before termination in 3. In 2 dogs SMVT was induced after BRB-I-28 was given whereas they were non-inducible in the control state (proarrhythmic effect: 13%). Furthermore the hemodynamic state during the SMVTs was more stable after BRB-I-28 (mean aortic blood pressure = 65 +/- 7 mm Hg; post-BRB-I-28 vs post-lidocaine, p < 0.001). During sinus rhythm, lidocaine caused a transient lowering of the MBP (105 +/- 17 to 84 +/- 18 mm Hg; p < 0.001), whereas, BRB-I-28, induced a consistent but short-lasting pressor response (98 +/- 18 to 120 +/- 29 mm Hg; p < 0.001) after its bolus injection. The low proarrhythmic activity and the lack of a cardiodepressant action makes this new chemical class of antiarrhythmics worthy of further development.

A series of new 3,7,9-triheterabicyclo[3.3.2]decan-10-ones is reported for the first time. Members of the family of 3,7-diheterabicyclo[3.3.1]nonan-9-ones served as precursors of the title compounds. Spectral evidence suggests the 3,7,9-triheterabicyclo[3.3.2]decan-10-ones exist in a chair-boat (CB) reversible boat-chair (BC) equilibrium in solution. It is speculated that steric hindrance around the carbonyl group and possibly the variance in conformation BC versus CC of the individual 3,7-diheterabicydo-[3.3.1]nonan-9-one precursors in solution may influence the ease of oxygen and nitrogen insertion in the ring enlargement to give the title molecules. Confirmation that three members of the bicyclo[3.3.2] decan-10-ones exist in BC forms in the solid state was achieved via single crystal X-ray diffraction analysis for 7-benzyl-3-thia-7,9-diazabicyclo[3.3.2]decan-10-one (4a), 3,7-dibenzyl-3,7,9-triazabicyclo-[3.3.2]decan-10-one (4c), and 3,7-dibenzyl-9-oxa-3,7-diazabicyclo[3.3.2]decan-10-one (4d).

A HPLC method has been developed to determine the concentrations of SAZ-VII-23 (3-benzoyl-7-isopropyl-3,7-diazabicyclo[3.3.1]nonane.HClO4), a novel antiarrhythmic agent, in dog plasma and urine. Plasma treated with acetonitrile and alkalinized urine were extracted with chloroform- propanol (9:1). An aliquot was injected on to HPLC system using a C6 reversed-phase column and acetonitrile-methanol-37.5 mM phosphate buffer, pH 6.8 (28.5:28.5:43 v/v) containing 4.0 mM triethylamine as mobile phase. Detection wavelength was 255 nm. The linear range were 0.04-8 mug/ml, and the lower limit of quantitation was 0.04 mug/ml in plasma and urine, respectively. The method was applied to determine plasma and urine concentrations and preliminary pharmacokinetic profiles of SAZ-VII-23 in a dog.

The effects of BRB-I-28, SAZ-VII-22 and SAZ-VII-23, a novel class of antiarrhythmic agents and other 3,7-diheterobicyclo[3.3.1]nonane (DHBCN) derivatives on guinea pig myocardial Na+,K(+)-ATPase and Mg(2+)-activated ATPase activities were investigated in comparison with those of tedisamil, lidocaine and ouabain. BRB-I-28, SAZ-VII-22, SAZ-VII-23, tedisamil and their derivatives produced concentration-dependent inhibition on both Na+,K(+)-ATPase and Mg(2+)-activated ATPase. Ouabain had no effect on the Mg(2+)-activated ATPase activity and GLG-IV-44 had no significant inhibition on Na+,K(+)-ATPase. Molar refractivity, retention time in reverse-phase HPLC, and partition coefficients were determined and the influence of these three parameters on the inhibitory effects of DHBCN on ATPase was examined. It seems that inhibitory effects of DHBCN derivatives on Na+,K(+)-ATPase and Mg(2+)-activated ATPase increase with an increase in lipophilicity, while hydrophilic groups of the drugs may not be important for interaction between drugs and ATPases. The effects of BRB-I-28 on contractile force development in rabbit atrial and papillary muscles were studied. At paced rates of 0.5 and 1.0 Hz in atrial muscle, BRB-I-28 produced an apparent positive inotropic effect in isolated rabbit atrial muscle, which is consistent with its inhibitory effects on Na+,K(+)-ATPase and Mg(2+)-ATPase activities. Inhibitory effects on myocardial Na+,K(+)-ATPase and Mg(2+)-activated ATPase activities may be the basis of some electrophysiological effects of antiarrhythmic properties of BRB-I-28, SAZ-VII-22, SAZ-VII-23, and tedisamil.

A sensitive reversed-phase high-performance liquid chromatographic (HPLC) technique with ultraviolet detection has been developed to determine the concentration of BRB-I-28 (I), a novel antiarrhythmic agent, in dog plasma and urine. The mobile phase was acetonitrile—methanol—37.5 mM phosphate buffer, pH 6.8—triethylamine (50:50:75:0.1, v/v). The compound was extracted from dog plasma and urine with chloroform after alkalinization with sodium hydroxide. The extraction recovery was 83% from plasma and 84% from urine. Good linearity (r > 0.996) was observed throughout the ranges 0.1–12.0 μg/ml (plasma) and 0.1–8.0 μg/ml (urine). Intra- and inter-assay variabilities were less than 4%. The lower limit of quantitation was 0.08 μg/ml in either plasma or urine. HPLC analysis of plasma and urine samples from a dog treated with I has demonstrated that the method was accurate and reproducible.