Biodistribution of paclitaxel and poly(L-glutamic acid)-paclitaxel conjugate in mice with ovarian OCa-1 tumor.

PURPOSE: Poly(L-glutamic acid)-paclitaxel (PG-TXL) is a water-soluble paclitaxel (TXL) conjugate made by conjugating TXL to poly(L-glutamic acid) via ester bonds. In preclinical studies, PG-TXL has shown significant antitumor activity against a variety of solid tumors. To elucidate the relationship between tissue distribution and antitumor efficacy of PG-TXL, we studied and compared the biodistribution of PG-TXL and TXL. METHODS: Female C3Hf/Kam mice bearing syngeneic ovarian OCa-1 tumors were injected with either [3H]TXL or PG-[3H]TXL at an equivalent TXL dose of 20 mg/kg. Mice were killed at various times after drug injection, and samples of blood, spleen, liver, kidney, lung, heart, muscle, brain, fat, and tumor were removed and the radioactivity counted. In addition, concentrations of free [3H]TXL released from PG-[3H]TXL in the spleen, liver, kidney, and tumor were analyzed by using high-performance liquid chromatography (HPLC). Whole-body autoradiographs of mice killed 1 day and 6 days after administration of PG-[3H]TXL were obtained to study the intratumoral distribution of PG-TXL. RESULTS: When [3H]TXL was conjugated to polymer, the biodistribution pattern of PG-[3H]TXL differed from that of [3H]TXL. Based on area under the tissue concentration-time curve (AUC) values, tumor exposure to [3H]TXL was five times greater when administered as PG-TXL than as TXL formulated in Cremophor EL/alcohol vehicle. Furthermore, concentrations of free paclitaxel released from PG-[3H]TXL remained relatively constant in tumor tissue, being 489, 949 and 552 ng/g tumor tissue at 5, 48 and 144 h after dosing, respectively. Autoradiographic images of mice injected with PG-[3H]TXL revealed that radioactivity was primarily located in the periphery of the tumor on day 1 after drug administration and was homogeneously diffused into the center of the tumor by day 6. Over the 144-h study period, [3H]TXL concentrations, predominantly as the inactive conjugate, were higher in tissues with a more abundant reticular endothelial system (i.e. liver, kidney, spleen, lung) than in tissues with less abundant or lacking RE systems (i.e. muscle, fat, brain). Both [3H]TXL and PG-[3H]TXL were excreted primarily through the hepatobiliary route, with a small fraction of each drug (5% and 8.7%, respectively) excreted into the urine within 48 h. CONCLUSIONS: This study indicates that the distribution to tumor tissue was enhanced when [3H]TXL was administered as a macromolecular conjugate, and that free TXL was released and maintained within the tumor for a prolonged period. Thus, the antitumor activity of PG-TXL observed in preclinical studies may be attributed in part to enhanced tumor uptake of PG-TXL.

A systemic bioactivity comparison of double-strength and regular-strength beclomethasone dipropionate MDI formulations.

BACKGROUND: The efficacy and safety of regular-strength beclomethasone dipropionate MDI prescribed within its recommended dosing range of 2 to 5 puffs three to four times daily has been well established in more than 25 years of worldwide use. A more concentrated formulation delivering 84 microg per puff was developed to provide for a more convenient twice-daily dosing regimen. OBJECTIVE: This randomized, single-blinded, positive and placebo-controlled, parallel-group, multiple-dose bioactivity study was conducted to assess the potential of a new beclomethasone dipropionate 84 microg double-strength metered-dose inhaler (Vanceril 84 microg Double Strength Inhalation Aerosol/Key) to cause hypothalamic-pituitary-adrenocortical axis suppression. METHODS: Beclomethasone dipropionate double-strength 84 microg was compared with beclomethasone dipropionate regular-strength 42 microg, orally administered prednisone, and placebo inhaler after 36 consecutive days of administration in adults with moderate asthma. Beclomethasone dipropionate double-strength was administered as 5 puffs BID and beclomethasone dipropionate regular-strength was administered as 10 puffs BID for the same total daily dose of 840 microg of beclomethasone dipropionate. Oral prednisone was administered by mouth at 10 mg once a day. The potential for hypothalamic-pituitary-adrenocortical axis suppression was evaluated by an adrenocorticotropic hormone (ACTH) stimulation test using cosyntropin 250 microg in 500 mL normal saline infused over six hours on the 36th day of treatment. Sixty-four patients completed this study. RESULTS: No clinically significant post-study findings were observed from physical examination, electrocardiogram, or clinical laboratory evaluation for any treatment group. No serious or unexpected adverse events were reported. On the 36th day of treatment, there was a significant (P < .01) difference in the plasma cortisol concentration response to cosyntropin stimulation between the prednisone and placebo treatment groups at the sixth hour of infusion. There was no significant difference in the plasma cortisol concentration response to cosyntropin stimulation between the beclomethasone dipropionate double-strength and beclomethasone dipropionate regular-strength treatment groups and the placebo group. In addition, comparison of the response between the beclomethasone dipropionate double-strength and beclomethasone dipropionate regular-strength groups showed no significant difference. CONCLUSION: Beclomethasone dipropionate, administered either via a double-strength (84 microg/puff) or regular-strength (42 microg/puff) inhaler dosed at 840 microg/day showed no evidence of hypothalamic-pituitary-adrenocortical axis suppression in adults with moderate asthma.

Safety and tolerability of once-daily mometasone furoate aqueous nasal spray in children.

Sensitive and reproducible assessments of hypothalamic-pituitary-adrenal (HPA) axis function were used to assess the systemic exposure and tolerability of mometasone furoate aqueous nasal spray (MFNS) in 96 children aged 3 to 12 years with allergic rhinitis. In the first phase of the study, older children (aged 6 to 12 years) received MFNS at 50, 100, or 200 micrograms or placebo once daily for 7 days, and plasma cortisol concentrations were measured by radioimmunoassay before and after treatment. Plasma cortisol concentrations were not statistically significantly different from baseline values on day 7 or day 8 (1 day after treatment was stopped). Also, the mean plasma cortisol and 24-hour urinary free-cortisol concentrations of the MFNS-treated and placebo groups were not statistically significantly different. Additionally, mometasone furoate was undetectable in almost all plasma samples collected at 0.5, 1, and 2 hours after dosing on days 1 and 7. Because these findings indicated that MFNS could be safely administered to patients aged 6 to 12 years, a more rigorous assessment was conducted in younger patients (aged 3 to 5 years). The younger patients also received MFNS at 50, 100, or 200 micrograms or placebo once daily, but for a longer duration (14 days). HPA axis function was determined by the response to cosyntropin stimulation on the final day of treatment. The younger patients demonstrated a normal cortisol response to cosyntropin stimulation on day 14; that is, all the patients had an increase in plasma cortisol concentration of at least 7 micrograms/dL to at least 18 micrograms/dL. Mean plasma cortisol concentrations for the MFNS-treated groups were not statistically significantly different from the mean concentration for the placebo group, either before or after cosyntropin stimulation. MFNS was also found to be well tolerated by both the younger and older children, with headache the most frequently reported adverse event in both the placebo- and MFNS-treated groups. No clinically relevant changes in the results of physical examinations, clinical laboratory determinations, or electrocardiography were noted. These results indicate that the intranasal administration of up to 200 micrograms of MFNS once daily for up to 14 days in children aged 3 to 12 years who have allergic rhinitis is well tolerated and does not result in clinically relevant systemic exposure.

Loratadine administered concomitantly with erythromycin: pharmacokinetic and electrocardiographic evaluations.

OBJECTIVE: To evaluate the effects of coadministration of loratadine and erythromycin on the pharmacokinetics and electrocardiographic repolarization (QTc) pharmacodynamics of loratadine and its metabolite descarboethoxyloratadine in healthy volunteers. METHODS: Twenty-four healthy volunteers were studied in a prospective, double-blind crossover design while confined in a Clinical Research Center. The primary pharmacodynamic end point of the study was the difference between baseline and day 10 mean QTc intervals obtained from surface electrocardiograms. Plasma concentrations of loratadine, descarboethoxyloratadine, and erythromycin were measured on treatment day 10 for pharmacokinetic analysis. Subjects received in random sequence the following three treatments for 10 consecutive days during three separate study periods: 10 mg loratadine every morning plus 500 mg erythromycin stearate every 8 hours, or 10 mg loratadine every morning plus placebo every 8 hours, or placebo every morning plus 500 mg erythromycin stearate. RESULTS: Concomitant administration of loratadine and erythromycin was associated with increased plasma concentrations of loratadine (40% increase in area under the plasma concentration-time curve [AUC]) and descarboethoxyloratadine (46% increase in AUC) compared with loratadine alone. Analysis of variance showed no difference between the treatment groups in effect on QTc intervals compared with baseline, and no significant change from baseline was observed. No clinically relevant changes in the safety profile of loratadine were observed, and there were no reports of sedation nor syncope. CONCLUSION: Although concomitant administration of loratadine and erythromycin was associated with increased plasma concentrations of loratadine and descarboethoxyloratadine, no clinically relevant changes in the safety profile of loratadine were observed. In this study, 10 mg loratadine administered orally for 10 consecutive days was well tolerated when coadministered with therapeutic doses of erythromycin stearate.

Biopharmaceutic characteristics of a new extended-release theophylline formulation (Uni-Dur).

BACKGROUND: There is a close relationship between improvement in airway function and the plasma concentration of theophylline, as well as between rapidly rising plasma theophylline concentrations and increased frequency of undesired effects. Development of pharmaceutical formulations and prescribed dosage intervals for theophylline dosage forms should therefore be directed toward providing the most stable plasma concentrations attainable. OBJECTIVE: To characterize the steady-state biopharmaceutic profile of Uni-Dur following once-daily or twice-daily administration. METHODS: Twenty-four adult male volunteers with average theophylline clearance (3.0 and 5.5 L.h-1) received three treatments on separate occasions: Uni-Dur 800 mg once-daily, Uni-Dur 400 mg twice-daily, and Uniphyl 800 mg once-daily. Treatments were taken after a meal for five days with at least 1 week washout between treatment periods. Trough blood samples were collected prior to the AM dose on days 3, 4, and 5, and at specified intervals up to 48 hours after the AM dose on day 5 for subsequent determination of theophylline concentrations in plasma. RESULTS: The area under the plasma concentration-time curve (AUC; microgram.mL-1.h) for theophylline over 24 hours on day 5 was 187 for Uni-Dur 800 mg once-daily, 187 for Uni-Dur 400 mg twice-daily, and 172 for Uniphyl 800 mg once-daily; the peak plasma concentrations were 10.4, 9.4, and 11.0 micrograms.mL-1 and the trough concentrations were 5.5, 7.2, and 3.5 micrograms.mL-1, respectively; fluctuation index (peak minus trough divided by trough) was 78%, 16%, and 231%, respectively. No further accumulation of theophylline occurred after day 3. No serious nor severe adverse events were reported during any treatment. CONCLUSIONS: Uni-Dur is an extended-release formulation that provides stable plasma concentrations of theophylline over a 24-hour period with less fluctuation than observed with a once-daily reference formulation. In subjects with normal theophylline clearance, Uni-Dur administered twice-daily provided remarkably stable theophylline plasma concentrations over a 24-hour period. Absorption of theophylline from Uni-Dur was not affected by food, and no evidence of dose-dumping was observed. Uni-Dur should provide efficacious theophylline therapy with minimal adverse events in patients with symptoms of asthma and reversible bronchospasm associated with chronic bronchitis and emphysema.

Lack of hypothalamic-pituitary-adrenal axis suppression with once-daily or twice-daily beclomethasone dipropionate aqueous nasal spray administered to patients with allergic rhinitis.

The potential for a newly developed, double-strength (0.084%) beclomethasone dipropionate (BDP) aqueous (AQ) nasal suspension to produce effects associated with exposure to systemic corticosteroids was assessed by the plasma cortisol response to cosyntropin stimulation induced by a 6-hour intravenous infusion of 250 micrograms of cosyntropin in 500 mL of normal saline. Sixty-four patients with allergic rhinitis were enrolled in this study. Patients were randomly assigned to one of the following four treatment groups: (1) BDP AQ Forte (0.084%) nasal spray 336 micrograms once daily; (2) BDP AQ (0.042%) nasal spray 168 micrograms twice daily; (3) placebo nasal spray twice daily; or (4) oral prednisone 10 mg once daily in the morning. After 36 consecutive days of treatment, there was a significant (P < 0.01) difference in the plasma cortisol response to cosyntropin stimulation between the prednisone and placebo groups; however, there were no significant differences between the BDP AQ Forte or the BDP AQ groups compared with the placebo group. Secondary analyses comparing BDP AQ Forte administered as 336 micrograms once daily with BDP AQ administered as 168 micrograms twice daily showed no significant differences in plasma cortisol responses to cosyntropin stimulation. No serious adverse events were reported. Adverse events consisted of headache, pharyngitis, or nasal irritation, with headache being reported most frequently. These adverse events were similarly distributed among active treatment groups and were similar to placebo. No clinically relevant changes were observed in any treatment group in findings on clinical laboratory tests, physical examination, or electrocardiography. Vital signs, obtained daily, were consistent with values observed in healthy individuals. No patient exhibited signs of oral candidiasis. All patients met the plasma cortisol concentration criteria for discharge relative to expected hypothalamic-pituitary-adrenal axis function. In conclusion, there were no significant differences in plasma cortisol responses to cosyntropin stimulation between groups of patients with allergic rhinitis treated with either BDP AQ Forte (0.084%) nasal spray 336 micrograms once daily or BDP AQ (0.042%) nasal spray 168 micrograms twice daily compared with the placebo group. These results indicate that the dosing regimens of BDP AQ nasal suspensions used in this study lack systemic effects and are safe and well tolerated.

Differential plasma duration of antiplatelet-activating factor and antihistamine activities of oral Sch 37370 in humans.

Preclinical studies have established that Sch 37370 (1-acetyl-4-(8-chloro-5,6-dihydro-11H-benzo[5,6]-cyclohepta [1,2-b]pyridin-11-ylidene)piperidine) is an orally active antagonist of platelet-activating factor (PAF) and histamine H1-receptors with potential therapeutic use in the treatment of asthma. To evaluate the efficacy and duration of anti-PAF and antihistamine actions of oral Sch 37370 in humans, a single dose (5 mg/kg) of Sch 37370 was given orally to each of 10 male subjects in a placebo-controlled, double-blind crossover study. Blood samples were drawn before and at various times (2 to 48 hours) after Sch 37370 or placebo. Plasma samples were analyzed for Sch 37370 by a gas chromatographic method, for the anti-PAF activity by measuring the aggregation of platelets stimulated with PAF, and for the antihistamine activity by measuring displacement of [3H]pyrilamine from rat brain membrane binding sites. The plasma anti-PAF activity declined from high levels at 2 hours to barely detectable levels at 24 hours; however, significant activity was still present at 12 hours. The plasma levels of Sch 37370 closely paralleled the anti-PAF profile. The plasma antihistamine activity reached a maximum within 2 to 8 hours and declined thereafter. However, 48 hours after Sch 37370, the antihistamine activity was still present at a significant level in most subjects. It is concluded that, in humans, oral Sch 37370 antagonizes both PAF and histamine with plasma antihistamine activity lasting longer than plasma anti-PAF activity.

Pharmacology of bepridil.

Bepridil is an antianginal agent with multiple therapeutic actions. It decreases calcium influx through potential-dependent and receptor-operated sarcolemmic calcium channels and acts intracellularly as a calmodulin antagonist and calcium sensitizer. Thus, in cardiac muscle it enhances the sensitivity of troponin C to calcium, stimulates myofibrillar adenosine triphosphatase activity, removes calmodulin's inhibitory effect on sarcoplasmic reticulum calcium release, and inhibits sodium-calcium exchange--actions that tend to offset the effects of calcium influx blockade on cardiac contractile force. However, in vascular smooth muscle where the calcium-calmodulin complex promotes muscle contraction by activating myosin light-chain kinase phosphorylation of contractile proteins, calmodulin antagonism, coupled with bepridil's blockade of calcium influx, leads to vasorelaxation. In animal models of ischemia, bepridil and other calmodulin inhibitors show antiarrhythmic efficacy following reperfusion. Additionally, interfering with calmodulin's role in sympathetic nerve terminal function may help to limit the ischemia-induced catecholamine release that contributes to arrhythmogenesis. Bepridil shows a lidocaine-like fast kinetic block of inward sodium current (as distinct from the slow or intermediate kinetic inhibition expressed by encainide or quinidine, respectively). This inhibition is pH-dependent; activity is expressed to a greater degree at lower pH levels. This, this potentially antiarrhythmic mechanism is activated by conditions of ischemia. Bepridil's blockade of outward potassium currents and its inhibition of sodium-calcium exchange increase action potential duration and ventricular refractoriness, prolong the QT interval, and form the basis for a class III antiarrhythmic mechanism. Because hypokalemia also prolongs the QT interval, the addition of bepridil in the presence of hypokalemia can lead to excessive prolongation. Bepridil both increases myocardial oxygen supply through coronary vasodilation and decreases myocardial oxygen demand through mild heart rate and afterload reduction, and shows potential antiarrhythmic activity through class IB, III, and IV mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)

Structurally novel antihypertensive compound, McN-5691, is a calcium channel blocker in vascular smooth muscle.

These studies were conducted to gain greater understanding of the mechanism of action of the chemically novel antihypertensive agent, McN-5691. McN-5691 (1 and 10 microM) prevented 60 mM KCl-induced contraction and calcium uptake and caused concentration-dependent relaxation (EC50 = 190 microM) of 30 mM KCl-contracted aortic rings. At or below 10 microM, McN-5691 had no effects on basal tone or calcium uptake (45Ca) in isolated rings of rabbit thoracic aorta. McN-5691 caused complete high affinity inhibition (Kd = 39.5 nM) of specific diltiazem binding to the benzothiazepine receptor on the voltage-sensitive calcium channel in skeletal muscle microsomal membranes. In contrast to diltiazem, McN-5691 inhibited specific dihydropyridine receptor binding, but the effect was biphasic with high (Kd = 4.7 nM) and low (Kd = 919.8 nM) affinity components. These findings suggest that McN-5691 is a voltage-sensitive calcium channel blocker. Unlike other calcium channel blockers, McN-5691 inhibited norepinephrine (NE)-induced contraction (10 microM) and calcium uptake (1 and 10 microM) and caused concentration-dependent relaxation (EC50 = 159 microM) of 1 microM NE-contracted rings of rabbit thoracic aorta. The vascular relaxant effects of McN-5691 were not related to increased calcium (45Ca) efflux from vascular smooth muscle cells. The effects of McN-5691 on NE-induced contraction were unrelated to intracellular mechanisms because McN-5691 did not affect NE-induced contraction in the absence of extracellular calcium. McN-5691 had weak activity in rat cerebral cortical membrane alpha-1 or alpha-2 adrenergic receptor binding assays. McN-5691-induced vasodilation of phenylephrine-contracted rat aortic strips was not reversible by high potassium, indicating that McN-5691 does not induce relaxation of blood vessels through potassium channel activation. In summary, these studies suggest that the primary vasodilator mechanism of McN-5691 is calcium channel blockade through competitive binding at the diltiazem site on the voltage sensitive calcium channel. McN-5691 may possess an additional vasodilator mechanism of action distinct from alpha adrenergic receptor blockade but involving a cell membrane-related event apparently leading to attenuation of receptor-operated calcium channel activity.

Cardiac electrophysiologic effects of McN-5691, a new calcium-channel blocking antihypertensive agent.

The purpose of this study was to evaluate the cardiac electrophysiological effects of McN-5691, a new calcium-channel blocking antihypertensive drug. In anesthetized dogs, the primary electrophysiological effect of McN-5691 was dose-related prolongation of AV-nodal conduction time and refractoriness (0.1-1.0 mg/kg i.v.), which correlated with McN-5691 plasma levels. There were no significant effects on atrial or ventricular conduction times, QTc, or ventricular monophasic action potential duration. This profile was similar to that of verapamil. McN-5691 caused concentration-related, rate-dependent reductions in Vmax and amplitude of slow-response action potentials in guinea pig papillary muscle: ED-20% for depression of Vmax was 0.72 +/- 0.32 microM. Verapamil was more potent in depressing these action potentials: ED-20% for depression of Vmax was 0.03 +/- 0.01 microM. McN-5691 also caused rate-dependent reduction in Vmax and amplitude of canine Purkinje fiber action potentials, but only at relatively high concentrations: ED-20% for depression of Vmax was 55 +/- 12 microM. McN-5691 also reduced the action potential duration (0.3-30 microM) without affecting the slope of phase 4 depolarization and the maximum diastolic potential. Verapamil also reduced Vmax in Purkinje fibers (ED-20% for depression of Vmax was 32 +/- 3 microM) and shortened the action potential duration. The results show that McN-5691 has cardiac electrophysiological effects consistent with blockade of the slow inward calcium current, and that this activity occurs at concentrations well below those having local anesthetic activity. In addition, its lower potency in comparison to verapamil in depressing slow responses suggests a lesser propensity for negative inotropic effects.

Effects of the novel coronary selective calcium channel blocker, McN-6186, on cardiocirculatory dynamics, coronary vascular resistance, and cardiac output distribution in normal, conscious rats.

The purpose of this study was to characterize the cardiocirculatory effects of the novel calcium channel blocker, McN-6186 (McN), normal, conscious rats. Animals were instrumented under halothane anesthesia for right atrial, left ventricular, arterial, and venous pressure recordings. The radioactive microsphere technique was used to measure regional blood flow (RBF) and cardiac output (CO) before (control) and during intravenous (i.v.) infusion of either McN at three doses (0.03, 0.1, 0.3 mg/kg) or vehicle at an equal infusion rate (0.0408 ml/min). Nifedipine (NIF) was also studied at three similar blood pressure (BP)-lowering doses (0.025, 0.150, and 0.375 mg/kg). The predominant effect of McN in conscious rats was to cause coronary vasodilation. The coronary vasodilator potency of McN was similar to NIF (ED25, McN = 0.03 mg/kg, NIF = 0.025 mg/kg). Neither McN nor NIF significantly changed systemic vascular resistance (SVR) over their respective coronary vasodilator dose ranges, suggesting that both compounds are selective coronary vasodilators. The doses of McN and NIF that reduced mean arterial pressure (MAP) by 25% (ED25) were similar (McN = 0.3 mg/kg, NIF = 0.375 mg/kg). At equal BP-lowering doses, McN increased coronary flow by 145% versus 110% for NIF. McN did not have major effects on other regions of the peripheral circulation. There was, however, some vasodilator activity in the renal and cerebral vascular beds. Because McN reduced coronary vascular resistance at a dose lower than that required to reduce resistance in other vascular beds, this compound appears to be a selective coronary vasodilator and may have therapeutic efficacy as an antianginal agent.

Antiarrhythmic and antifibrillatory properties of McN-4130 in several animal models.

McN-4130 is an experimental compound having antiarrhythmic and antifibrillatory activity in several animal models. In anesthetized, open-chest pigs subjected to total occlusion and subsequent reperfusion of the left anterior descending coronary artery, McN-4130 dose-dependently (2.5-10.0 mg/kg i.v.) protected against fibrillation and death. Mean arterial pressure was not significantly affected, but heart rate was dose-dependently reduced. In anesthetized normal dogs, McN-4130 increased ventricular fibrillation threshold for up to 45 min. This increase in fibrillation threshold was associated with concurrent increases in ventricular conduction time and ventricular effective refractory period. In conscious dogs subjected to occlusion of the left anterior descending coronary artery 24 h previously, McN-4130, 2.5 and 5.0 mg/kg i.v., significantly reduced the rate of ventricular arrhythmias for up to 45 min. McN-4130 was more effective and had a longer duration of action than comparable doses of lidocaine and disopyramide. McN-4130 was orally effective in this model at 10 mg/kg. These results indicate that McN-4130, a structurally unique experimental antiarrhythmic compound, may be useful as a ventricular antiarrhythmic agent with antifibrillatory properties.

Effects of the novel calcium channel blocker, McN-5691, on cardiocirculatory dynamics and cardiac output distribution in conscious spontaneously hypertensive rat.

The purpose of this study was to characterize the cardiocirculatory effects of McN-5691 in the conscious spontaneously hypertensive rat (SHR) and in age matched Wistar-Kyoto (WKY) control rats. Animals were instrumented under halothane anesthesia for right atrial, left ventricular arterial, and venous pressure recordings. The radioactive microsphere technique was used to estimate regional blood flow and cardiac output before (control) and during intravenous (i.v.) infusion of either McN-5691 at three dosage levels (0.3, 1.0, 3.0 mg/kg), or vehicle (VH) at an infusion rate of 0.0408 ml/min. The predominant hemodynamic effect of McN-5691 (cumulative dose = 0.3-4.3 mg/kg i.v.) in conscious SHR was dose-related reduction in mean arterial pressure with normalization occurring at a cumulative dose of 1.3 mg/kg i.v. The antihypertensive effect of McN-5691 was accompanied by reductions in left ventricular peak systolic pressure (cumulative dose = 1.0-4.3 mg/kg i.v.), arterial pressure-rate product (1.3-4.3 mg/kg i.v.), and systemic vascular resistance (4.3 mg/kg i.v.). McN-5691 had no statistically significant effect on heart rate or cardiac contractility as measured by dP/dt/peak left ventricular pressure. The predominant peripheral vascular effects of McN-5691 were increases in skeletal muscle blood flow (4.3 mg/kg i.v.) and reductions in skeletal muscle (1.3-4.3 mg/kg i.v.), renal (1.3-4.3 mg/kg i.v.), gastrointestinal (4.3 mg/kg i.v.), and coronary (1.3-4.3 mg/kg i.v.) vascular resistances. Despite the fall in renal vascular resistance, renal blood flow was not changed by McN-5691. McN-5691 did not have major effects on other regions of the peripheral circulation. Thus, McN-5691 is an antihypertensive agent as defined by its ability to normalize blood pressure in the SHR, and the hemodynamic mechanism leading to this effect is reduction in peripheral vascular resistance. This antihypertensive effect is not accompanied by reflex tachycardia and is not associated with negative inotropic activity or detrimental peripheral circulatory changes in the conscious SHR.

2-Ethynylbenzenealkanamines. A new class of calcium entry blockers.

A series of 2-(aryl- or alkylethynyl)benzenealkanamines were synthesized. They exhibit antihypertensive activity in spontaneously hypertensive rats and coronary vasodilator activity with minimal negative inotropic activity in the "Langendorff" guinea pig heart in vitro. They have been shown to exert their activity by inhibition of Ca2+ influx across cell membranes. Optimal activity is found among the N-(arylethyl)-5-methoxy-alpha-methyl-2-(phenylethynyl)ben zeneethanamines and -propanamines.

Electrophysiologic effects of McN-4130, a new antiarrhythmic compound, on isolated cardiac tissue.

McN-4130 has antiarrhythmic efficacy in a number of animal models of ventricular arrhythmia and fibrillation. We used standard microelectrode techniques to characterize the electrophysiological effects of McN-4130 on isolated cardiac tissue. In canine Purkinje fibers, McN-4130 reduced the maximum rate of depolarization (Vmax) and shortened action potential duration at 50% repolarization (APD50) in a concentration-dependent manner (2-10 microM). These effects occurred without significant changes in membrane potential. APD100 tended to prolong with continued superfusion with McN-4130. The depression of Vmax was rate dependent and accompanied by increases in conduction time. The reductions in Vmax and APD50 induced by McN-4130 did not reach a steady-state until 90-150 min of superfusion. At 10 microM, fibers became inexcitable within 60-90 min. In addition, the effects on the action potential were not readily reversible. McN-4130 depressed membrane responsiveness in Purkinje fibers. It shortened the effective refractory period slightly but had a much greater effect on APD50. McN-4130 also reduced Vmax in ventricular muscle preparations. In contrast to its effects on the Purkinje fiber action potential, McN-4130 prolonged the duration of the ventricular muscle transmembrane potential and effective refractory period. Slow-response action potentials induced by high [K+]o and isoproterenol were not affected by McN-4130 at concentrations up to 10 microM. McN-4130 (2 and 4 microM) had no significant effect on normal Purkinje fiber automaticity. However, continued exposure to McN-4130 at 4 microM induced early afterdepolarizations and triggered activity in five of eight spontaneously discharging fibers. In guinea pig papillary muscle, McN-4130 caused marked rate-dependent depression of Vmax at concentrations that caused minimal tonic depression of Vmax. These results indicate that McN-4130 has effects at the cellular level that are similar to those of other potent local anesthetic antiarrhythmic agents. These effects may contribute to the antiarrhythmic and antifibrillatory activity of McN-4130.

Effects of bepridil hydrochloride on calcium-induced responses in guinea pig Langendorff heart.

A spontaneously beating guinea pig Langendorff heart preparation was used to evaluate and compare the effects of bepridil hydrochloride (BP) and other Ca blockers. Cardiac contractile force was measured in isolated hearts perfused at constant pressure with nonrecirculating Krebs-Henseleit physiological salt solution (PSS). The calcium-induced inotropic response was assessed by measuring contractile force during stepwise increases in PSS Ca concentration. The results suggest that the effects of BP on cardiac muscle are different from those of the other Ca blockers tested and may involve multiple cellular mechanisms of action.

Effects of mefenidil hydrochloride on cerebral blood flow in conscious and anesthetized rat.

The purpose of this study was to determine the effects of the putative cerebral vasodilator, mefenidil hydrochloride (MF), on cardiocirculatory dynamics and the total distribution of cardiac output in the conscious rat. The radioactive microsphere technique was used to measure regional blood flow and cardiac output before (control) and during intravenous infusion of either MF (2.5, 5.0, 10.0 mg/kg) or vehicle (VH; saline, 0.0204, 0.0408. 0.0816 ml/min, respectively). Neither MF nor VH were found to have significant effects on cerebral blood flow or vascular resistance in conscious rats. MF significantly increased cerebral blood flow and lowered cerebral vascular resistance compared to VH in anesthetized animals without having significant effects in other circulatory regions.

Neuroleptic drugs attenuate calcium influx and tension development in rabbit thoracic aorta: effects of pimozide, penfluridol, chlorpromazine, and haloperidol.

This study was designed to determine whether neuroleptic drugs have calcium channel blocking activity in isolated rings of rabbit thoracic aorta. The results confirm previous findings that pimozide and penfluridol are calcium channel blockers. However, the data do not support the conclusion that these agents are selective for the voltage-sensitive calcium channel. The results also show that both haloperidol and chlorpromazine (which represent different classes of neuroleptic drugs) are also calcium channel blockers in vascular smooth muscle.

A comparison of the cardiovascular effects of haloperidol, thioridazine and chlorpromazine HCl.

Transient hypotension, electrocardiographic conduction changes and cardiac arrhythmias have been reported with the use of certain anti-psychotic agents. To assess these observations, we compared the effects of haloperidol, thioridazine and chlorpromazine HCl on alpha-adrenergic receptors, mean aortic pressure, myocardial contractile force and myocardial electrophysiology in anesthetized dogs. The results from these studies indicated that, on a milligram basis, chlorpromazine HCl was equipotent to haloperidol, and thioridazine was 0.5 times as potent as haloperidol as an alpha-adrenergic receptor blocker and as a myocardial depressant. Each compound induced conduction nonhomogeneity in myocardial conducting tissue. However, as a neuroleptic, when tested in dogs, haloperidol was 50 times more potent than chlorpromazine HCl and 180 times more potent than thioridazine. The therapeutic safety indices (cardiovascular effect dose/neuroleptic dose) for haloperidol regarding alpha-adrenergic blockade, hypotension, myocardial depression and ventricular conduction delay were 4, 145, 235 and 125, respectively, whereas these indices for chlorpromazine and for thioridazine were 0.06, 2, 4, 6 and 0.05, 1, 3 and 1, respectively. Therefore, because of differences in neuroleptic potency, therapeutic doses of haloperidol are less likely to cause adverse cardiovascular effects than are those of either chlorpromazine HCl or thioridazine.

Plasma concentration of lidocaine after endotracheal spray.

The rate of absorption and plasma concentrations of lidocaine were determined in 15 supine patients under general anesthesia following either endotracheal spray of 200 mg. (average 3.3 mg./kg.) of 4 percent lidocaine hydrochloride solution with a special cannula (LTA Kit, Abbott) (N = 6) or 1 mg./kg. of 2 percent lidocaine solution as an intravenous bolus injection (N = 9). In the 6 patients after endotracheal spray, peak plasma lidocaine levels were reached at 15 to 20 minutes (mean 3.54 plus or minus 0.76 S.E. mug./ml. at 20 minutes). In the 9 patients given 1 mg./kg. intravenously, dose peak concentrations were reached within 2 minutes (mean 5.63 plus or minus 0.18 S.E. mug./ml. at 2 minutes). Plasma concentrations of lidocaine in both groups were within nontoxic ranges.