Preclinical evaluation of the cardiac toxicity of HMR-1826, a novel prodrug of doxorubicin.

Cardiotoxicity represents the major side-effect limiting the clinical use of anthracyclines, especially doxorubicin, in cancer chemotherapy. The use of non-toxic prodrugs, or of liposome-encapsulated drugs, allows a better targeting of the tumours and may, therefore, improve the tolerance to the treatment. Using the model of isolated perfused rat heart, we have evaluated the cardiotoxicity of a novel prodrug of doxorubicin, HMR-1826, which consists of the association of doxorubicin to glucuronic acid. We have compared the cardiac effects (developed pressure, contractility and relaxation of the left ventricle) induced by HMR-1826 to those induced by doxorubicin and Doxil, a liposomal form of doxorubicin. HMR-1826 was administered intravenously every other day for 11 days at doses of 50-200 mg kg(-1) per injection while doxorubicin was administered according to the same protocol at doses of 1-3 mg kg(-1) per injection. Doxorubicin strongly decreased the cardiac functional parameters at the doses of 2.5 and 3 mg kg(-1) per injection. Doxil (3 mg kg(-1) and HMR-1826 (50-150 mg kg(-1)) were largely devoid of cardiotoxicity. HMR-1826 only induced significant alterations of the cardiac function at the highest dose used (200 mg kg(-1) per injection). These alterations were much lower than those of doxorubicin at 2.5 mg kg(-1) per injection, despite similar general toxicity symptoms (weight loss, nose bleeding and diarrhoea) at these respective doses. Thus, HMR-1826 appeared about 100-fold less cardiotoxic than doxorubicin.

Penetration of levofloxacin into lung tissue after oral administration to subjects undergoing lung biopsy or lobectomy.

STUDY OBJECTIVE: To evaluate the pulmonary tissue distribution of levofloxacin, the new once-daily fluoroquinolone, after a single 500-mg oral dose. DESIGN: Open-label study. SETTING: One pulmonary clinic and two university-affiliated teaching hospitals. PATIENTS: Eighteen adults undergoing lung biopsy or lobectomy. INTERVENTIONS: Levofloxacin plasma and lung tissue concentrations were determined by high-performance liquid chromatography with fluorescence detection. Lung tissue levofloxacin concentrations were corrected for blood contamination by measuring hemoglobin. MEASUREMENTS AND MAIN RESULTS: After a single 500-mg oral dose, concentrations of levofloxacin in lung tissue consistently exceeded those in plasma at every time point over the 24-hour sampling period, with tissue:plasma penetration ratios of 2.02 (2-3 hrs), 5.02 (4-6 hrs), 5.13 (11-17 hrs), and 4.13 (22-25 hrs). The mean penetration ratio over the 24-hour sampling period was 3.95 (range 1.06-9.98). Lung tissue concentrations of levofloxacin also exceeded minimum inhibitory concentration values for most community-acquired respiratory tract pathogens over the 24 hours. CONCLUSION: This study supports clinical evaluation of levofloxacin as once-daily oral therapy for community-acquired lower respiratory tract infections.

Efficacy and safety of Minipress XL, a new once-a-day formulation of prazosin.

The efficacy and safety of prazosin GITS (gastro-intestinal therapeutic system), a new extended-release once-a-day formulation, were assessed both as monotherapy in mild essential hypertension and in combination with a diuretic in moderate essential hypertension in two multicenter, double-blind, placebo-controlled trials. Prazosin GITS (Minipress XL) given once daily in doses of either 10 or 20 mg significantly reduced sitting and standing systolic and diastolic blood pressure compared with placebo in both mild and moderate essential hypertension. There were minimal, clinically insignificant changes in heart rate following prazosin-GITS treatment (2.5, 10, and 20 mg) compared with placebo treatment. Prazosin GITS was well tolerated; the most common adverse experiences reported were headache, dizziness, and fatigue. All adverse experiences in the moderate hypertension group and the majority (91 percent) in the mild hypertension group were mild-to-moderate in severity. The results from these multicenter trials demonstrate the efficacy and safety of this new extended-release once-a-day formulation of prazosin in the treatment of patients with mild and moderate essential hypertension.

Effect of sulfinpyrazone on ventricular arrhythmia, prostaglandin synthesis, and catecholamine release following coronary artery occlusion in the cat.

We examined if inhibition of endogenous prostaglandin (PG) synthesis reduced the severity of ventricular arrhythmia and the incidence of ventricular fibrillation (VF) following occlusion of the left anterior descending coronary artery (LAD) in anesthetized cats. We also determined whether the PGs were interacting in a facilitory manner with the sympathetic nervous system to produce arrhythmia and VF after LAD occlusion. Sulfinpyrazone, an inhibitor of cyclo-oxygenase enzyme, or vehicle was administered intravenously to cats 1 h before LAD occlusion. Sulfinpyrazone completely (p less than 0.001) inhibited the release of 6-keto-PGF1 alpha into the great cardiac vein following LAD occlusion. Sulfinpyrazone (100 mg/kg) significantly (p less than 0.001) reduced the amount of ventricular arrhythmia and the incidence of VF (p less than 0.05) in the 1st h after LAD occlusion. In addition to 6-keto-PGF1 alpha sulfinpyrazone also (p less than 0.001) inhibited the increase in plasma norepinephrine from the heart due to sympathetic nervous system stimulation following LAD occlusion. Since sulfinpyrazone was ineffective in increasing the dose of digoxin required to produce arrhythmia and death, sulfinpyrazone apparently did not depress cardiac excitability. Finally, the extent of infarction resulting from LAD occlusion was not different in sulfinpyrazone-treated animals compared with control. These data indicate that sulfinpyrazone, by inhibiting endogenous PG synthesis in the heart following LAD occlusion, may prevent a facilitory interaction between PGs and the sympathetic nervous system that contributes, in part, to the development of ventricular arrhythmia and VF normally associated with this event.

The influence of prostacyclin on coronary occlusion induced arrhythmia in cats.

The present study examined the effect of prostacyclin (PGI2) on ventricular arrhythmias following coronary artery occlusion in the cat. The left anterior descending coronary artery (LAD) was occluded abruptly in 50 cats anesthetized with alpha-chloralose. The ECG (Lead II) along with arterial blood pressure were monitored before and for at least one hour after occlusion. Either vehicle or PGI2 was infused at a rate of 0.15 ml . min-1 into the left atrium 15 min before and 1 hour after LAD occlusion. PGI2 was infused at 4 doses: 2.7,27,270 and 2700 pmole . kg-1 . min-1. Infusion of PGI2 before occlusion produced a dose dependent decrease in mean arterial blood pressure with no significant change in heart rate. Abrupt occlusion of the LAD produced ventricular arrhythmia in all cats ranging from ventricular premature beats to ventricular fibrillation (VF). In cats infused with PGI2 the incidence of VF ranged from 30-40% at the low and middle doses to a maximum of 60% at the highest dose (2700 pmole . kg-1 . min-10. The incidence of VF in the latter group was two times greater than that observed in the control group (30%). In addition, the mean number of ventricular ectopic beats was greater at the 27 and 2700 pmole . kg-1 . min-1 doses of PGI2 than in the control group. An increase in ventricular ectopic beats was not observed at the 2.7 or 270 pmole . kg-1 . min-1 doses of PGI2. These data indicate the PGI2 can exert an arrhythmogenic effect following coronary artery occlusion and that this effect occurs in a biphasic manner i.e., the increase in arrhythmia observed at 27 did not occur at 270 but occurred again at the 10 fold higher dose (2700 pmole . kg-1 . min-1). At the lowest dose of PGI2 infarct size was approximately 14% less than in the control group while, at the highest dose, infarct size was 20% greater than control and approximatey 40% greater than the lowest dose of PGI2.

Comparison of the effects of prostaglandins E1 and A1 on coronary occlusion induced arrhythmia.

The present study compares the effects of PGE1 and PGA1 on ventricular arrhythmias following coronary artery occlusion. The left anterior descending coronary artery (LAD) was occluded abruptly in 55 cats anesthetized with alpha-chloralose. Lead II of the ECG along with arterial blood pressure were monitored for one hour after occlusion. Either vehicle or prostaglandin was infused into the left atrium (LA) or femoral vein (IV) 15 min prior to and for 1 hour after LAD occlusion at a rate of 0.15 ml/min. Prostaglandin was infused at either a high dose (1.0 microgram/kg/min) or a low dose (0.1 microgram/kg/min). Infusion of either PGE1 or PGA1 produced a marked fall in blood pressure and heart rate which returned toward control before occlusion. Abrupt occlusion of the LAD produced ventricular arrhythmia in all cats ranging from ventricular premature beats to ventricular fibrillation (VF). The control animals had a 38% incidence of VF. VF occurred in 75% of the animals in which PGE1 was administered into the LA at either the high or low dose while the occurrence in those administered PGA1 was 67% and 50%, respectively. Intravenous administration of the high dose of PGE1 or PGA1 resulted in VF in 13% and 67% of the animals after LAD occlusion, respectively. These data indicate that the IV administration of PGE1 may protect the heart from VF while the infusion of PGE1 or PGA1 into the LA may enhance VF after LAD occlusion.

Possible ion-pair-mediated absorption of mixidine II: plasma levels and histology.

Plasma intact 14C-mixidine levels in rats increased when the drug was administered intraduodenally with 1:3 and 1:5 molar ratios of 2-naphthalenesulfonic acid. Upon histological examination of the duodenums, similar doses of mixidine combined with 2-naphthalenesulfonic acid produced no dose-related lesions. These and previous observations demonstrate that mixidine absorption may be enhanced by ion-pair formation.

Withdrawal syndrome upon cessation of chronic clonidine treatment in rats.

Clinical reports indicate that cessation of treatment with the antihypertensive agent clonidine is associated with a withdrawal syndrome which may include a hypertensive overshoot of critical proportions. We have attempted to produce an animal model of this syndrome in rats. Rats were treated with clonidine in the drinking water (5 microgram/ml; total dose 300-500 microgram/kg/day) which produced a significant (approx. 20%) decrease in heart rate and blood pressure. Within 24 h of cessation of treatment a significantly greater (approximately 100 beats/min) heart rate was seen in treated animals than in control animals when measurements were made in conscious animals. No hypertensive overshoot was observed. Cessation of treatment was associated with an increase in sympatho-adrenal tone as shown by a trans-synaptic induction of adrenal tyrosine hydroxylase activity. Adrenal denervation prevented the rise in adrenal tyrosine hydroxylase seen after cessation of treatment. Administration of clonidine to pregnant rats (10th day until term) did not alter the development of adrenal tyrosine hydroxylase in the offspring. The data indicate that a withdrawal syndrome is produced upon cessation of chronic clonidine treatment.