Cardiotoxicity of a new anthracycline derivative (SM-5887) following intravenous administration to rabbits: Comparative study with doxorubicin

The degree of cardiotoxicity of SM-5887 compared with that of doxorubicin was investigated in rabbits.Two experimental groups were administered high and low doses of SM-5887, respectively. One group was administered doxorubicin and another group was administered the vehicle only were prepared as positive and negative controls, respectively. Drugs were intravenously administered 3 times a week for 8 weeks.At terminus, electrocardiograms were recorded under anesthesia. The blood was collected for haematology and blood biochemistry analyses. Myocardial tissue damage was evaluated using light and electron microscopy.In the electrocardiogram study, prolongation of QTc interval and ST-T change were observed in rabbits administered SM-5887 and doxorubicin.Morphological studies showed that myocardial tissue damage in animals administered SM-5887 was comparable to that in the negative controls, and less than that observed in the positive controls.The general toxicological investigations uniformly indicated lower toxicity in the SM-5887 group than in the doxorubicin group at equivalent dosages.In total, considering the results of antitumor efficacy studies comparing SM-5887 with doxorubicin, these results indicate that the cardiotoxicity of SM-5887 is very slight, and that the general toxicity of SM-5887 is lower than that of doxorubicin.     

General pharmacology of beraprost sodium. 2nd communication: effect on the autonomic, cardiovascular and gastrointestinal systems, and other effects

Beraprost sodium (sodium (+/-)-(1R*,2R*,3as*,8bS*)-2,3,3a,8b-tetrahydro-2- hydroxy-1-[(E)-(3S*)-3-hydroxy-4-methyl-1-octen-6-ynyl]-1H- cyclopenta[b]benzofuran-5-butyrate, TRK-100) is an orally active epoprostenol (prostaglandin I2, PGI2) analogue. Its general pharmacological effects on peripheral organs were studied. 1. In isolated organs, beraprost sodium relaxed the trachea and increased atrial beating rate (2.4 x 10(-5) mol/l). It also dose-dependently contracted the stomach, aorta, ileum and uterus (2.4 x 10(-7)-2.4 x 10(-4) mol/l). These effects of beraprost sodium were similar, but inferior to those of PGI2 and PGE1. 2. Intravenous administration of beraprost sodium produced a dose-related decrease in blood pressure (BP), its potency being about 1/3 times that of PGI2 in anesthetized rats and dogs. Beraprost sodium and PGI2 had no effects on heart rate (HR), and enhanced respiration in conjugation with a decrease in BP. Oral administration of beraprost sodium in high doses (1-3 mg/kg in rats and 0.3 mg/kg in dogs) caused a decrease in BP. A compensatory tachycardia and an elevated plasma renin activity (PRA) occurred after low doses (0.1-0.3 mg/kg) in rats. In contrast, a change of HR and PRA in rabbits and dogs was mild. 3. Beraprost sodium produced suppression of digestive organs: markedly, gastric motility and secretion and intestinal transport; slightly, but significantly, biliary secretion. On the other hand, it enhanced ileal motility at a high dose (300 micrograms/kg i.v.). 4. Oral administration of beraprost sodium caused a decrease in urinary volume and electrolyte excretion in rats. 5. Oral administration of beraprost sodium prolonged bleeding time in mice, while it had no effect on the blood coagulation system in vitro. In addition, beraprost sodium had no hemolytic action. 6. The other effects of beraprost sodium were weak. Beraprost sodium had no local anesthetic activity and no effect on salivation, pupil size and neuromuscular transmission in the skeletal muscle. Beraprost sodium slightly contracted the uterus of non-pregnant rats in situ and dose-independently inhibited carrageenin-induced paw edema. In conclusion, beraprost sodium produced various effects on the autonomic, cardiovascular, and gastrointestinal systems. Probably, these effects may be based on its own action like PGI2.     

Suppression of Rabbit VX-2 Subcutaneous Tumor Growth by Gadolinium Neutron Capture Therapy

VX-2 tumors growing in hind legs of New Zealand White rabbits (n=4) were exposed to thermal neutrons for 40 min (2.1 × 10¹² neutrons cm⁻²) while one of two hind leg tumors of each rabbit was infused continuously with meglumine gadopentetate through a branch of the left femoral artery. The contralateral (uninfused) tumors served as controls. Although no differential distribution of gadolinium was achieved between the tumor and its adjacent normal tissue, the gadolinium concentration in the infused tumor was approximately 5–6 fold higher than that in the contralateral tumor. Growth of gadolinium-infused tumors was significantly inhibited compared to that of control tumors (P<0.05) between the 16th and 23rd days after treatment.     

Amplification of IMR-32 clones 8, G21, and N-myc in human neuroblastoma xenografts

Amplification of clones 8, G21, and N-myc, which were derived from human neuroblastoma cell lines IMR-32 and NB-19, were studied in nine neuroblastoma xenografts. N-myc was amplified from 50- to 120-fold in eight of nine xenografts, clone 8 was amplified in five of the xenografts, and clone G21 was amplified in four of these five. Each of these clones was localized by in situ hybridization to homogeneously staining regions in metaphase spreads of xenograft chromosomes. In one xenograft a DNA rearrangement of clone 8 was observed, and only two of the sequences detected by G21 were amplified. Restriction enzyme mapping indicated that the rearrangement within clone 8 occurred at a position close to the rearrangement previously noted in neuroblastoma cell line NB-9.     

A comparative double-blind trial of HSR-902 and butylscopolamine bromide for relieving colic in ureteral stone patients

The clinical efficacy and safety of HSR-902 (tiquidium bromide, Thiaton) in patients with spastic pain caused by ureteral stones were evaluated in a double blind comparative trial. A daily dose of 30 mg HSR-902 or 60 mg butylscopolamine bromide as a control drug was orally administered for 7 days. With either drug marked improvement of spastic pain was observed. The time to obtain relief from spastic pain and utility rating were significantly more excellent with HSR-902 than with butylscopolamine bromide. With all other parameters used no significant difference was observed between the two drugs. Mild adverse effects such as abdominal discomfort and constipation were observed in 2 of the 87 cases in the butylscopolamine bromide group but none of the 83 cases in the HSR-902 group. Taking efficacy and safety of the treatment into consideration, no significant difference was observed in usefulness between the two drugs, and we were able to confirm the usefulness of HSR-902 for relief from spastic pain caused by ureteral stones.     

A case of mitochondrial myopathy, encephalopathy and lactic acidosis due to cytochrome c oxidase deficiency with neurogenic muscular changes

An 18-year-old male with mitochondrial myopathy, encephalopathy and lactic acidosis was studied by electromyography (EMG) along with histological and biochemical studies on his biopsied muscle. Mitochondrial cytochrome c oxidase deficiency with a decrease in the amounts of the subunits 2, 6, and 7 was discovered. Although no apparent symptoms of peripheral neuropathy were present, EMG revealed high-amplitude motor unit action potentials with a reduced interference pattern and the histochemical study revealed fiber type grouping without grouped atrophy. These findings indicated lower motor neuron damage, probably due to the mitochondrial disorder, followed by reinnervation. Coenzyme Q10 administration was effective in reducing both the lactate and pyruvate levels and for recovering the muscle atrophy.     

Successful utilization of the median sternotomy approach in the management of descending necrotizing mediastinitis: Report of a case

We describe herein the case of a patient in whom a median sternotomy was successfully employed for mediastinal drainage in the treatment of descending necrotizing mediastinitis (DNM). Although most reports describe cervical or thoracotomy approaches, our experience strongly suggests that median sternotomy is a satisfactory alternative approach for treatment of this disease.     

ENDOTHELIAL SURFACE OF THE BLOOD FLOW LOADED CANINE CAROTID ARTERY

In order to study the ultrastructural changes of the endothelial surface induced by blood flow change, an arterio-venous shunt was constructed between the common carotid artery and the external jugular vein in 10 dogs. Blood flow rate was measured before anastomosis, after anastomosis, and after 1 week. After the final measurement (1 week), the arteries were fixed under normal pressure by 2.5% glutaraldehyde solution in phosphate buffer (pH 7.4) and were examined with scanning and transmission electron microscopes. Protrusion of nucleic parts of the endothelial cells, microvilli-like surface projections, and disturbance of pinocytotic vesicles predominated in the shunted arteries exposed to elevated blood flow. No significant ultrastructural changes could be defined in the intercellular junction of the endothelial cells which supported the increased permeability through the junction. It was suggested that the wall shear stress exerted a reactive change on the endothelial cells as well as a direct mechanical deformative effect in the endothelial plasma membrane.