Phase I study of E1040, a new parenteral cephem antibiotic

The safety and pharmacokinetics of E1040, a new injectable cephem antibiotic, were evaluated in healthy volunteers. In single-dose studies, 125, 250, 500, 1000 and 2000 mg of E1040 were administered by I.V. infusion over 1 hour. Results of 5 minutes I.V. infusions of 500, 1000 and 2000 mg of the drug were also studied. Plasma concentration-time profiles were well suited to a two-compartment open model. The half-life of elimination from plasma was 1.85 +/- 0.16 hours, and the Cmax and AUC paralleled the doses given. The mean urinary recovery within the first 24 hours was 85.7 +/- 6.43% of the dose. In a multiple-dose study, 2000 mg of E1040 (I.V. over 1 hour) was administered every 12 hours (total 9 times) and no abnormal accumulation of the drug in plasma was observed. There were no significant differences in plasma levels or in urinary recoveries between single- and multiple-dose regimens. There were no subjective or objective abnormal findings definitely attributable to the drug except that one subject given 250 mg over 1 hour reported diarrhea, and another complained of nausea during the infusion of 2000 mg over 5 minutes. From these results E1040 was concluded to be safe and well tolerated.     

Intrarenal localization of receptors for alpha-rat atrial natriuretic polypeptide: an autoradiographic study with [125I]-labeled ligand injected in vivo into the rat aorta

We examined intrarenal localization of receptors for alpha-rat atrial natriuretic polypeptide (alpha-rANP) by injecting [125I]-labeled ligand in vivo into the rat aorta. We found that the receptors for alpha-rANP are distributed also on the vasa recta of the outer and inner medulla in addition to the previously reported sites, i.e., the renal arteries, renal pelvis, glomeruli, and inner medullary tissues including collecting tubules. In the vascular bundle of the outer medulla, the majority of grains was preferentially localized on the arterial vasa recta. The electron microscopic autoradiography of the glomerulus showed that the binding sites were mainly localized on the foot process of the podocyte. Since alpha-rANP injected into the aorta under physiological conditions was bound to the glomerulus and vasa recta in the kidney, the effect of ANP on these binding sites may be important in the mechanism of natriuresis.     

Effects of vancomycin and ofloxacin on rabbit ERG in vivo

The retinal toxicity of vancomycin and ofloxacin was studied by electroretinogram (ERG) before and after intravitreal injection in rabbits. Vancomycin is known to be effective on methicillin-resistant Staphylococcus aureus. A dose of 1mg vancomycin caused no ERG change for at least eight weeks after injection. The feature that ERG became non-recordable during one to four weeks after an intravitreal injection of 10mg vancomycin, with recovery of only the c-wave was conspicuous. A dose of 200 micrograms ofloxacin did not cause deterioration of the b-wave, the c-wave or the oscillatory potentials throughout the follow-up period up to eight weeks. Judging from the susceptibility of each ERG component to antimicrobials and taking into account the difference of vitreous volume between rabbits and humans, clinical doses of intravitreal single-shot injection should be less than 1mg for vancomycin and 200 micrograms for ofloxacin.     

ROLE OF f3-RECEPTOR IN THE RADIX ANGELICAE SINENSIS ATTENUATED HYPOXIC PULMONARY HYPERTENSJON IN RATS

Acute pulmonary hypertension was caused by inhalation of 5% 02 in rats. Pulmonary vascujar re- sistance (PVR) increased, but heart rate (HR), cardiac output (CO) and carotid arterial pressure (CAP) were not obviously changed. After an intravenous admini- stration of Radix Angelicae sinensis, the acute pulmonary hypertension induced by inhalation of 5% O2 could be attenuated, but this effect disappeared if propranolol was given before Radix Angelicae sinensis. In chronic experiments, the same results were obtained, but the protective effect of Radix Angelicae sinensis on heart function was not influenced by propranolol. It is suggested that Radix Angelicae sinensis rmght play a role by stimulating the βz-receptor in the prevention of acute and chronic hypoxic pulmonary hypertension. However, prevention of hypertrophy of the right ventricle and enhancement of heart function in chronic hypoxic rats might not be attributed to the β1 receptor in the heart.     

Subretinal neovascularisation and snow banking in a case of sarcoidosis: case report.

A 49-year-old Japanese man presented with chronic granulomatous uveitis in his left eye. Later he developed macular subretinal neovascularisation. The chest x-ray showed bilateral hilar lymphadenopathy. Bronchoscopy and gallium-67 scanning were positive, PPD skin test negative, and serum angiotensin converting enzyme (ACE) levels increased. Ophthalmoscopy and fluorescein angiography of the left eye showed perivasculitis, retinochoroidal exudates, snow banking, and vitreous opacity. On these findings, the diagnosis of sarcoidosis was made. Treatment was based on topical corticosteroids, mydriatics, beta blockers, and oral carbonic anhydrase inhibitors. After 15 months the visual acuity decreased in the left eye, and a neovascular membrane was observed in the macula. Fluorescein angiography confirmed subretinal neovascularisation. Almost two years later the patient still has the neovascular membrane in his left eye.     

Fusariotoxicoses of farm animals and mycotoxic leucoencephalomalacia of the equine associated with the finding of trichothecenes in feedstuffs

Mycotoxicoses involving horses, rabbits and cattle have been studied. Fusarium tricinctum and T-2 toxin were isolated from all incriminated feedstuffs. Other isolated trichothecenes from the feed included HT-2, verrucarins and roridin. The toxins were separated, identified and quantitated using thin-layer chromatography, gas-liquid chromatography and mass spectrometry. T-2 toxin was detected in amounts varying from 0.5-204 ppm. The contaminated feedstuffs in connection with the affected horses and rabbits, included cereal grains (corn, cornstalks, bran and barley), whereas fescue hay was associated with the mucocutaneous findings in the bovine episode. The effects of the toxin(s) seemed to be host specific and varied according to the different animal species. Horses and rabbits developed primarily central nervous disorders with conspicuous pathological findings in the brain. Hepatitis and nephritis were also seen in naturally intoxicated horses and experimentally fed rats. Affected cattle developed mucocutaneous eruptions around the mouth and nostrils. In addition, dermonecrotic findings were observed involving the extremities, ear and tail. Fusariotoxicoses are toxic conditions of farm animals and man caused by the ingestion of cereal grains and forages contaminated by different fungal species of the genus Fusarium. A variety of clinical and pathological findings have been reported (5,6,10,13,15,17,31). This study concerns neuropathic findings in horses and rabbits and mucocutaneous lesions in cattle in association with T-2 toxin contamination.