Causes of death and renal tubular dysfunction in residents exposed to cadmium in the environment.

OBJECTIVES: To clarify the causes of death of residents with renal tubular dysfunction induced by cadmium (Cd) in the environment. METHODS: A 15 year follow up study was performed with the inhabitants living in the Cd polluted Kakehashi River basin in Japan. Standardised mortality ratios (SMRs) for causes of death, classified by ICD-9, were computed using the person-years method to investigate the excess mortality of subjects with urinary beta2-MG (microglobulin) > or =1000 microg/gCr. Mortality risk analysis was performed using Cox's proportional model to compare mortality between subjects with urinary beta2-MG > or =1000 and <1000 microg/gCr, and to investigate the relationship between the degree of urinary beta2-MG and mortality. RESULTS: Excess mortality due to heart failure and cerebral infarction in both sexes, and nephritis and nephrosis in men, was observed among subjects with urinary beta2-MG > or =1000 microg/gCr. Significant increases in mortality risk for cerebral infarction in men and for malignant neoplasms in women with urinary beta2-MG > or =1000 microg/gCr were observed during the first five year observation period. For nephritis and nephrosis, the mortality risks for men and women with urinary beta2-MG > or =1000 microg/gCr significantly increased over the 15 year observation period. The mortality risks for heart failure and cerebral infarction increased in proportion to the increased urinary beta2-MG in both sexes. Increased mortality risks for nephritis and nephrosis were identified in the subjects with urinary beta2-MG > or =10000 microg/gCr in both sexes. CONCLUSION: Renal tubular dysfunction induced by Cd affected the causes of death, and mortality for heart failure, cerebral infarction, and nephritis and nephrosis was increased among inhabitants living in a Cd polluted area in Japan. In women, cancer mortality may have been increased while Cd pollution was ongoing.

Effect of probucol on serum lipoprotein levels in normal and dyslipoproteinemic mice.

The effect of probucol was studied on serum lipoprotein levels in normal and cholesterol-fed, hypercholesterolemic mice. In normal mice, probucol caused a significant reduction in LDL + VLDL cholesterol at daily doses above 25-50 mg/kg and also in HDL cholesterol at higher doses. In cholesterol-fed mice, probucol treatment decreased LDL + VLDL cholesterol at daily doses exceeding 200 mg/kg and also HDL cholesterol at a daily dose of 800 mg/kg. The ratio of LDL + VLDL cholesterol to HDL cholesterol was significantly reduced by treatment at 25-100 mg/kg in normal mice and at 200 mg/kg in hypercholesterolemic mice. The ratio was not reduced at doses above these ranges. These dose-effect relationships were not modified by duration of probucol treatment. These findings suggest that there is an optimum dosage of probucol to lower LDL + VLDL cholesterol and the atherogenic index, and that the actual optimum dosage for the beneficial effect depends on blood lipid levels or types of hyperlipidemia. This may be important in the clinical application of this drug, because a negative correlation has been demonstrated between HDL cholesterol levels and ischemic heart disease. Clofibrate treatment did not affect serum lipid levels significantly in either normal or cholesterol-fed mice. Probucol was again effective in lowering LDL cholesterol values in cholesterol-fed mice which had previously been treated with clofibrate for 2 weeks without any beneficial effect. In an additional experiment, it was found that the probucol-induced reduction in cholesterol returned to the pre-treatment levels gradually over several days, depending on the dose and without rebound elevation after withdrawal of the drug.

Effect of pantethine on lipoprotein profiles and HDL subfractions in experimentally hypercholesterolemic rabbits.

A high-cholesterol diet caused in rabbits a great increase in beta-migrating VLDL and a significant decrease in HDL 2 (43% of normal) and HDL 3 masses (64% of normal), without significant changes in HDL cholesterol values. Chemical analysis of the HDL subfractions indicated an abnormal lipid-protein composition in the hypercholesterolemic rabbits, an increase in cholesterol and a decrease in the contents of triglycerides and phospholipid. When these rabbits were treated for about 1 month with pantethine, and intermediate precursor of coenzyme A, the increase in cholesterol levels was effectively prevented in the beta-VLDL (11%) and LDL fractions (43%) but, conversely, HDL-cholesterol was significantly increased (151%). In a separate experiment, HDL 2 and HDL 3 masses were calculated to be increased to 186% and 193%, respectively, by pantethine treatment, when compared with those in control cholesterol-fed rabbits. Serum apolipoprotein AI antigen levels were also significantly increased by the treatment.

Fluorine-containing amino acids and their derivatives. 4. Synthesis and antibacterial activity of threo and erythro 1-fluorodehydroxylated chloramphenicol analogues.

Both threo and erythro 1-fluorodehydroxylated chloramphenicol analogues were synthesized and tested for antimicrobial activity. None showed antibacterial or antifungal activity, clearly demonstrating that substitution of the secondary hydroxyl group with fluorine abolishes the antibacterial activity of the parent compound, chloramphenicol. This finding sharply contrasts with that of previous workers, in which fluorination of the 3-hydroxyl group enhanced antibacterial activity against many chloramphenicol-resistant strains.

Synthesis and in vitro antimicrobial property of o-carborane derivatives.

Various o-carboranes and nido-type dicarbollide anions have been synthesized and tested for antimicrobial activity. Nearly all of the dicarbollide monoanions investigated were active in vitro against fungi such as Candida albicans, Aspergillus fumigatus, and Tricophyton asteroides, as well as against Gram-positive bacteria. From a consideration of the structure-activity relationships, it seems most reasonable to conclude that the introduction of lipophilic alkyl or o-carboranyl groups to the hydrophilic dicarbollide anions leads to the antimicrobial activity.

1-[1-[2-[(3-Chlorobenzyl)oxy]phenyl]vinyl]-1H-imidazole hydrochloride, a new potent antifungal agent.

The synthesis and antifungal properties of 1-[1-[2-[(3-chlorobenzyl)oxy]phenyl]vinyl]-1H-imidazole hydrochloride (1 . HCl) are described. Topical application of cream and gel formulation of 1 . HCl showed high efficacy against guinea pig dermatophytosis.

Synthesis and oral antifungal activity of novel azolylpropanolones and related compounds.

To find orally active antifungal agents, novel imidazolyl- and 1,2,4-triazolylpropanolones I and related compounds II-IV were synthesized. Compounds I were derived from ketones V (method A), alpha-diketone IX (method B), alpha-hydroxy ketones X (method C), alpha-chloro ketone XII (method D), and enones VI (method E). Diols II, synthesized from I with NaBH4, were cyclized to five-membered cyclic compounds III by using N,N'-carbonyldiimidazole, thionyl chloride, N,N'-(thiocarbonyl)diimidazole, bromochloromethane, 2,2-dimethoxypropane, and cyclohexanone dimethyl ketal. Diols IV were synthesized from I by Grignard reaction (method F), hydroxymethylation of X (method G), and reaction of ketones XXI with 1-[(trimethylsily)methyl]-1,2,4-triazole (method H). Compounds I-IV were examined for their antifungal activities in vitro by evaluation of broth dilution MIC values against three species of fungi and the inhibitory effect on pseudomycelium of Candida albicans, and they were examined for oral efficacy in vivo against subacute systemic candidiasis in mice and superficial dermatophytosis in guinea pigs. Compounds 2, 12, 38, 39, and 92 exhibited strong oral antifungal activity. An asymmetric synthesis and the structure-activity relationships of the compounds examined are discussed.

Synthesis and antifungal activity of new 1-vinylimidazoles.

Carbonyl compounds I were subjected to an imidazole transfer reaction with N,N'-sulfinyldiimidazole or N,N'-carbonyldiimidazole to obtain the diimidazole II and the monoimidazole III. Various 1-vinylimidazoles IV, derived from o-hydroxyacetophenones by imidazole transfer reaction, were alkylated to furnish the title compounds V. The structure-activity relationships of these 1-vinylimidazole compounds V are described.

Synthesis and antifungal activity of a series of novel 1,2-disubstituted propenones.

To find an antifungal agent other than those of the imidazole and triazole series, a new class of 1,2-disubstituted propenones I and II was prepared and tested for antifungal activity. Comparison of the structure-activity relationships showed that the conjugated structure of carbonyl and exomethylene groups in I and II plays an important role in potent antifungal activity. However, it is noteworthy that compounds 53, 54, and 56, which have a hydroxymethyl or methoxymethyl group instead of an exo-methylene group in I, also showed potent activity. Although many compounds exhibited strong antifungal activity in vitro, none showed activity in vivo of oral efficacy against subacute systemic candidiasis in mice.

Absence of changes in drug disposition and catecholamine sensitivity in the hyperthyroid dog.

1 In order to study the relative contribution of hepatic drug metabolizing enzymes and hepatic blood flow to the clearance of drugs in the hyperthyroid state, the disposition kinetics of two model compounds (antipyrine and propranolol) were examined in thyroid-fed dogs as compared to euthyroid and phenobarbitone-pretreated animals. 2 In hyperthyroid dogs, the possibility of catecholamine hypersensitivity was evaluated by assessing the chronotropic response to isoprenaline and by constructing a drug concentration-effect (beta-blockade) relationship. 3 The plasma propranolol half-life (0.97 +/- 0.12 h) of the hyperthyroid animals did not differ significantly from either the euthyroid group or the phenobarbitone-pretreated group. This was observed with no significant change in the apparent volume of distribution among the three experimental groups. 4 Phenobarbitone pretreatment accelerated significantly the elimination of antipyrine (half-life, 1.09 +/- 0.15 h, P less than 0.01) as compared to the euthyroid (2.84 +/- 0.35 h) and the hyperthyroid groups (2.58 +/- 0.13 h), respectively, without any changes in the apparent volume of distribution in any group. 5 Neither the chronotropic responses to exogenously administered catecholamine, nor the antagonist concentration-effect relationships support the concept that the hyperthyroid state potentiates sensitivity of the receptor-effect system of the heart. 6 The data obtained from the present study fit best with the view that thyroid hormone excess alters neither the disposition of the model compounds used nor the catecholamine-sensitivity examined.

Clinical pharmacologic observations on timolol. II. Antihypertensive effect and kinetic disposition on twice-daily dosing in patients with mild or moderate hypertension.

Timolol given on a twice-daily schedule has shown both antihypertensive effectiveness and plasma renin-suppressing action in eight patients with mild or moderate hypertension. However, the causal relationship between the drug plasma level, blood pressure fall, and change in plasma renin activity was not so clearly demonstrated in the present study. The disposition profiles of timolol at the steady state show an elimination half-life of 4.7 +/- 0.7 hours and a total plasma clearance of 225 +/- 21 ml/min. These values are found to be different from those of our previous observations obtained in normal individuals. Although the range of mean timolol concentrations at steady state varies to a certain extent among different patients, the dosage regimens for patients who will receive treatment for certain chronic disease states (e.g., arrythmias, obstructive cardiomyopathy, and angina pectoris, but not hypertension) in relation to plasma levels should be based on the disposition data obtained under steady state conditions. Bronchospasm developed in one of eight patients whose timolol level was found to be higher than the average of other patients given the same dosage.

Clinical pharmacologic observations on timolol. I. Disposition and effect in relation to plasma level in normal individuals.

The disposition profiles of a new beta-adrenergic blocking drug, timolol, were investigated at 11 different times in normal individuals after a single oral dose. The disposition of timolol follows first-order kinetics and may be adequately described by a one-compartment model. The pharmacokinetic data were not significantly different among the three dose levels examined. After the single oral doses, overall elimination half-life was 3.2 +/- 0.2 hours (mean +/- S.E.M.), with an observed peak time of 2.0 +/- 0.2 hours; extrapolated volume of distribution was 1.81 +/- 0.15 liter/kg; and the total plasma clearance was 557 +/- 61 ml/min. Approximately 20 per cent of elimination from the human body was dependent on the kidney. The area under the curve from zero to infinity and the peak concentration observed were dose dependent. A linear relationship was found between timolol plasma concentrations and beta-adrenergic blocking effects (per cent inhibition), as estimated from exercise-induced tachycardia. Timolol is a beta blocker which must await further clinical trials for the assessment of therapeutic implications in relation to plasma levels.

Evaluation of the ACR-NEMA standard for communications in digital radiology.

An implementation and evaluation of a prototype multivendor communications system which complies with the American College of Radiology (ACR) and the National Electrical Manufacturers Association (NEMA) standard for communications in digital radiology is discussed. The system allows communications between interfaces from different manufacturers within a networked environment. The implementation includes network software compatible with the International Standards Organization's Open Systems Interconnect standard. The experience of the implementation effort and the evaluation of the system provide the basis for a critique of the ACR-NEMA standard. It is concluded that the ACR-NEMA standard is not well suited for application to the networked environment of picture archiving and communications systems. Two possible solutions are recommended for this problem. The first is a major revision of the existing standard. The second is the development of a family of network communications standards for digital radiology.

Quinolone antibacterial-agent-induced cutaneous phototoxicity: ear swelling reactions in Balb/c mice.

The phototoxic potentials of quinolone derivatives and the possibility of free radical contribution to their phototoxicity were investigated by measuring increments in ear thickness. Balb/c mice, fasted overnight, were orally administered ofloxacin (OFLX), lomefloxacin (LMFX), enoxacin (ENX), ciprofloxacin (CPFX) and DR-3355 (the s-isomer of OFLX), and immediately exposed to ultraviolet-A light (UVA: 320-400 nm) for 4 h (21.6 joules/cm2). Measurement of ear thickness was carried out 0, 24 and 48 h after the end of irradiation. The time-course profiles of ear thickness varied with both the doses and the quinolone used, but linear dose-response curves were obtained from the data 24 h after irradiation ended. The 50% ear thickness increment-inducing doses of LMFX, ENX, OFLX, CPFX and DR-3355 were calculated as 24.8, 81.9, 428.0, 457.9 and 526.6 mg/kg, respectively. The phototoxic potential of these quinolones coincided with the data obtained previously by measuring the incidence of erythema on the ears. Pretreatment with butylated hydroxtoluene, a free radical scavenger, almost completely prevented all swelling reactions induced by the quinolones. These results suggest that the degree of phototoxicity induced by the quinolones used could depend on the balance between the generation of free radicals and the effectiveness of the defense systems against toxic radicals.

Phototoxic potential of quinolone antibacterial agents in Balb/c mice.

The phototoxic potentials of quinolone antibacterial agents were investigated in Balb/c strain mice. The mice were orally administered nalidixic acid (NA), enoxacin (ENX), ofloxacin (OFLX), ciprofloxacin (CPFX), lomefloxacin (LMFX) and DR-3355 (s-isomer of OFLX), and immediately exposed to ultraviolet-A (UVA) for 4 h (21.6 joules/cm2). The ears were examined for overt damage, as a major phototoxic parameter, 0, 24 and 48 h after irradiation ended. At doses of 200 mg/kg, LMFX, NA and ENX caused marked cutaneous phototoxic reactions on the ears, whereas CPFX, OFLX and DR-3355 caused none. At 800 mg/kg, however, CPFX, OFLX and DR-3355 also caused phototoxic reactions on the ears. These phototoxic changes were characterized grossly by erythema, and histopathologically by edema and infiltration of inflammatory cells, especially neutrophils, into the connective tissue surrounding the cartilage. The 50% erythema-inducing doses of LMFX, ENX, NA, OFLX, DR-3355 and CPFX were calculated at 19, 102, 143, 553, 619 and 741 mg/kg, respectively. Thus, the phototoxic potencies of the quinolones tested were: LMFX greater than ENX, NA greater than OFLX, DR-3355, CPFX.

Isolation of cepafungins I, II and III from Pseudomonas species.

New acylpeptide antibiotics named cepafungins I, II and III were isolated from the culture broth of a strain identified as Pseudomonas sp. These antibiotics are neutral substances, soluble in aqueous alcohols and dimethyl sulfoxide, and show UV maxima at 260.5 nm. The IR spectra indicated these to be peptides. Molecular formulas C28H46N4O6, C27H44N4O6 and C26H42N4O6 for cepafungins I, II and III were indicated by elemental analysis and SI-MS. Cepafungins exhibited inhibitory activity against yeast and fungi, and antitumor activity against P388 leukemia in mice.

Isolation of CB-25-I, an antifungal antibiotic, from Serratia plymuthica.

A new antifungal antibiotic, CB-25-I, was isolated from the culture broth of a strain of Serratia plymuthica. The antibiotic, a water-soluble dipeptide, is structurally related to Sch 37137 and A 19009, both produced by strains of Actinomycetales. The antibiotic exhibits inhibitory activity against Candida albicans in YNB medium (a synthetic medium), but the activity is significantly reduced in Sabouroud dextrose medium.

Studies on experimental conditions for detecting phototoxic potentials of drugs in Balb/c mice.

This study was designed to establish a procedure for detecting the phototoxicity of drugs in an animal model. Experimental conditions in relation to intensity distribution of ultraviolet-A (UVA), duration of irradiation, and suitable region for irradiation were investigated. One black light gave a wide constant-energy region when the distance from the light source to the irradiation area was 15 cm. The intensity distribution of a bank of 10 black lights formed a pattern like the contour map of a truncated cone in the irradiation area. In phototoxic studies, Balb/c strain mice were orally administered chlorpromazine and nalidixic acid, clinically known as photosensitizers, and were immediately exposed to UVA irradiation. The optimal irradiation time was 4 hours at an energy of 20 Joules/cm2, which with a high frequency caused erythema on the surface of the ears in the central area, which received about 1.5 mW/sec.cm2, but no reaction occurred in the surrounding area (0.5-0.8 mW/sec.cm2). These results indicate that it is important to select a suitable irradiation area and sufficient intensity of irradiation in order to determine whether a drug has phototoxic potential.

A case of dermatomyositis associated with mechanic's hand.

A 67-year-old man was referred to the Department of Internal Medicine at Tokyo Medical University with interstitial pneumonia in July 1999. He presented with keratotic plaques on both palsm and on the ventral and lateral sides of his fingers. Erythematous keratosis was observed on the dosal aspect of his fingers and metatarsophalangeal (MP) joints. Edematous erythema was seen on the patient's chest, back, and the extensor surfaces of his arms. Electromyography revealed a myogenic pattern and an increased level of myogenic enzymes was found in the blood. Histological findings of the ventral sides of his fingers showed hyperkeratosis and parakeratosis of the dermal tissue and liquefaction degeneration of the basal layer at the papilla. Based on these findings, the patient was given a diagnosis of dermatomyositis associated with mechanic's hand. A systemic examination confirmed interstitial pneumonia and carcinoma of the duodenal papilla. Mechanic's hand is a type of dermatitis associated with myopathy first reported by Stahl et al. in patients with collagen disease. We report herein the first documented case of mechanic's hand in Asians.

[Studies on the pharmacokinetics and effects of beta-adrenergic blocking agents, sotalol (author's transl)].

Present investigation was undertaken to elucidate what pharmacokinetic parameters in animal experiment could be of more predictable for human clinical trial of beta-blocking agents. Sotalol was administered as a model drug to dogs, rats, and men. Dog experiments disclosed that the apparent volume of distribution of sotalol was about 4 times larger than the space of total body water and the plasma level of sotalol was 1.0-2.0 and 2.3-3.4 microgram/ml when the beta-blocking index showed 50 and 100% to the intravenous bolus injection of isoproterenol (0.1-1.0 microgram/kg). The clearance studies of dogs and men suggested that the elimination of sotalol depended essentially on renal excretion. The regression coefficient of beta-blocking index and plasma level of this agent in dog experiment using 0.1 microgram/kg isoproterenol was nearly equal to that of human study in which maximal exercise test was performed. Rat experiments showed a large apparent volume of distribution as well as in human study and high concentrations of sotalol in various tissues of rats. The plasma level of sotalol was well correlated with the content of the drug in such organs as heart, lung, liver, and kidneys.