[Effect of background factors concerning both elderly persons and their families with regard to the caregiver burnout in the home].

A cross sectional survey was performed to quantify factors that exhaust caregivers. We report that the degree of difficulty for caregivers correlated well with the burnout score (r = -0.517; p < 0.001), but the correlation between caregivers' burnout score and the level of their patient's basic ADL was lower (r = -0.317; p = 0.014). In this paper, we investigated other factors related to exhaustion. Caregivers' burnout score correlated with their age. The level of disease that caregivers complained increased burnout score. The need for nocturnal care and continuous observation, as well as rejection of aid burned out caregivers. Multiple regression analysis clarified that significant independent contributing factors for burnout score were help with toilet use, nocturnal aid and diseases suffered by caregivers.

Histamine release induced by antimicrobial agents and effects of antimicrobial agents on vancomycin-induced histamine release from rat peritoneal mast cells.

Vancomycin and certain fungicides may cause anaphylactoid reactions. We investigated the effects of vancomycin, miconazole and fluconazole on histamine release in rat peritoneal mast cells. Vancomycin and miconazole provoked histamine release in a dose-dependent manner. In contrast, fluconazole did not provoke histamine release at concentrations of 3 x 10(-6)-3 x 10(-3) M. Vancomycin is efficacious in the treatment of gram-positive bacterial infections; patients presenting themselves with mixed infections require concomitant therapy with a second antimicrobial agent. We investigated the effect of fosfomycin sodium, cilastatin sodium or fluconazole on vancomycin-induced histamine release. Fosfomycin sodium inhibited vancomycin-induced histamine release but neither cilastatin sodium nor fluconazole inhibited it in the mole ratios of daily doses used in humans. These results suggest that vancomycin and miconazole provoke histamine release in rat mast cells, but that fluconazole probably does not, while fosfomycin sodium may inhibit vancomycin-induced histamine release.

Effects of MS-31-038, a novel Na(+)-H+ exchange inhibitor, on the myocardial infarct size in rats after postischemic administration.

The abilities of 2-(2-methylphenyl)-5,7-dimethoxy-4-quinolyl carbonylguanidine dihydrochloride (CAS 181048-29-3, MS-31-050) and 2-phenyl-8-(2-methoxyethoxy)-4-quinolyl carbonylguanidine bismethanesulfonate (CAS 181048-36-2, MS-31-038) in inhibiting Na(+)-H+ exchange, ischemia- and reperfusion-induced injury were determined and compared with those of 4-isopropyl-3-methylsulfonylbenzoyl guanidine methanesulfonate (CAS 159138-81-5, IMGM), a selective inhibitor of Na(+)-H+ exchange. MS-31-050 and IMGM exhibited comparable inhibitory effects on Na(+)-dependent pH recovery and antiarrhythmic effects during ischemia in anesthetized rats. In rats subjected to ischemia and reperfusion, MS-31-050 (10 mg/kg i.v.) significantly reduced the infarct size when given prior to the onset of ischemia. However, postischemic treatment with either MS-31-050 or IMGM failed to protect reperfused hearts. In contrast, MS-31-038 reduced the infarct size dramatically from 65.4 +/- 7.4% in control to 29.9 +/- 11.6% at 3 mg/kg and 9.8 +/- 3.4% at 10 mg/kg even when administered before the onset of reperfusion. These results suggest the beneficial effects of Na(+)-H+ exchange inhibitors on myocardial ischemia/reperfusion injury.

Antiaggregatory, antithrombotic effects of MS-180, a novel platelet glycoprotein IIb/IIIa receptor antagonist.

The antiaggregatory and antithrombotic effects of (S)-(-)-ethyl[6-[4-(morpholinoformimidoyl)benzamido]-3,4-dihydro-2 H-1-benzo-pyran-3-yl]acetate hydrochloride (MS-180), a novel platelet glycoprotein IIb/IIIa receptor antagonist, were investigated. Ma-HCl, (S)-(-)-[6-[4-(Morpholinoformimidoyl)benzamido]-3,4-dihydro-2H-1-b enzopyran-3-yl]acetic acid hydrochloride, the hydrochloride salt of Ma (active metabolite), inhibited the binding of fibrinogen to immobilized human glycoprotein IIb/III receptor with an IC50 value of 0.12+/-0.03 nM without affecting binding to either fibronectin or vitronectin receptors. In anesthetized guinea pigs, intraduodenal administration of MS-180 caused dose-dependent inhibition of both ADP- and collagen-induced ex vivo platelet aggregation. At the same dosages, occluded thrombus formation and platelet release reactions were also markedly suppressed. In anesthetized dogs, the bleeding time was prolonged slightly even when submaximal inhibition (< 90%) of ex vivo platelet aggregation was achieved following i.v. administration of Ma-HCl. Aspirin (100 mg/kg) prolonged the bleeding time to the same extent as MS-180 (1 mg/kg), although it suppressed only collagen-induced platelet aggregation. Therefore, MS-180 may be clinically useful for the treatment of thrombotic diseases.

Nephrotoxicity of vancomycin and drug interaction study with cilastatin in rabbits.

The nephrotoxic effects of vancomycin hydrochloride (VCM) and the potential drug-drug interaction with cilastatin sodium (CS) were examined in rabbits. The aim of the study was to measure the possible dose-related suppressive effects or elimination by cilastatin of the adverse reactions generated by vancomycin in the kidneys of rabbits. To clarify the interactions of these two drugs, we examined the nephrotoxicity and pharmacokinetics of VCM in the rabbit when administered alone and when coadministered with CS. VCM administered alone (300 mg/kg of body weight as an intravenous bolus; n = 5) caused typical symptoms of nephrotoxicity, such as increases in serum creatinine and blood urea nitrogen (BUN) levels, as well as morphological changes in the kidneys. A lack of such signs of nephrotoxicity was observed in the groups administered VCM plus CS (i.e., CS at 150 mg/kg plus VCM at 300 mg/kg or CS at 300 mg/kg plus VCM at 300 mg/kg, intravenous bolus; n = 5/group). At a reduced combination ratio of VCM plus CS (4:1 ratio, VCM at 300 mg/kg plus CS at 75 mg/kg, intravenous bolus; n = 5) some symptoms of nephrotoxicity induced by VCM were present, but the degree of this effect was much reduced and was significantly different from preadministration values by only modest increases of the BUN and N-acetyl-beta-D-glucosaminidase levels (P < 0.05). Overall clearance of VCM was accelerated by coadministration of CS and was found to be dose dependent upon CS. No changes in renal function values from the preadministration values were observed for animals receiving CS alone (300 mg/kg, intravenous bolus; n = 3). These results suggest that CS has the ability to reduce or eliminate in a dose-dependent manner the nephrotoxic effects caused by VCM administration in rabbits.

[Effects of plasma albumin on theophylline concentration in lung tissue].

To study the relationship between plasma and lung tissue theophylline concentrations, we changed the number of binding sites for theophylline on serum albumin. Cefazoline, which competes with theophylline for those binding sites, was given to rats, and free theophylline was separated by ultrafiltration. The dose of cefazoline was directly related to the percentage of free theophylline and was inversely related to the plasma total theophylline concentration. The plasma free theophylline concentration, however, was unchanged at the lower doses of cefazoline and was low only at the highest dose. The concentration of theophylline in lung tissue was inversely related to the dose of cefazoline. The concentration of 1, 3-dimethyluric acid, a major metabolite of theophylline, was also inversely related to the dose of cefazoline, which suggests that the metabolic rate of theophylline did not increase. Excretion of theophylline via the urine might be accelerated by its diuretic action. We conclude that when the binding of theophylline to plasma proteins is altered in rats, the concentration of free theophylline in plasma does not reflect the concentration of theophylline in lung tissue. Instead, the total theophylline concentration in plasma can be used as an index of the concentration in lung tissue.

[Effect of serum albumin concentration on percentage of free theophylline fraction].

The authors experienced three cases in which serum free theophylline concentrations (F) rose with unchanged or decreased serum total theophylline concentrations (T). To clarify the causes of changes in F or T within a short time, we studied the relationship between F and serum albumin concentration or T in patients, and the relationship between T and F using aminophylline alone or aminophylline and cefazoline (CEZ) in rabbits. In patients, the fraction of free theophylline (F/T) showed a reverse relation to the serum albumin concentration, and a positive relation to T. In rabbits, when aminophylline was injected with CEZ, F/T increased in proportion to the dose of CEZ and T decreased when aminophylline alone was injected. The data suggested that F/T increased accompanied with decreasing serum albumin concentration or increasing T, since the albumin binding-site of theophylline is limited. The present study also suggested that the protein-bound theophylline decreased in competition with CEZ, therefore F/T increased when aminophylline was injected with CEZ. It is likely that decreased T is a result of augmented movement of theophylline to the tissue due to decreased serum albumin concentration. To evaluate the clinical conditions of the patients taking theophylline, it is necessary to directly monitor F, or to measure serum albumin concentration if direct measurement of F is not possible.

Elevations of cathepsin B and cathepsin L activities in forelimb and hind limb muscles of genetically dystrophic mice.

The combined activities of cathepsin B and cathepsin L were studied in the forelimb and hind limb muscles of dystrophic mice. The activities of these proteases in the forelimb and hind limb muscles of young and adult dystrophic mice were significantly higher than those in normal mice. However, clinical involvement of dystrophy appeared in the hind limbs but not in the forelimbs. We therefore suggest that the increase in protease activity begins at a very early age and that the clinical involvement is not linked with the increase in cathepsin B and L.

Beneficial effect of new thiol protease inhibitors, epoxide derivatives, on dystrophic mice.

We studied the effect of E-64, a new thiol protease inhibitor derived from Aspergillus japonicus TPR-64, and of its synthesized analogue, E-64-d, on dystrophic mice (C57BL/6J-dy). The locomotor activity of normal mice increased markedly, reaching a plateau at 8 weeks of age. In dystrophic mice, it increased until they were 7 weeks old, thereafter, it decreased gradually. This decrease reflected the degradation of the hind legs. Serum activities of creatine phosphokinase were significantly greater in dystrophic than in normal mice. When 3-week-old dystrophic mice were injected with E-64 (1 mg/kg, i.p.) or E-64-d (40 to 60 mg/kg, p.o.), the decrease in their locomotor activity was retarded and their serum enzyme activities decreased significantly. In addition, the survival time of treated dystrophic mice was prolonged. The locomotor activity of normal mice and their serum enzyme levels were not affected by the administration of E-64-d. We posit that the new thiol protease inhibitors we tested retard the progression of dystrophy in mice.

Creatine kinase isoenzyme of high relative molecular mass in serum of a cancer patient.

We describe an atypical serum creatine kinase isoenzyme in the serum of a woman with cancer of the left breast. This isoenzyme migrated toward the cathode, closely following the MM isoenzyme on agarose gel electrophoresis. Its relative molecular mass was estimated to be about 325,000, fourfold that of normal creatine kinase. It is more heat-stable and is inhibited more by urea than the normal MM isoenzyme. Isoenzyme monomer B activity was observed to be 20 U/liter in the serum, as measured with use of an antibody against the M monomer. On anion-exchange column analysis, creatine kinase activity was observed only in the MM fraction, in spite of the fact that B activity was observed in the patient's serum. Results of the immunological investigation make it unlikely that the atypical isoenzyme is linked to immunoglobulin or beta-lipoprotein. It may have been present as the result of modification of normal creatine kinase by the therapeutic radiation the patient was receiving.