Inhibitory effect of rhetsinine isolated from Evodia rutaecarpa on aldose reductase activity.

Aldose reductase inhibitors have considerable potential for the treatment of diabetic complications, without increased risk of hypoglycemia. Search for components inhibiting aldose reductase led to the discovery of active compounds contained in Evodia rutaecarpa Bentham (Rutaceae), which is the one of the component of Kampo-herbal medicine. The hot water extract from the E. rutaecarpa was subjected to distribution or gel filtration chromatography to give an active compound, N2-(2-methylaminobenzoyl)tetrahydro-1H-pyrido[3,4-b]indol-1-one (rhetsinine). It inhibited aldose reductase with IC(50) values of 24.1 microM. Furthermore, rhetsinine inhibited sorbitol accumulation by 79.3% at 100 microM. These results suggested that the E. rutaecarpa derived component, rhetsinine, would be potentially useful in the treatment of diabetic complications.

Thalamic asymmetry on interictal SPECT in patients with frontal lobe epilepsy.

BACKGROUND: Interictal brain single photon emission computed tomography (SPECT) is useful for the detection of seizure focus. Recent reports indicate a hypoperfusion in the ipsilateral thalamus as a seizure focus on interictal SPECT in temporal lobe epilepsy. In frontal lobe epilepsy (FLE), however, the alteration of perfusion in the thalamus has not been well documented. This study aimed to assess whether perfusion analysis on the thalamus may add useful information for the detection of epileptic foci in patients with FLE. METHODS: Interictal brain SPECT was performed in 11 patients with FLE. The asymmetry index for the thalamus and frontal area in the SPECT image was calculated in order to compare the laterality of the seizure foci. RESULTS: Thalamic asymmetry was seen in seven patients (64%), while cortial asymmetry was seen in six patients (55%). The concordance with the lateralization of the seizure foci was 6/7 (86%) in the thalamus, and 4/6 (67%) in the frontal area. Four patients showed only thalamic asymmetry. Concordance with the lateralization of the seizure focus was found in all of them. CONCLUSION: These preliminary results suggest that hypoperfusion in the thalamus may have a complementary role to lateralize the epileptic foci in patients with FLE.

Pharmacokinetics of a Chinese traditional medicine, danshensu (3,4-dihydroxyphenyllactic acid), in rabbits using high-performance liquid chromatography.

An injectable solution of Danshen was prepared and its in vivo disposition was examined in rabbits. The presence of Danshensu, one of the active components of Danshen, in the obtained solution was confirmed by a simple high-performance liquid chromatographic (HPLC) method. The pharmacokinetics of Danshensu in rabbits was evaluated by the HPLC method for plasma Danshensu. The calibration curve for Danshensu was linear (r = 0.998) over the concentration range of 0.25-40.0 micrograms/ml. The intra-assay coefficients of variation (CVs) were 3.8, 3.1, and 3.1% at 1, 10, and 50 micrograms/ml, respectively, and the inter-assay CVs were 5.3, 5.3, and 2.9% at 1, 10, and 50 micrograms/ml, respectively. The analytical recovery of Danshensu in plasma averaged 95.2%. From the plasma concentration profile of Danshensu after its intravenous administration, the t1/2, mean residence time (MRT), Vdss, and Cltot were determined as 32 min, 48 min, 149 ml/kg, and 3.13 ml/min/kg, respectively.

Preparation and characterization of dextran magnetite-incorporated thermosensitive liposomes: an on-line flow system for quantifying magnetic responsiveness.

PURPOSE: Dextran magnetite (DM)-incorporated thermosensitive liposomes, namely thermosensitive magnetoliposomes (TMs), were prepared and characterized in order to investigate their possibility for magnetic drug targeting. METHODS: TMs containing calcein were prepared at various DM concentrations by reverse-phase evaporation of dipalmitoylphosphatidylcholine (DPPC). They were evaluated for their physicochemical properties including size, DM capture, magnetite distribution within liposomes, and temperature-dependent calcein release. Moreover, a novel on-line flow apparatus with a sample injector, a coil of tubing placed in an electromagnet, and a fluorescence detector was developed for quantifying the magnetic responsiveness of TMs. This device allowed us a real-time measurement of percentage holding of TMs by magnetic field. RESULTS: Due to water-soluble property of DM, higher contents of magnetite up to 490 mg per mmol DPPC were successfully incorporated into the liposomes with DM than with conventional magnetite (Fe3O4). Thermosensitivity and lipid integrity of TMs were not influenced by inclusion of DM. Using the on-line flow system, percentage holding of TMs by magnetic field was shown to vary with several factors; it increases as the magnetic field strength increases, the fluid flow rate decreases, the magnetite content increases, and the liposome concentration increases. Typically, at 490 mg incorporated magnetite per mmol DPPC, 0.5 ml/min-fluid flow rate, and high magnetic field strength (> or = 10 kiloGauss), approximately 100% of TMs were found to be held. CONCLUSIONS: The TMs were suggested to be useful in future cancer treatment by magnetic targeting combined with drug release in response to hyperthermia.

Enhancement of the intestinal absorption of a cyclosporine derivative by milk fat globule membrane.

A cyclosporine derivative, dihydrocyclosporine D, was used for the evaluation of milk fat globule membrane (MFGM) as an emulsifier of lipophilic cyclopeptides. As compared with olive oil formulation, MFGM emulsion significantly enhanced the blood and lymphatic fluid concentrations of the cyclosporine derivative after intraduodenal dosing in rats. Thus, it was suggested that MFGM can be used as an intestinal absorption enhancer of cyclosporines.

Pharmacological studies on a new dihydrothienopyridine calcium antagonist. 4th communication: prophylactic and therapeutic effects of S-(+)-methyl-4,7-dihydro-3-isobutyl-6-methyl-4-(3-nitrophenyl)thieno[2, 3- b]pyridine-5-carboxylate in stroke-prone spontaneously hypertensive rats.

The prophylactic and therapeutic effects of S-312-d (S-(+)-methyl-4,7-dihydro-3-isobutyl-6-methyl-4-(3-nitrophenyl)thieno[2, 3- b]pyridine-5-carboxylate, CAS 120056-57-7) were compared with those of nimodipine or nicardipine using male stroke-prone spontaneously hypertensive rats (SHRSP). The survival rate of SHRSP was dose-dependently increased by once a day oral administration of S-312-d (0.3, 1, and 3 mg/kg) or nimodipine (10 mg/kg), while all non-treated SHRSP fed with high Na+ diet died within 40 days after the start of the experiment. All SHRSP treated with 3 mg/kg S-312-d survived during the 60-day experiment periods. Marked decreases of body weights and various neurological symptoms were also inhibited with S-312-d or nimodipine. Moderate diuretic effects were observed with S-312-d at doses of 1 and 3 mg/kg. The appearance of urinary occult blood in control SHRSP was markedly inhibited with S-312-d at 1 mg/kg and nimodipine at 10 mg/kg. Histological examination of the brain of SHRSP showed that cerebral stroke lesion including edema, hemorrhage, and/or softening was dose-dependently inhibited with S-312-d. Once a day oral administration of S-312-d (1, 3, or 10 mg/kg) dose-dependently increased the body weights and improved the neurological symptoms of diseased SHRSP. The appearance of proteinuria and of occult blood in the urine of SHRSP were also markedly inhibited with S-312-d or nicardipine. Histological examination of the brain of SHRSP showed that the arbitrary neurotoxic index (ANI) for stroke lesion dose-dependently decreased with S-312-d at 1, 3, and 10 mg/kg as follows: 4.8, 3.0, 2.3. The ANI for non-treated SHRSP was 7.6. The therapeutic effects of nicardipine (ANI 3.9) at 10 mg/kg corresponded to those of S-312-d at 3 mg/kg. Thus, S-312-d can be recommended for the treatment of cerebral insufficiency or vasospasm following stroke as well as in essential hypertension.

[Role of supporting therapy of Juzentaiho-to (JTT) in advanced breast cancer patients].

The patients were randomized with the envelope method, dividing into either A- or B-group. A-group was treated with JTT combined with chemoendocrine therapy. B-group was treated with only chemo-endocrine therapy. Between May 1985 and December 1987, 130 pts were used for this trial, 119 pts were evaluable, and 58 pts belonged to A-group and 61 to B-group. The pts characteristics were well balanced in both those groups. There was no significant difference in the response rates between A- and B-groups. The survival rate up to 38 months was not significantly different between the two groups, but in JTT-SHO group, the survival was significantly higher in the pts belonging to the A-group (Greenwood, p less than 0.05). The quality of life (QOL) was expressed as self-assessment scores for physical condition, appetite and the coldness of extremities. It improved significantly in A-group, especially, by prevention of bone marrow suppression by chemotherapy. It was concluded that treatment with JTT is better than without JTT in treatment for advanced breast cancer patients.

Production of immunoreactive pancreatic growth hormone-releasing factor in small cell carcinoma of the lung.

A specific and sensitive radioimmunoassay for human pancreatic growth hormone-releasing factor (hpGRF) was developed. Using this radioimmunoassay, it was found that immunoreactive hpGRF (which is present in hypothalamic tissues) of at least two different molecular sizes is often produced by small cell carcinoma of the lung.