Increased plasma drug concentration and decreased additional insulin secretion following oral administration of glimepiride in Spontaneously Diabetic Torii rats.

We aimed to evaluate the pharmacokinetics and pharmacological effects of glimepiride in the Spontaneously Diabetic Torii (SDT) rat, which is a non-obese model of type 2 diabetes. After oral administration of glimepiride (10 mg/kg), the maximum plasma concentrations and the area under the curve from 0 to 6 h of glimepiride in SDT rats were significantly higher than those in age-matched Sprague-Dawley rats. Whereas, additional insulin secretion following glimepiride treatment was markedly reduced in SDT rats. Thus, the SDT rat can be regarded as a model that reflects type 2 diabetes with reduced insulin secretory capacity. Our findings suggested that glimepiride could be ineffective in sever type 2 diabetic patients.

Simultaneous LC-MS analysis of plasma concentrations of sildenafil, tadalafil, bosentan, ambrisentan, and macitentan in patients with pulmonary arterial hypertension.

Phosphodiesterase-5 (PDE-5) inhibitors and endothelin receptor antagonists (ERAs) are standard therapies for pulmonary arterial hypertension (PAH). The inter-individual variability of these pharmacokinetics is reported remarkably large, and therapeutic drug monitoring (TDM) can be useful to improve the likelihood of the desired therapeutic and safety outcomes. This study aimed to develop a LC-MS method to determine the concentrations of five PAH drugs (PDE-5 inhibitors: sildenafil and tadalafil, ERAs: bosentan, macitentan, and ambrisentan) from plasma samples using a simple process followed by a single mass spectrometric run, and to validate this approach through pharmacokinetic analyses in patients. A solid extraction method was used for sample preparation of the drugs from human plasma. The total run time for a single injection was within 10 min. The calibration curves for all drugs were linear, and the lower limits of quantitation were 1 (sildenafil), 2 (tadalafil), 5 (ambrisentan), and 10 ng/mL (bosentan, macitentan). The accuracy and precision values suggested that the assay had high accuracy and reliability. To prove the utility of this method, the plasma concentrations of the five PAH drugs were determined after their oral administration to nine PAH patients.

Hayabusa2 arrives at the carbonaceous asteroid 162173 Ryugu-A spinning top-shaped rubble pile.

The Hayabusa2 spacecraft arrived at the near-Earth carbonaceous asteroid 162173 Ryugu in 2018. We present Hayabusa2 observations of Ryugu's shape, mass, and geomorphology. Ryugu has an oblate "spinning top" shape, with a prominent circular equatorial ridge. Its bulk density, 1.19 ± 0.02 grams per cubic centimeter, indicates a high-porosity (>50%) interior. Large surface boulders suggest a rubble-pile structure. Surface slope analysis shows Ryugu's shape may have been produced from having once spun at twice the current rate. Coupled with the observed global material homogeneity, this suggests that Ryugu was reshaped by centrifugally induced deformation during a period of rapid rotation. From these remote-sensing investigations, we identified a suitable sample collection site on the equatorial ridge.

The geomorphology, color, and thermal properties of Ryugu: Implications for parent-body processes.

The near-Earth carbonaceous asteroid 162173 Ryugu is thought to have been produced from a parent body that contained water ice and organic molecules. The Hayabusa2 spacecraft has obtained global multicolor images of Ryugu. Geomorphological features present include a circum-equatorial ridge, east-west dichotomy, high boulder abundances across the entire surface, and impact craters. Age estimates from the craters indicate a resurfacing age of [Formula: see text] years for the top 1-meter layer. Ryugu is among the darkest known bodies in the Solar System. The high abundance and spectral properties of boulders are consistent with moderately dehydrated materials, analogous to thermally metamorphosed meteorites found on Earth. The general uniformity in color across Ryugu's surface supports partial dehydration due to internal heating of the asteroid's parent body.

Chronological effects of rifampicin discontinuation on cytochrome P450 activity in healthy Japanese volunteers, using the cocktail method.

Cytochrome P450 (CYP) 1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A are major factors involved in the metabolism of clinically prescribed drugs. Because the time course after drug treatment discontinuation has received little attention, we aimed to clarify the chronological changes of rifampicin-induced CYP enzyme activities after rifampicin discontinuation. Thirteen volunteers took 450 mg of rifampicin once daily, and the cocktail method, which uses caffeine, losartan, omeprazole, dextromethorphan, and midazolam as CYP-specific probes, was repeatedly used for the evaluation of CYP levels. Concentrations of probes and metabolites were determined by liquid chromatography-tandem mass spectrometry. Seven-day rifampicin administration increased CYP2C19 and CYP3A enzyme activities. The induced CYP2C19 and CYP3A activities remained elevated at 4 days after rifampicin discontinuation and returned to baseline levels 8 days after rifampicin discontinuation. CYP1A2 and CYP2D6 enzyme activities showed no significant changes, and CYP2C9 enzyme activity was increased with rifampicin administration, with a tendency toward statistical significance. Drug interactions can occur even after rifampicin discontinuation.

Graphical comparison of coronary arterial culprit lesions in acute myocardial infarction and unstable angina pectoris.

OBJECTIVE: The culprit lesion morphology at acute myocardial infarction (AMI) and unstable angina pectoris (UAP) was investigated by observing the responsible vessels through intravascular ultrasound (IVUS) during the acute stage. METHODS: As the subjects of study, 54 lesions of 54 ACS patients (26 in AMI patients, 28 in UAP patients) were enrolled prospectively from June 1994 to June 1998. The appearance of plaque in the lesion, the distal and proximal sites, extent of calcification, eccentricity, remodeling and shrinkage were observed through IVUS before the intervention. RESULTS: At lesion and distal site, significantly more soft plaques were observed in AMI than UAP. As to the extent of calcification in the former, mild calcification was noted significantly more in distal site as well as a tendency of more mild calcification in the lesion and proximal site. CONCLUSION: These results suggested that the condition of responsible coronary artery is involved in the onset mechanism of AMI and UAP.

Studies on development of dosage forms for pediatric use (V) oral mucosal irritation study of gummi drugs in hamster cheek pouch.

In the present study we investigated irritation of the oral mucosa and the safety of gummi drugs containing acetaminophen (AAP). The oral mucosae of hamsters were macroscopically examined for any evidence of irritation after gummi drugs were inserted into the cheek pouch and left there for 1 h. The cheek pouch tissue was also macroscopically and microscopically examined 24 h after gummi drugs were withdrawn from the cheek pouch. As a result, no evidence of irritation was found macroscopically 1 h after insertion, or macroscopically and microscopically 24 h after the withdrawal of the gummi drugs or placebos as compared with negative controls (saline). Considering these results, the gummi drugs administered in the present study produced no irritation to the oral mucosa.

Impact crater densities on volcanoes and coronae on venus: implications for volcanic resurfacing.

The density of impact craters on large volcanoes on Venus is half the average crater density for the planet. The crater density on some classes of coronae is not significantly different from the global average density, but coronae with extensive associated volcanic deposits have lower crater densities. These results are inconsistent with both single-age and steady-state models for global resurfacing and suggest that volcanoes and coronae with associated volcanism have been active on Venus over the last 500 million years.

Studies on improvement of pharmaceutical preparations prescribed in hospitals. VI. Oxaprozin nasal spray.

Many nasal sprays used in the treatment of rhinitis contain a steroidal agent, giving rise to fear of side effects when they are used frequently and continually. Accordingly, we undertook the development of a nasal spray containing oxaprozin, a nonsteroidal anti-inflammatory agent. Suitable discharge pressure and surfactants were determined by applying trial aerosols to human subjects in "feeling" tests to assess approval rating. Other tests showed that about 80% of the expelled oxaprozin was released into the nasal cavity, and that the chosen formulation caused only a low level of irritation to the nasal mucosa. Most of the aerosol particles were found to adhere to Kiesselbach's area and the frontal region of the inferior concha, which are the major areas where inflammation and nasal haemorrhage occur. When the nasal spray was administered to 50 patients, a sufficient therapeutic effect was achieved, especially in the treatment of nasal haemorrhage, and side effects have not yet been detected.

Studies on improvement of pharmaceutical preparations prescribed in hospitals. IV. Dibekacin sulfate viscous solution for treatment of mouth and throat wounds.

For the purpose of preventing suppuration of wounds of the oral cavity and throat, we attempted to develop a viscous solution of dibekacin sulfate (DKB) as a suitable medication. Solutions of different viscosity and antibacterial potency were prepared by mixing DKB, sodium carboxymethyl cellulose (CMC-Na), and water in varying proportions. Studies were then performed to ascertain relationships between the concentration of CMC-Na pH and viscosity, and between the viscosity and diffusion of DKB. The concentration of CMC-Na giving rise to optimal clinical efficacy was determined, and the concentration of DKB necessary for clinical treatment was estimated on the basis of the ionic binding constant between DKB and CMC-Na. As a result, the optimum CMC-Na concentration was found to be 2%, while the optimum DKB concentration was estimated to be 100 micrograms/ml.

Studies on improvement of pharmaceutical preparations prescribed in hospitals. V. Nifedipine hollow type suppository.

Nifedipine is a calcium antagonist used for the treatment of hypertension and angina pectoris. However, commercial nifedipine preparations are only available in forms suitable for oral administration, e.g. soft capsules and tablets. Therefore, we developed a suppository form in which the drug was incorporated into a hollow type suppository. The suppository preparation was administered to humans for evaluation of the clinical and commercial usefulness. It was as fast-acting as the soft capsule, but the blood concentration of nifedipine immediately after administration was lower than that seen with the soft capsule. It was considered to be superior to the soft capsule and similar to the tablet in terms of its long-acting effect. Thus, the hollow type suppository form of nifedipine should have useful clinical applications.

Studies on improvement of pharmaceutical preparations prescribed in hospitals. II: Study on pharmaceutical manufacturing of dibekacin sulfate gauze tampon.

A gauze tampon, which contains an ointment incorporating dibekacin sulfate, was prepared and investigated as a device to prevent bacterial infection after operation of chronic sinusitis. It was proved that no loss of potency occurred upon heat sterilization and that it was stable even after storage for a long period. This gauze tampon was easy to insert into the paranasal sinuses, achieving satisfactory therapeutic efficacy in terms of hemostasis and disinfection. No adverse reactions have been observed.