Search

Background Alpha1-Proteinase Inhibitor, Modified Process (Alpha-1 MP) is used for augmentation therapy in alpha1-antitrypsin deficiency (AATD), an extremely rare disease in Japan. Weekly doses of 60 mg/kg Alpha-1 MP have been shown to be safe and well tolerated in non-Japanese subjects, but the safety and pharmacokinetics (PK) have not been evaluated in Japanese subjects. The objectives of this study were to evaluate the safety and PK of 60 mg/kg Alpha-1 MP administered by weekly IV infusions over 8 weeks in Japanese subjects with AATD. Methods This was a multicenter, open-label trial in Japanese adults aged ≥20 years with AATD. Samples for evaluation of serum alpha1-PI concentration and PK parameters were collected at 10 time points until the seventh day after the last dose at Week 8: immediately before dosing, immediately after dosing (time 0), and 0.25, 2, 4, 8, 24, 48, 120, and 168 hours after dosing. Results Four subjects were analyzed. The median tmax was 0.534 h. Mean ± SD values for t½, Cmax, and AUC0–7days were 150.4 ± 36.18 h, 174.2 ± 30.51 mg/dL, and 14,913.2 ± 1633.45 mg*h/dL, respectively. Mean trough concentration at week 8 was 55.4 ± 7.23 mg/dL. Alpha-1 MP therapy was safe, with no serious adverse events or deaths reported. Two treatment-emergent adverse events of fatigue in one subject were considered to be possibly related. Conclusions The PK and safety of Alpha-1 MP in Japanese subjects with AATD were consistent with the Alpha-1 MP profile in non-Japanese subjects (ClinicalTrials.gov: NCT02870309; JAPIC CTI: JapicCTI-163160).

Corrosion behavior of parent and weld materials of F82H and JPCA was studied in the circulating LBE loop under impinging flow. These are candidate materials for Japanese Accelerator Driven System (ADS) beam windows. Maximum temperatures were kept to 450 and 500 °C with 100 °C constant temperature difference. Main flow velocity was 0.4–0.6 m/s in every case. Oxygen concentration was controlled to 2–4 × 10−5 mass% although there was one exception. Testing time durations were 500–3000 h. Round bar type specimens were put in the circular tube of the loop. An electron beam weld in the middle of specimens was also studied. Optical microscopy, electron microscopy, X-ray element analyses and X-ray diffraction were used to investigate corrosion in these materials. Consequently corrosion depth and stability of those oxide layers were characterized based on the analyses. For a long-term behavior a linear law is recommended to predict corrosion in the ADS target design.

An enolate-like intermediate A derived from 1,2-dioxo-3-isopropyloxy-4-methyl-3-cyclobutene ( 6 ) has proven to be a novel nucleophilic synthon for an aldol condensation reaction with an arylaldehyde to give a variety of 4-hydroxy-2,3-dioxocyclobut-1-enyl group (Sq group)-containing cinnamic acid derivatives.

Olopatadine hydrochloride (olopatadine, 11-[(Z)-3-(dimethylamino)propylidene]-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid monohydrochloride) is a novel antiallergic/histamine H1-receptor antagonistic drug that was synthesized and evaluated in our laboratories. Oral administration of olopatadine at doses of 0.03 mg/kg or higher inhibited the symptoms of experimental allergic skin responses, rhinoconjunctivitis and bronchial asthma in sensitized guinea pigs and rats. Olopatadine is a selective histamine H1-receptor antagonist possessing inhibitory effects on the release of inflammatory lipid mediators such as leukotriene and thromboxane from human polymorphonuclear leukocytes and eosinophils. Olopatadine also inhibited the tachykininergic contraction in the guinea pig bronchi by prejunctional inhibition of peripheral sensory nerves. Olopatadine exerted no significant effects on action potential duration in isolated guinea pig ventricular myocytes, myocardium and human ether-a-go-go-related gene channel. Olopatadine was highly and rapidly absorbed in healthy human volunteers. The urinary excretion of olopatadine accounted for not less than 58% and the contribution of metabolism was considerably low in the clearance of olopatadine in humans. Olopatadine is one of the few renal clearance drugs in antiallergic drugs. Olopatadine was shown to be useful for the treatment of allergic rhinitis and chronic urticaria in double-blind clinical trials. Olopatadine was approved in Japan for the treatment of allergic rhinitis, chronic urticaria, eczema dermatitis, prurigo, pruritus cutaneous, psoriasis vulgaris and erythema exsudativum multiforme in December, 2000. Ophthalmic solution of olopatadine was also approved in the United States for the treatment of seasonal allergic conjunctivitis in December, 1996 (Appendix: also in the European Union, it was approved in February 2002).

We investigated whether the polycation poly-L-arginine elicited cutaneous vascular hyperpermeability and scratching behavior and, if so, whether these responses involved mast cells and sensory nerves in rats. Intradermal injections of poly-L-arginine induced vascular hyperpermeability and scratching behavior. Combined treatment with chlorpheniramine and methysergide almost completely suppressed the poly-L-arginine (50 microg/site)-induced plasma leakage. Capsaicin desensitization and the tachykinin NK(1) receptor antagonist LY303870, (R)-1-[N-(2-methoxybenzyl)acetylamino]-3-(1H-indol-3-yl)-2-[N-(2-(4-(piperidin-1-yl)piperidin-1-yl)acetyl)amino]propane, partially inhibited the leakage. In mast cell-deficient rats, poly-L-arginine only minimally induced plasma leakage. On the other hand, capsaicin desensitization and LY303870, but not chlorpheniramine or methysergide, suppressed the poly-L-arginine (200 microg/site)-induced scratching. Moreover, poly-L-arginine elicited the scratching even in mast cell-deficient rats. These results suggest that substance P is at least partly involved in both the cutaneous plasma leakage and the scratching behavior induced by poly-L-arginine. Moreover, mast cell-derived amines are suggested to be involved in the plasma extravasation but scarcely, if any, in the scratching behavior.

Olefination of dialkyl squarates 1–5 with several ylides 6 and phosphonates 7 gave the corresponding alkylidene products 8–12 . In the case of Horner-Emmons reactions, stereoselective formation of Z -alkylidene products was observed. An acid-catalyzed hydrolysis of 8–12 gave squarylacetic acid esters 13 .

In June, 1984, a large-scale outbreak of type A botulism occurred in 14 different prefectures in Japan, involving 36 cases and 11 deaths, due to consumption of vacuum-packed ‘karashi-renkon’ (deep-fried mustard-stuffed lotus root). The onset of symptoms ranged from June 9th through July 28th and many batches of ‘karashi-renkon’, having been manufactured by a factory during a period of three weeks from June 5th to June 25th, were found to be contaminated with type A spores. Type A spores (1.0 × 104 cfu/g) experimentally inoculated into the mustard-miso stuffing [water activity (aw) 0.92, pH 5.0, NaCl 5.7%] did not multiply. By adjusting the stuffing to aw 0.98 (pH 5.4) growth of type A was still inhibited. When the stuffing with elevated aw and pH was heat-treated for 60 min at 80°C or autoclaved, it supported growth of Clostridium botulinum type A as indicated by the achievement of toxin levels higher than 105 LD50/g. When mustard-miso was stuffed into the holes of lotus roots and refrigerated overnight or a longer period, both aw and pH of the stuffing increased to 0.98 and 5.3, respectively. The changes were apparently due to dialysis between the stuffing and the lotus root. This refrigeration process was actually performed at the plant, where the incriminated foodstuff was manufactured. The dialyzed mustard-miso stuffing, when heat-treated, supported the growth of type A organisms. Thus, we substantiated the possibility of primary multiplication of C. botulinum type A in mustard-miso stuffing subjected to refrigeration in lotus roots and then heat-treated.