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We conducted a survey of inquiries from the Pharmaceuticals and Medical Devices Agency (PMDA) for the 13 New Drug Applications (NDAs) submitted by Pfizer Japan Inc. in order to investigate their impact on the NDA review period. The results showed that PMDA raised an average of 130 inquiries (103–180) for nine new chemical entities (NCEs) and an average of 39 inquiries (28–59) for four products with line extensions (PLEs) for the time before and after the first interview meeting. The total number of inquiries received during the period between NDA submission and approval was on average 300 (167–432) for seven NCEs and 82 (53–123) for four PLEs. It was recognized that the NDA review period correlated with the total number of inquiries, the total number of inquiries with potentially high impact on approval (inquiries with high impact), and the frequency of inquiries including those with high impact, which were received during the period between NDA submission and approval. The survey results suggested the possibility that the approval timeline would be affected by these factors related to inquiries from PMDA.

The effect of glutathione (GSH) isopropyl ester on the progression of X-ray-induced cataract was investigated in rats. Intraperitoneal administration of 20 mg/kg GSH isopropyl ester, three times weekly, 1 day after a single irradiation dose delayed the progression of X-ray-induced cataracts significantly. The amount of non-protein SH groups and the Na+/K+ ratio in the lenses of drug-treated rats were maintained at the normal levels even 27 weeks after irradiation. Posttreatment with the drug resulted in a significantly lower level of malondialdehyde in the irradiated lenses than in the nontreated lenses. When 500 mg/kg GSH-isopropyl ester was administered by i.p. injection to normal rats, the GSH-ester was detected in plasma and aqueous humor after 15 min. In the lenses of the GSH-isopropyl ester-injected rats, the GSH level was 120% of that in the non-treated rats after 4 h, suggesting that GSH-isopropyl ester is transported from the aqueous humor to the lens and there converted to GSH after about 4 h. Our observations lead us to conclude that the delay of X-ray-induced lens opacity progression is due to maintenance of normal lenticular GSH levels achieved by post-irradiation administration of GSH-isopropyl ester. However, continuous administration of 100 mg/kg after irradiation had no effect on the progression of cataracts induced by X-rays.

The effect of 2-mercaptopropionylglycine on the development of cataract induced by a single dose of X-ray (10 Gy) was investigated in rats. Intraperitoneal injection of 20 mg/kg, three times weekly starting 1 day after irradiation delayed the development of X-ray-induced cataracts significantly. The amounts of non-protein SH groups, malondialdehyde and the Na+/K+ ratio, in the lenses of rats post-treated with the drug were significantly maintained at normal levels even at 27 weeks after irradiation. On the other hand, a single administration of 250 mg/kg of the compound, 30 min prior to irradiation had no effect on cataract progression induced by X-ray.

Sulphur-containing compounds in the lens were studied in relation to galactose cataract formation. Female Wistar rats were fed a 35% galactose diet and the changes in lens sulphur concentration and its distribution on a gel filtration column were compared with age-related changes. Concentration of sulphur in the whole lens decreased with time. A low constant level was attained on the fifth day of the galactose diet. A decrease of sulphur concentration in the soluble fraction of the lens paralleled that of the whole lens which was correlated with the decrease of glutathione and taurine concentrations on a gel filtration column by high-performance liquid chromatography-inductively coupled argon plasma atomic emission spectrometry (HPLC-ICP). Concentration of magnesium in the lens decreased after the fifth day, while the ratio of sodium to potassium increased. These changes in sulphur-containing compounds and metals were observed prior to the onset of cataract formation.

The effects of ivermectin (IVM) on cultured chick spinal neurons sensitive to GABA agonists were investigated. IVM caused a change of membrane potential which was associated with an increase in membrane conductance, apparently reversed at about −40 mV and weakened by repetitive application. Furthermore, this agent did not have any effects on either the actions of GABA agonists on neurons or [ 3 H]GABA efflux from those cells. These results suggest that IVM increases membrane conductance through sites which are different from GABA recognition sites.

Changes in lens proteins induced at the early stages of cataractogenesis in cac (Nakano) mice were investigated by two-dimensional gel electrophoresis (2D-PAGE). The 2D-PAGE profile of lens proteins in 21-day-old cac mice differed from that in 27-day-old normal mice, even though the appearance of 'pin-head' nuclear opacity (26-day-old) had not yet been observed in the lenses. Especially noticeable were great differences in the polypeptides associated with the alpha- and beta- crystallin subfractions, the appearances of which corresponded to an increase in a ratio of the amounts of Na+ to that of K+ in the lenses of defective mice. No dramatic decrease in the gamma-crystallin fraction was observed until the mature cataract stage.

1. 1. Ivermectin enhancement of [ 3 H]diazepam binding was abolished by pretreatment of membranes with 0.05% Triton X-100, whereas GABA-induced enhancement was not changed after this treatment. 2. 2. Ivermectin enhancement was neither affected by picrotoxinin nor dependent on the chloride ion. 3. 3. 4,4′-Diisothiocyano-2,2′-disulfonic acid stilbene (DIDS) dose-dependently reduced [ 3 H]diazepam binding enhanced by 10 −6 M ivermectin, without affecting the basal specific binding. 4. 4. The effects of DIDS were derived from reduction of increased binding affinity of benzodiazepine receptors by ivermectin, but were not dependent on chloride ion in the assay medium. 5. 5. DIDS inhibited GABA- and pentobarbital- but not chloride ion-induced enhancement of [ 3 H]diazepam binding.