A Pharmacokinetic/Pharmacodynamic Drug-Drug Interaction Study of Tofogliflozin (a New SGLT2 Inhibitor) and Selected Anti-Type 2 Diabetes Mellitus Drugs.

OBJECTIVE: Tofogliflozin is an oral hypoglycemic agent with a novel mechanism of action that reduces blood glucose levels by promoting glucose excretion in urine, achieved by selectively inhibiting sodium-glucose co-transporter 2 (SGLT2). We evaluated the effects of several selected anti-type 2 diabetes mellitus (T2DM) drugs-glimepiride, metformin, sitagliptin, pioglitazone, miglitol, nateglinide, and voglibose-on the pharmacokinetics and pharmacodynamics of tofogliflozin, and the effects of tofogliflozin on the pharmacokinetics of these anti-T2DM drugs in healthy male volunteers. METHODS: A single dose of either tofogliflozin alone, one of the anti-T2DM drugs alone, or co-administration of tofogliflozin and the anti-T2DM drug was administered to 108 healthy men. Cmax, AUCinf, and cumulative urine glucose excretion after co-administration of tofogliflozin and each of the anti-T2DM drugs was evaluated relative to the values of those parameters after administration of each drug alone. RESULTS: None of the anti-T2DM drugs had any effect on tofogliflozin exposure. Tofogliflozin had no or little effect on the exposure of any anti-T2DM drug. No anti-T2DM drug had any major effect on the cumulative urine glucose excretion induced by tofogliflozin. There were no safety concerns evident after administration of any drug alone or in co-administration. CONCLUSIONS: Neither the pharmacokinetics nor the pharmacodynamics of tofogliflozin was affected by any of the anti-T2DM drugs evaluated in this study, nor was the pharmacokinetics of any of the anti-T2DM drugs affected by tofogliflozin in healthy male volunteers.

East-West development: understanding the usability and acceptance of foreign data in Japan.

The introduction in Japan of New GCP regulations, as well as the internationalization of clinical trials under the ICH process (International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use), has meant that the system is now faced with a number of serious challenges. This is shown by the dramatic decrease in registration of new drugs. Identifying the actors in the new context is essential. We shall first define precisely what is the Regulatory Authority in Japan, and which are the Regulatory Requirements to be fulfilled. We shall then describe the new process for evaluation of foreign clinical data. One of the major issues will be to determine in which cases a complete clinical data package will be sufficient to support regulatory submission, and in which cases additional clinical studies or bridging studies, and what kind of bridging studies will be required.

Effects of morphine, naloxone, buprenorphine, butorphanol, haloperidol and imipramine on morphine withdrawal signs in cynomolgus monkeys.

This study was conducted to characterize the opiate dependence potential of a number of opiate and non-opiate psychoactive drugs in morphine-dependent cynomolgus monkeys (Macaca fascicularis). In addition, the agonist/antagonist profiles of buprenorphine and butorphanol were directly compared. Six male cynomolgus monkeys were maintained on morphine (3.0 mg/kg, q.i.d.) for 6 months. On evaluation days, monkeys were scored for opiate withdrawal signs 18 h after the last dose of morphine. Single dose suppression studies were conducted by giving subcutaneous injections of morphine (3 or 6 mg/kg), naloxone (0.01, 0.05 or 0.1 mg/kg), buprenorphine (1, 3, 10, 30 or 100 micrograms/kg), butorphanol (0.01, 0.1, 1.0 or 3.2 mg/kg), haloperidol (0.01, 0.05 or 0.1 mg/kg), imipramine (2, 5 or 10 mg/kg) or saline and measuring the number and frequency of withdrawal signs that appeared over a 2-h period. In a separate precipitation experiment either saline or 0.01 or 0.1 mg/kg butorphanol was administered 2 h after the last maintenance dose of morphine. In the single dose suppression test, morphine completely suppressed most withdrawal signs while naloxone increased the severity of withdrawal. All doses of buprenorphine increased many withdrawal signs such as backward gait, rearing, chafing face, chain biting, vomiting, masturbation, and vocalizations after intimidation. Only a few signs were reduced, but the overall withdrawal scores were not significantly increased. Low doses of butorphanol suppressed some signs while the highest dose almost completely eliminated all withdrawal signs. Butorphanol also failed to precipitate opiate withdrawal, and actually reversed the signs present in the saline-treated monkeys. Imipramine and haloperidol had little effect on the morphine withdrawal syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)

[A study of children with cerebral palsy who were born between 1977 and 1985 in Kyoto City; a report from an institution for handicapped children].

First, we longitudinally analyzed 177 cerebral-palsied children (CP) who were born in Kyoto City between 1977 and 1985. They were all visited St. Joseph Hospital for Crippled Children in Kyoto during the period 1977 to 1991 in order to investigate the relationship between the prognosis of perinatal care and the changing panorama of CP in Kyoto. The average occurrence rate of CP per 1,000 live birth during the 9 years in Kyoto was 1.12. 177 CP were divided into 3 groups according to their birth years: 1977-1979 (47 CP); 1980-1982 (62 CP); and 1983-1985 (68 CP). Then we compared the distribution of birthweights and gestational periods among the 3 groups. We found a significant increasing trend in the percentage of CP in babies with birthweight less than 2,000 g. Second, we examined 162 CP; 15 born outside of Kyoto were excluded because of extraneous influences of perinatal care. 162 were divided into 3 groups according to their birth years: 1977-1979 (44); 1980-1982 (56); and 1983-1985 (62). We also compared the risk factors and prognosis according to the birthweights and gestational ages among the 3 groups. This study revealed a decreasing trend in the frequency of convulsions of full term CP, dyspnea and oxygen administration of premature CP in the neonatal period. At the same time, the motor development of CP without mental retardation had improved significantly in the later period. However, in the last 3 years the distribution of the severity of motor disturbance at 4 years of age among CP with birthweight of 1,000-2,000 g was either mild or severe.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic receptors and adenylate cyclase activity in hepatocytes of the streptozotocin-diabetic rat.

Effects of short and long exposure to the diabetic state induced by an injection of streptozotocin to young female rats on glucagon- and catecholamine-sensitive adenylate cyclase activity and adrenergic receptors of hepatic membranes have been studied. The short period of exposure to the diabetic state exhibited an increase in the sensitivity of the enzyme to isoproterenol without changes in the affinity and the number of beta-adrenergic receptors. The increased response of adenylate cyclase activity to isoproterenol was accompanied with a greater GTP-induced lowering of the affinity to the beta-adrenergic agonist in diabetic membranes than in the controls. The chronic diabetic state produced a decrease in the adenylate cyclase activity to hormonal or non-hormonal stimuli with a fall in the number of alpha- and beta-adrenergic receptors. These results suggest that the observed effects of the diabetic state on hormonally sensitive adenylate cyclase activities and their receptor binding sites of the hepatic membranes would vary depending on the duration and/or severity of the diabetic state experimentally induced.

[The comparison of motor developmental processes between spastic diplegic children and athetotic children who have been treated since infancy].

We studied the correlation between motor developmental processes and prognosis of locomotion at the age of 4 years, among 15 spastic diplegic children (S) and 21 athetotic children (A), who started treatment under 1 year of age. The children of each type were divided into two groups according to the ability of locomotion at the age of 4 years; S- I: 6 walkers, S- II: 9 crawler, A- I: 11 walkers and A- II: 10 crawler. We compared the average corrected ages when the subjects attained the abilities to roll over, creep, sit with hands, crawl, sit up, cruise with support, stand up, and walk alone, and made a statistical analysis by t test among 4 groups. Also we compared the cumulative frequency percentages for the ages about the locomotion mentioned above. The S- I group attained all of the abilities of locomotion significantly earlier than the S- II group. The A- I group could crawl and sit up significantly earlier than the S- II group. The A- I group could crawl and sit up significantly earlier than the A- II group. The S- I group began to creep and sit with hands significantly earlier than the A- I group. We found no significant differences between the S- II group and the A- II group in motor developmental processes. These studies revealed that it would be possible to expect the prognosis of ambulation at the age of 4 years according to the early motor developmental processes among the spastic diplegic children.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin stimulates adenylate cyclase activity via prostaglandins in the adrenal glomerulosa membrane.

The effects of angiotensin II (A II) on adenylate cyclase activities in membranes of the zona glomerulosa (the capsular fraction) and the zona fasciculata (the decapsulated fraction) from rat adrenocortical glands were investigated. A time- and GTP-dependent stimulation by A II of adenylate cyclase activity was observed in the capsular fraction but not in the decapsulated fraction. The activation of adenylate cyclase by ACTH and A II was additive. Stimulation by A II was inhibited by an angiotensin antagonist, DD-3487 (DD). Moreover, the addition of a prostaglandin antagonist, a mixture of polyesters of polyphloretin phosphate (PPP) and an inhibitor of prostaglandin synthesis, indomethacin, was effective in inhibiting A II-induced stimulation of the capsular adenylate cyclase activity, suggesting that the activation of A II receptors located on the capsular membrane leads to the release of prostaglandins, which in turn stimulates the adenylate cyclase.

An electromyography in spastic diplegia.

To evaluate the pathologic state accurately and objectively, fifteen patients with spastic diplegia were examined with surface electromyography (EMG) of the rectus femoris, medial hamstring, anterior tibial and gastrocnemius muscles. Seven showed disturbed reciprocal innervation (disturbed group) and 8 showed reciprocal innervation (non disturbed group). The disturbance of reciprocal innervation on EMG showed a positive correlation with delay in onset of crawling by 10 months (p less than 0.05), a low level of motor development (p less than 0.005) and more abnormal CT findings. Four patients in the disturbed group showed various abnormalities in X-rays of the hips. Surface EMG findings of crawling muscle may be useful for understanding the pathologic state of crawling in spastic diplegia.

Synthesis and alpha-D-glucosidase inhibitory activity of N-substituted valiolamine derivatives as potential oral antidiabetic agents.

Various kinds of N-substituted valiolamine derivatives, including compounds 23a, 24a, and 34a, which are structurally analogous to the key pseudodisaccharides (25a and 26a) of naturally occurring oligosaccharide alpha-D-glucosidase inhibitors, have been synthesized and estimated by the measure of inhibitory activity against porcine sucrase and maltase. The N-substituted valiolamine derivatives evaluated in this study have been found to be more potent than the corresponding N-substituted valienamine derivatives as well as the parent valiolamine. It is noteworthy that even simple N-substituted valiolamine derivatives such as N-[2-hydroxy-1-(hydroxymethyl)ethyl]-, N-[(1R,2R)-2-hydroxycyclohexyl]-, and N-[(R)-(-)-beta-hydroxyphenethyl]valiolamine (6, 8a, and 9a) have the stronger alpha-D-glucosidase inhibitory activity against porcine intestinal maltase and sucrase than naturally occurring oligosaccharide alpha-D-glucosidase inhibitors.

Structure of alahopcin (nourseimycin), a new dipeptide antibiotic.

The structure of alahopcin (nourseimycin) (1), a new dipeptide antibiotic isolated from Streptomyces, has been established to be (2S, 3R)-2-[(L-alanyl)amino]-4-formyl-3-(hydroxy-aminocarbonyl)butyric acid. 1 exists in two cyclic hemiacetal type tautomers formed by intramolecular ring closure between the hydroxyamino group and the formyl group in aqueous solution. The structure of the new weakly acidic amino acid (2), a constituent of 1, is revealed to be (2S, 3R)-2-amino-4-formyl-3-(hydroxyaminocarbonyl)butyric acid, and 2 also exists in two cyclic hemiacetal type tautomers in aqueous solution.

Isolation of dealanylalahopcin, a new amino acid, and its biological activity.

A new amino acid, dealanylalahopcin, was isolated from a culture filtrate of Streptomyces albulus subsp. ochragerus; it was also formed by the enzymatic hydrolysis of alahopcin using microbial alpha-amino acid ester hydrolase. The amino acid was obtained as colorless needles and its molecular formula is C6H10N2O5. It showed very weak antibacterial activity against Gram-positive and Gram-negative bacteria, and weak inhibitory activity against the collagen prolylhydroxylase.

Valiolamine, a new alpha-glucosidase inhibiting aminocyclitol produced by Streptomyces hygroscopicus.

Valiolamine, a new aminocyclitol has been isolated from the fermentation broth of Streptomyces hygroscopicus subsp. limoneus and its structure has been determined to be (1(OH),2,4,5/1,3)-5-amino-1-C-(hydroxymethyl)-1,2,3,4-cyclohexanetetr ol. Valiolamine has more potent alpha-glucosidase inhibitory activity against porcine intestinal sucrase, maltase and isomaltase than valienamine, validamine and hydroxyvalidamine which were reported as building blocks of validamycins and microbial oligosaccharide alpha-glucosidase inhibitors. In addition, valienamine, validamine and hydroxyvalidamine have been isolated from the fermentation broth.

Early physiotherapy in the treatment of spastic diplegia.

This study reports the effect of early physiotherapy, using Vojta's method, on children with spastic diplegia. Eight children with spastic diplegia (in spite of early treatment which was started before nine months of age) were compared with 21 children with spastic diplegia in which treatment was started between nine months and three years of age. The average age of starting to walk was eight months earlier in the group treated early, although they had more severe complications. They tended to walk steadily with a gait pattern which was quite different from the classical pattern. All of the early treated patients had confirmed organic brain damage with abnormal CT scan or microcephaly. In conclusion, Vojta's method of treatment is one system which improves the prognosis for walking if performed early.