Malotilate (diisopropyl-1, 3-dithio1-2-ylidenemalonate) exists in two polymorphic forms, designated A and B. The transformation from A to B easily occurs at relatively low temperatures. Since different crystalline forms of a drug may influence its absorption and hence its therapeutic efficacy, two crystalline forms of malotilate (A and B) were assessed in 20 healthy male subjects using a two-way cross-over design. The concentration-time curve was shifted slightly to the right in the group that received the B form; however, there were no significant differences in the AUC, C_max, and t_max between the two groups. Statistical evaluation of the data involved an analysis of variance for a cross-over design (ANOVA). This revealed significant differences for “Time Periods” and “Between Subjects, ” but not for “Group or Sequence” or “Drugs.” With 95% confidence, the confidence intervals of each parameter satisfied the criteria for AUC but not for C_max and t_max. From the data obtained and taking into consideration their clinical use, we conclude that both the A and B forms of malotilate are bioequivalent.

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A phase 1 study of N-696, a new β-adrenoceptor blocking agent, was performed in normal healthy volunteers to define its pharmacological characteristics and safety.
Following a single oral administration of 10 and 20 mg of N-696 after a meal (n=4 for each), both C_max and AUC_0-24 were twice as high in the group receiving 20 mg as in the group receiving 10 mg. However, T_max was 3.0 hours in the 10-mg group and 4.3 hours in the 20-mg group with no statistically significant difference between groups. Also, T_e1/2was as much as 12 hours, and urinary recovery of N-696 during 48 hours was 48% on both dosage regimens.
Following a repeated oral administration of 20 mg of N-696 for 14 days (n=6), plasma concentration reached its plateau in 3 days and remained stable during rest of the study. The effects on hemodynamics appeared in 2-3 days. There was a 15.7% decrease in heart rate, a 9. 4% decrease in systolic blood pressure, a 11.4% decrease in diastolic blood pressure, and a 23.0% decrease in double products. The AUC_0-∞ on the 1st day coincided well with the AUC_0-24 on the 14th day, indicating no accumulation of N-696 in the body during the study. Neither adverse effects nor significantly abnormal changes in laboratory tests were noted in any volunteer.
We conclude that N-696 is a long-acting and potent β-A-adrenoceptor blocking agent and can be safely used in a clinical setting.

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The inhibitory effect of famotidine, a new H₂-receptor antagonist, on hepatic oxidative metabolism of cortisol in six healthy volunteers was compared with that of cimetidine by monitoring the change in urinary 6β-hydroxycortisol (6β-OHF), an oxidative metabolite of cortisol. The ratio of 6β-OHF to 17-hydroxycorticosteroids (17-OHCS) in urine was measured before, during, and after treatment with famotidine and cimetidine for 3 days in a cross-over study. The ratio was decreased by 25% -35% of the original level after 1-3 days of oral treatment with cimetidine (800 mg, b. i. d.). The reduction vanished within 2 days after the last dose of cimetidine. The ratio was not significantly changed during oral treatment with famotidine (40 mg, b. i. d.). These findings indicate that famotidine, in contrast to cimetidine, does not affect the hepatic oxidative metabolism of cortisol in man, and it is suggested that famotidine does not affect the hepatic drug-metabolizing capacity in humans.

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The usefulness of a spray (E-1000) of isosorbide dinitrate (ISDN), a new dosage form, has been determined and compared with that of its sublingual preparation (NR) in a cross-over study.
Twelve healthy young male adults participated in this study. A total dose of 2.5 mg of E-1000 was sprayed over the both sides of the buccal mucous membrane, and a 5-mg tablet of NR was administered sublingually. The changes in blood pressure and heart rate, and the plasma levels and urinary excretions of ISDN and its two metabolites, were compared after administration.
The plasma levels of unchanged ISDN and its metabolites isosorbide-2-mononitrate (2-ISMN) and isosorbide-5-mononitrate (5-ISMN) were determined by gas-liquidchromatography with an electron-capture detector. The area under the plasmaconcentration-time curve (AUC) for unchanged ISDN hardly differed between E-1000 (1300.8 ± 127.2 ng·Emin/ml) and NR (1260.4 ± 159.4 ng·Emin/ml), although the doseof the spray form was half of that of NR. Furthermore, the maximum plasmaconcentration (C_max) of ISDN was about the same for both of the formulations (36.5 ±4.2 ng/ml for E-1000 and 35.7 ± 6.4 ng/ml for NR), and the time to reach the peakplasma level (T_max) was 7.7 ± 0.9 min for E-1000, which was significantly shorter thanthe 18.2 ± 3.2 min taken with NR (P<0.01).
These results indicated that the E-1000 dosage form offers a much higher bioavailability of ISDN than the sublingual form.
On the other hand, the AUCs of 5-ISMN and of 2-ISMN were approximately proportional to the dose, and the percentage of urinary excretion of the two metabolites and their glucuronides were almost identical. Finally, an earlier manifestation of the blood pressure-lowering effect was elicited by E-1000 than by NR.
Our results suggested that E-1000 rapidly exhibits an inhibitor effect on anginal attacks.

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The singie and multiple dose pharmacokinetics of orally administered aciclovir (ACV) were studied in 19 healthy Japanese male volunteers, Eight men were each . given either a single tablet, of 200 mg (group 1) or 400 mg (group 2).Additionally, 8men, including 5 in group 2, were given a 200-mg tablet every 4 hr 5 times daily and 8hr after the finai administration for a total of 15 doses (3days).In the single-dose study, the plasma ACV concentration increased dose-dependently, and C_max was 2.80 ±0.30and3.76±0.75μMatT_max of 1.31±0.46and1.50±0.38 hr in groups 1 and 2, respectively. Thereafter, the ACV level monoexponentially decreased with a T_1/2 of 2. 51±0. 30 and 2. 56±0. 28 hr in groups 1 and 2, respectively. This process fitted the one-compartment model. The AUC was significantly greater in group 2 (17.62 μmol·hr/l) than that in group 1 (11.72, μmol·hr/l).Renal clearance was similar in both groups (301±23 and 297±42ml/min in groups 1 and 2, respectively). These clearances exceeded the normal glomerular filtration rate, indicating tubular secretion of ACV in addition to glomerular filtration. The mean urinary elimination of unchanged ACV in the two groups was 25.0% and 18.6% of the administered dose within 48 hr, respectively. The total urinary elimination of metabolite (9-carboxy methoxymethylguanine, CMMG) in group 2 was less than 1.4% of the administered dose within 48 hr. In the multiple-dose study, the plasma ACV concentration almost reached a steady state after the fifth administration, and the mean maximum and mini - mum plasma ACV concentrations were in the range of 3.41-3.76μM and 1.08-1.17μM, respectively. The simulation using the parameters obtained from group 1 was applied to the multiple-dose study and showed a good fit with the results obtained. All results seen in 8 subjects were within the 95 % confidence level. The mean urinary elim ination of unchanged ACV was 23.5% of the administered dose within 96 hr. No signi - ficant clinical or laboratory evidence of dose-related toxicity was noted in the 19 sub jects examined.

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We describe cyclosporin A therapy and drug monitoring by HPLC and RIA following renal transplantation or in a patient with Bechet's disease. There was considerable variation in the relationship between HPLC and RIA measurements. The concentrations of cyclosporin A measured by HPLC were invariably less than those measured by RIA. In concentration-time curves of cyclosporin A after dosing, the peak concentrations were observed at 1 to 2 hours in all patients. During the clinical course of patients after renal transplantation, there were considerable variations in RIA measurements, and attempts were made to achieve a concentration of from 100 to 300 ng/ ml by HPLC. During the study period, no renal toxicity or rejection episodes were observed in any patient.

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The influence of cimetidine on the kinetics of two benzodiazepines, diazepam and lorazepam, after a single oral dose (diazepam 5 mg or lorazepam 2 mg) was studied in 8 healthy male Japanese volunteers using an experimental design with two Latin squares. Cimetidine coadministration, 800 mg/day, was begun 24 hr prior to the benzodiazepine dose and continued during the trial. Cimetidine significantly prolonged the elimination half-life (P<0.05), increased the AUC (P <0.01), and decreased the clearance of diazepam (P <0.01), although it did not influence the peak plasma concentration, the time to reach peak concentration, and the volume of distribution of diazepam. However, cimetidine had a slight effect on the peak plasma concentration, the time to reach peak concentration, the elimination half-life, the AUC, the volume of distribution, and the clearance of lorazepam. The prolonged elimination half-life of diazepam with cimetidine coadministration was caused by decreased clearance of the drug. These results indicate that cimetidine influences differently the kinetics of diazepam and lorazepam due to the different metabolic characteristics of the two drugs, since lorazepam is directly biotransformed to glucuronide conjugates and diazepam is metabolized by reduction or oxidation prior to glucuronide conjugation.

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Famotidine is a histamine H₂-receptor antagonist that reduces gastric acid secretion. The effects of famotidine on gastric secretion were studied in 150 adult patients undergoing elective surgery. About one hour before induction of general anesthesia, 20 mg of famotidine was given to each patient either intramuscularly or intravenously at random. The volume and pH of gastric fluid aspirated via a gastric tube were measured immediately after orotracheal intubation and before extubation. In 67 of 76 patients (88.2%) given famotidine intramuscularly and 63 of 74 patients (85.1%) given famotidine intravenously, the gastric content pH was elevated above 2.5 or no gastric fluid could obtained any time during anesthesia. There were no significant side effects in either group.We conclude that intramuscular and intravenous famotidine are both useful preoperative medications to prevent aspiration pneumonia during general anesthesia.

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To investigate the antianginal effects of nisoldipine, a placebo-controlled study was performed using 10 patients with stable angina pectoris on effort. Anginal symptom-limited treadmill exercise tests were performed before and 2, 4, 7, and 24 hours after a single oral dose of placebo at 10: 00 am. A few days later, the exercise test was again performed before and after the administration of 10 mg of nisoldipine according to the same schedule followed in the placebo trial.
Between tests before placebo and nisoldipine administration, there were no significant differences in exercise time, pressure- rate product (PRP), or ST deviation at peak exercise.
Compared with the placebo trials, the exercise time was significantly prolonged after nisoldipine administration and its increments were 100.1, 74.5, 85.0, and 43.6 sec at 2, 4, 7, and 24 hours after administration, respectively. The plasma concentration of nisoldipine and the increment of exercise time reached maxima at 2 hours after nisoldipine administration. Two hours after administration, the peak PRP was significantly greater after nisoldipine administration than after placebo and before nisoldipine administration. The ST deviation at peak exercise was not significanty different between the placebo and nisoldipine trials.
This indicates that nisoldipine exerts an antianginal effect for more than 24 hours. It is considered to be a clinicaly useful agent in the management of angina pectoris on effort.

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The pharmacokinetics and pharmacologic effects of sustained release urapidil (BKU) were investigated in 6 healthy subjects after repeated oral administration. Thirty mg of BKU was given once a day on the first and seventh days at 7: 00 a.m., and twice a day on the second to sixth days at 7: 00 a.m. and 7: 00 p.m.
The calculated pharmacokinetic parameters on the first day of BKU administration were as follows: time to peak level (t_max), 4.5±0.3hr (mean±S.E.M.); peak concentration (C_max), 200.9±24.0ng/ml; biological half-life (t_1/2), 3.7±0.3hr. On the seventh day, the pharmacokinetic parameters were: t_max, 4.0±0.3hr; C_max, 268.1± 49.4ng/ml; t_1/2, 3.8±0.7hr.
Urapidil and three metabolites, p-hydroxylated urapidil, O-demethylated urapidi1, and uracil-N-demethylated urapidil, were found in urine after BKU administration. The percent excretion ratio of urapidil and its metabolites in 24-hr urine was not affected by repeated BKU administration.
The maximal blood pressure decrease was observed 4 hours in the sitting position after BKU administration, but no significant decrease was found during the study period. There was no significant change in heart rate in the same position. The increase in heart rate after postural change from sitting to standing tended to be reduced after repeated BKU administration. Neither the hormonal value nor the biochemical value was changed by BKU during the study period.

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Famotidine is a potent histamine H₂-receptor now undergoing clinical trial in Italy, Germany, the UK, France, and the USA, and has just come on the market in Japan. To study the effect of concurrent antacid administration on the oral absorption of famotidine, 10 subjects (8 patients with peptic ulcer, 2 normal adults) received 20 mg (5 subjects) or 40 mg (5 subjects) of famotidine with and without Maalox (aluminum hydroxide and magnesium hydroxide). Slight declines in the maximum plasma concentration and the areas under the plasma concentration time curve of famotidine were observed when an antacid was given simultaneously, indicating that concurrent antacid decreases the bioavailability of this new antisecretory compound. Although the plasma famotidine level was lowered by concurrent administration of antacid, it remained higher than the plasma concentration for 50% inhibition of stimulated acid secretion (IC₅₀) for up to 12 hours.

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It is known that increased calcium (Ca²⁺) concentration in the myocardium exacerbates cell damage with ischemia, and that Ca²⁺enters myocardial cells mainly through the voltage-dependent Ca channel (VDCC). Furthermore, it is thought that α1-and β-adrenergic receptors control the influx of Ca²⁺ through the sarcolemmal membrane. The present study was undertaken to determine whether the ischemia alters the affinity and number of ³H-Nitrendipine (³H-N) binding sites, and of α- and β-adrenergic receptors, using radioligand binding assay. ³H-N binding sites are thought to be closely linked with VDCC. The α- and β-adrenergic receptor binding assay was studied with ¹²⁵I-HEAT and ³H-dihydroalprenolol (³H-DHA) as radioligands respectively. 1) ³H-N binding assay: After 15 or 30 min of ischemia, there was no significant change in B_max. Sixty minutes after ischemia the number of ³H-N binding sites increased significantly (331 ± 14 fmolimg protein in ischemic areas vs 222 ± 11 fmol/mg protein in nonischemic areas). 2) ¹²³I-HEAT binding assay: Fifteen minutes after ischemia there was no significant change in B_max. Thirty and 60 min after ischemia the number of α1-adrenergic receptors increased significantly (77±10, 105 ± 4 fmol/mg protein in ischemic areas vs 55 ± 4, 50±11 fmol/mg protein, respectively.). 3) ³H-DHA binding assay: After 15 or 30 min of ischemia, there was no significant change in B_max. Sixty minutes after ischemia the number of β-adrenergic receptors increased significantly (111 ± 6 fmol/mg protein in ischemic areas vs 54 ±5 fmol/mg protein in nonischemic areas). However, there was no significant change in c-AMP level between ischemic and nonischemic areas. We concluded that after 60 min of ischemia the number of VDCC and β-adrenergic receptors in myocardial sarcolemmal membrane increased. After 30 minutes ischemia, the number of α1-adrenergic receptors increased.

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