Phase I studies of MK-217, a new aminobisphosphonate, were conducted in 27healthy Japanese male volunteers. The safety, tolerability and pharmacokinetics wereinvestigated. In a single-dose study, 5, 10, 20 and 40 mg of MK-217 were administered to12 subjects. In a 7-day multiple dose study, 20 mg was administered to 6 subjects. Inaddition, either 20 mg or placebo were administered to 9 subjects (20 mg: 6, placebo: 3) in a 14-day multiple-dose study which was a double-blinded, placebo controlled study.
No abnormal changes were observed in subjective symptoms, blood pressure, pulserate, respiratory rate, body temperature and ECG in each study. An increase in GPT wasobserved in one subject after a single dose of 5 mg.
In the 7-day multiple-dose study, elevations in GOT, GPT, Al-p andγ-GTP wereobserved in one subject who had flu-like symptoms. GPT and Al-p were increased inanother subject in this study. In the 14-day multiple dose study, however, there were noabnormal changes.
In the single-dose study, the serum concentration of MK-217 was under the detectable limit after 5 mg and 10 mg administration. In all three studies less than 2% ofadministered doses were excreted in urine.

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It is known that approximately 20-50% of acquired immunodeficiency syndrome (AIDS) patients are neutropenic and the cause of the neutropenia has not been conclusively elucidated. From 1993 to 1994, a pharmacokinetic study of single-dose rhG-CSF at5μg/kg i. v. was carried out to investigate the correlation between neutrophil counts andserum rG-CSF level using enzyme immunoassay (ETA) in 6 human immunodeficiencyvirus (HIV) patients with the following:
(A) chronic neutropenia (<1, 000/μl) for over 6 months in 5 patients
(B) septicaemia accompanied with acute neutropenia in 1 patient
In Class A, the serum concentration of G-CSF was undetectably low, and less than themeasurement limit (30.0 pg/ml) in 4 out of 5 patients. In Class B, the serum G-CSF levelwas 5, 830 pg/ml. The neutrophil count reached the maximum level at 8 hours afteradministration of rhG-CSF and the neutrophil count remained higher than the preadministration level at 24 hours after the administration. A transient decrease in themonocyte count was observed 1 hour after the rhG-CSF administration in 5 out of 6patients. No effect was observed in the other WBC differentials. Pharmacokinetic profileof rhG-CSF obtained in this study (Class A/B) are summarized as follows ;
*T_1/2 (α) =1.66±0.47/1.14 (h)
*T_1/2 (β) = 3.32±0.66/3.85 (h)
*V_c=38.66±6.48/26.38 (ml/kg)
*AUC (0-24) = 1201.73±560.06/995.46 (pg⋅h/ml)
*CL=10.78±3.61/11.4 (ml/h/kg)
Further, the serum rG-CSF concentration decreased biphasically. In conclusion, it wasfound that excretion, transformation and inactivation of G-CSF was not enhanced inHIV-positive hemophiliacs who showed neutropenia. It was suspected that a productiondisorder of G-CSF might be a factor in neutropenia in patients with chronic neutropenia (Class A), because the serum G-CSF concentration was low in these patients.

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A multicenter study was undertaken to evaluate the efficacy of nitroglycerin tape (NTG tape; 5 mg/sheet) on the exercise capacity in patients with angina pectoris. Aftertwo control cardiopulmonary exercise tests, 12 patients received a strip of NTG tapeevery 12 hours for 4 weeks. The exercise tests were repeated 3 hours after the firstapplication of NTG tape and after the 28th day to evaluate the acute and chronic effects, respectively. Using a treadmill, the ramp protocol was employed for the exercise test.Exercise time (Ex-Time: sec), peak oxygen uptake (peak VO₂), and the anaerobicthreshold (AT) and exercise time to AT determined by respiratory gas analysis weremeasured. Results were as follows: 1) Exercise time was prolonged significantly in the acute (p <0.05) and chronic (p <0.05) study. 2) Peak VO₂ was significantly increasedonly in the acute study (p <0.05). 3) In the acute study, exercise time to AT tended toincrease (p <0.05). In the chronic study, AT (p <0.01) and exercise time to AT (p <0.01) demonstrated further improvement. 4) Two patients who demonstrated an increase inexercise time in the acute study did not demonstrate an increase in the chronic study.
It was suggested that NTG tape improves not only myocardial ischemia, but also themetabolic response to submaximal exercise in patients with angina pectoris, whiletolerance to nitroglycerin may develop in some cases at three hours after applicationwith chronic use.

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Pharmacokinetic studies and examination of safety on single and multiple oralintake of cetirizine, a new antiallergic drug, were performed in 37 healthy male adult Japanese volunteers (single dose: 15 subjects, multiple dose : 22 subjects, 4 of whomreceived placebo, age: 23-45 years).
1) In the single-intake study (cetirizine: 2.5-30mg), the concentration of cetirizineplasma increased in a dose-dependent manner. When 10, 20 and 30mg of the drug wasgiven, the mean C_max was 214.5, 438.1 and 679.2ng/ml with the mean T_max of 1.44, 1.50and 2.20hr, respectively. The metabolite (ucb 026) in the plasma was detected in only afew cases and the level was very low, compared with the unchanged form. In the 10, 20and 30mg groups approximately 50% of the given doses was excreted in urine in theunchanged form by 24hr, but the metabolite was not detected in the urine.
2) In the multiple-dose study, 20mg(once per day, 20mg×1 group: twice per day, 10mg×2group), 30mg(once per day, 30 mg×1group)or placebo was given for 7 days.On the first day and the 7th day, the mean C_max was 547.8 and 624.5 ng/ml in the 20mg×1group, 272.7 and 424.2ng/ml in the 10mg×2group, and 852.7 and 832.7 ng/ml in the 30mg×1group, respectively. Simulation usin.g the parameters obtained on the first day ofthe multiple-dose study showed a constant plasma concentration of cetirizine from the2nd day after administration in the 20mg×1 and 30mg×1groups;this concentrationwas almost equivalent to the values obtained in the subsequent days. However, thesimulation did not correspond well with the actual values obtained in the 10mg×2group, this is probably due to the inability to measure the terminal phase. The metabolite inblood was detected on the 2nd day after administration and the level was nearly constanton 6 and 7th day. Urinary excretion of the unchanged form increased almost linearly to48-58% on the first day and 59-70% of the doses given on the 7th day in the three groups, but the metabolite was not detected in urine.
3) There were no abnormal findings due to cetirizine in blood, biochemical andurinary examinations, nor physiological signs such as pulse, respiration, blood pressureor ECG in the single or multiple doses study. No subjective symptoms due to the drugwere observed in either study except for one subject who became slightly sleepy duringdays 1-3 after administration of 20mg.

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