Pharmacokinetics, Safety, and Pharmacologic Effects of OPC‐21268, a Nonpeptide Orally Active Vasopressin V1 Receptor Antagonist, in Humans

Ohnishi, Akihiro; Ko, Yonge; Fujihara, Hiroaki; Miyamoto, Gohhachiroh; Okada, Keiko; Odomi, Masaaki

doi:10.1002/j.1552-4604.1993.tb03949.x

Cited by 21 publications

(10 citation statements)

References 19 publications

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“…An animal study with labeled "4C-OFLX clearly demonstrated greater accumulations in excretory organs such as the salivary gland and the trachea, in comparison with those in the serum (17). From 0.5 to 24 h after the single oral dose, the drug distribution to these organs was two to four times higher than that to the serum, and these higher distributions were maintained after multiple (once a day for 21 days) doses (16). These results suggested that OFLX may be particularly well distributed to the excretory organs and may be secreted into the extravascular fluids, by a process(es) which probably involves not only passive but also active transport.…”

Section: Resultsmentioning

confidence: 97%

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Effective monitoring of concentrations of ofloxacin in saliva of patients with chronic respiratory tract infections

Koizumi

Ohnishi

Takemura

et al. 1994

Antimicrob Agents Chemother

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To ascertain whether monitoring of the concentrations of ofloxacin in saliva during a course of treatment is more suitable and safer than that of its levels in blood, we simultaneously monitored its concentrations in three body fluids (blood, saliva, and expectorated sputum) after a 300-mg administration in 18 patients with chronic respiratory infection. The mean (± standard error of the mean) half-lives derived from the three drug level-time relationships were similar: 6.04 ± 0.58 h for serum, 6.34 ± 0.63 h for sputum, and 6.61 ± 0.65 h for saliva. The mean peak concentration (4.06 to 4.53 ,ug/ml) did not differ at the three sites, but the times taken to reach peak concentration in saliva and sputum (3.17 ± 0.46 h) were significantly longer than that in serum (2.22 ± 0.28 h). The ratios of the concentrations in saliva and sputum to the concentration in serum increased during the first 2 h and reached 1.0 between 2 and 8 h after administration. They rose above 1.0 16 h after administration: 1.14 ± 0.11 for saliva and 1.19 ± 0.10 for sputum. The concentration-time relationship for sputum corresponded closely with the concentration-time relationship for saliva, and an overall significant correlation between the concentrations in sputum and saliva was obtained (P < 0.01). These results suggest that monitoring concentrations in saliva may be more valid, as well as less invasive, than monitoring of the levels in blood for ensuring that the drug concentration reaches its therapeutic level in bronchial secretions.Ofloxacin (OFLX) is a fluoroquinolone antimicrobial agent having a broad spectrum of activity against gram-negative and -positive bacteria and some anaerobes in vitro (4, 13). Grassi reported the successful use of OFLX against respiratory tract infections in a multicenter study (6), and many other clinical investigations have proved its effectiveness in the treatment of various systemic bacterial infections (8,14,21).Ofloxacin is widely distributed in the body and penetrates thoroughly into extravascular fluids such as bronchial secretions (8, 10, 20, 21). We consider that its relatively high concentration in such secretions is especially important in chronic infections, since it maintains levels higher than the MICs for various respiratory pathogens. In chronic airway infections, it is necessary to maintain the concentration of an antibiotic in bronchial secretions at a level equal to or higher than the concentration in blood because the bacteria are usually present in and around the airways. On the other hand, since OFLX is mostly eliminated via the kidney and is excreted unchanged in the urine (3, 11), careful regulation of the dosage during chronic administration in patients with impaired renal function has been advised (3, 5).In the present study, we performed simultaneous monitoring of OFLX concentrations in three fluids, blood, expectorated sputum, and saliva, in patients with chronic respiratory infections and various degrees of renal impairment. Our purpose was to determine whether the measurement of ...

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Section: Resultsmentioning

confidence: 97%

“…Ofloxacin concentrations in serum, sputum, and saliva were fitted to a pharmacokinetic model by a nonlinear least-squares method, with the microcomputer program MULTI (22). We used an open one-compartment model with first-order absorption, and the weight for each analysis was 1 (16 …”

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confidence: 99%

Effective monitoring of concentrations of ofloxacin in saliva of patients with chronic respiratory tract infections

Koizumi

Ohnishi

Takemura

et al. 1994

Antimicrob Agents Chemother

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“…Japan), weighing 180-200 g. were housed in individual metabolic cages, fed on a standard rat powder chow(20g/day: Oriental Yeast Co.. Japan) in a deep cup with negligi ble spillage and given water ad libitum. They received two doses of Adriamycin (2 mg/kg) via tail vein at an interval of 3 weeks [1], At week 3 just after the second Adriamycin injection, the rats were ran domly divided into four groups, and the standard rat chow was sup plied with the drugs as follows: group 1, control rats without drugs (n = 6); group 2, rats given V 1 receptor antagonist (OPC-21268 [14][15][16], 200 mg/kg/day; n = 5): group 3. rats given V2 receptor antagonist (OPC-31260 [17.18], 50 mg/kg/day; n = 5). and group 4. rats given both V 1 and V2 antagonists (200 and 50 mg/kg/day, respectively; n = 5).…”

Section: Experimental Designmentioning

confidence: 99%

Evidence for the Involvement of Vasopressin in the Pathophysiology of Adriamycin-induced Nephropathy in Rats

Okada

Suzuki

Kanno

et al. 1996

Nephron

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The effect of orally available, nonpeptide vasopressin V1 and V2 receptor antagonists on chronic progressive glomerular disease was investigated in Wistar rats with Adriamycin-induced nephropathy. At weeks 0 and 3, Adriamycin was injected twice, and at week 3 drugs started to be given as follows: groups 2 and 3 were treated with V1 and V2 antagonists, respectively, while the untreated group 1 served as control. To block the effects of vasopressin totally, both V1 and V2 antagonists were simultaneously administered (group 4). At weeks 8 and 10, V1 and V2 antagonists given either alone or combined significantly reduced the urinary protein excretion to the same levels. Urinary volume increased in groups 3 and 4 from week 4. Systolic blood pressure did not significantly increase in all groups during the study. Histological alterations in the kidney of groups 2, 3 and 4 were significantly attenuated compared to the control. These results suggest that both vasopressin V1 and V2 agonism plays a role in the pathophysiology of Adriamycin-induced nephropathy despite plasma levels of vasopressin within the normal range. These findings also lead to the notion that in some types of nephrotic patients these orally available V1 and/or V2 receptor antagonists may be effective for reduction in proteinuria and for retardation of progression of renal failure.

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“…Nonetheless, many investigators have modified the structure (11)(12)(13)(14), but have as yet found no nonpeptide V1 / V2 receptor antagonist. Our previous reports (15,16), however, described a nonpeptide, orally active VI receptor antagonist, OPC-21268, and then OPC-31260, a nonpeptide V2 receptor antagonist, also has been developed. In vitro animal experiments using [3H ]AVP have demonstrated that OPC-31260 is a selective V2 receptor antagonist, and this agent has been shown to behave as an aquaretic agent in rats (9).…”

Section: Discussionmentioning

confidence: 99%

Potent aquaretic agent. A novel nonpeptide selective vasopressin 2 antagonist (OPC-31260) in men.

Ohnishi¹,

Orita²,

Okahara³

et al. 1993

J. Clin. Invest.

137

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Solute-free water diuretics (aquaretics) by antagonizing hydrosmotic vasopressin receptors (V2) may be useful in treating water-retaining diseases. The effects ofintravenous administration of a newly developed nonpeptide, selective V2 antagonist, OPC-31260, at doses ranging from 0.017 to 1.0 mg/kg to groups of healthy, normally hydrated men were compared with those of 0.33 mg/kg furosemide and placebo. OPC-31260 increased the hypotonic urine volume dose dependently for the first 4 h, while furosemide induced sodium diuresis for 2 h. The absolute increase in the cumulative response in the urine to the highest doses of OPC-31260 was not significantly different from that to furosemide. The higher doses of OPC-31260 rapidly lowered urine osmolality for 2 h, particularly between minutes 15 and 45 (e.g., 1.0-mg/kg dose: 63±2 mOsm/kg in urine collected between minutes 30 and 45). In a marked hypotonic diuresis, mean free water clearance of the 4-h urine increased dose proportionally into the positive range, reaching 1.80±0.21 ml/min at 1.0 mg/kg. Whereas furosemide induced marked Na and K diuresis, OPC-31260 increased urinary Na excretion only slightly. At 4 h, 0.75 and 1.0 mg/kg of OPC-31260 almost doubled the plasma arginine vasopressin; and the higher doses increased plasma osmolality and plasma Na slightly, but did not alter plasma K, blood pressure, or heart rate. OPC-31260 thus safely induced a potent aquaretic effect in men. (J. Clin. Invest. 1993. 92:2653-2659 Key words: vasopressin antagonist * aquaretic effect * urine osmolality -hyponatremia * arginine vasopressin

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Pharmacokinetics, Safety, and Pharmacologic Effects of OPC‐21268, a Nonpeptide Orally Active Vasopressin V1 Receptor Antagonist, in Humans

Cited by 21 publications

References 19 publications

Effective monitoring of concentrations of ofloxacin in saliva of patients with chronic respiratory tract infections

Effective monitoring of concentrations of ofloxacin in saliva of patients with chronic respiratory tract infections

Evidence for the Involvement of Vasopressin in the Pathophysiology of Adriamycin-induced Nephropathy in Rats

Potent aquaretic agent. A novel nonpeptide selective vasopressin 2 antagonist (OPC-31260) in men.

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