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Acute Aquaresis by the Nonpeptide Arginine Vasopressin (AVP) Antagonist OPC-31260 Improves Hyponatremia in Patients with Syndrome of Inappropriate Secretion of Antidiuretic Hormone (SIADH)

Department of Medicine (To. S., S.I.), Jichi Medical School, Tochigi; Second Department of Medicine (K.A.), Tohoku University School of Medicine, Sendai; Department of Medicine (K.K.), Nagaoka Red Cross Hospital, Nagaoka; Department of Medicine (K.Y.), National Sakura Hospital, Sakura; Department of Medicine (K.S.), Tokyo Rosai Hospital, Tokyo; Department of Medicine (Ta. S.), Keio University School of Medicine, Tokyo; Second Department of Medicine (S.Y.), Chiba University School of Medicine, Chiba, Japan

Address all correspondence and requests for reprints to: Toshikazu Saito, M.D., Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical School, 3311-1 Yakushiji Minamikawachi, Tochigi 329-04 Japan.

	Abstract

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The present study was undertaken to determine whether the nonpeptide V₂ arginine vasopressin (AVP) antagonist 5-dimethylamino-1[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine hydrochloride (OPC-31260) produces water diuresis and improves hyponatremia in patients with the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Eleven patients (9 males and 2 females, 64 ± 3.5 yr) with SIADH were included in the present protocol, which was comprised of 3 successive days. Day 1 was a control day, and on days 2 and 3 OPC-31260 was administered intravenously. Five blood and urine collections were made at 1–2 h intervals during the 6 h observation period each day. A single administration of 0.25 and 0.5 mg/kg OPC-31260 increased the 4 h cumulative urine volume and decreased urinary osmolality to below 225 mOsm/kg H₂O. Such a diuretic effect was independent of an increase in urinary solute excretions. This aquaresis by 0.5 mg/kg OPC-31260 caused a significant increase in serum sodium level by approximately 3 mEq/L. The antagonistic effect of OPC-31260 lasted for 4 h when it was given intravenously. These results indicate that OPC-31260 is an effective therapeutic agent for hyponatremia in patients with SIADH.

	Introduction

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CLINICAL and laboratory experiments have demonstrated that the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is associated with marked hyponatremia (1, 2, 3, 4, 5). Persistent elevation of plasma levels of arginine vasopressin (AVP) has been shown in spite of hypoosmolality, which should suppress the osmotic release of AVP to undetectable levels (6). Reversal of hyponatremia by using a specific inhibitor of AVP would provide conclusive evidence for the role of AVP in SIADH. Such a study was demonstrated by using the nonpeptide AVP antagonist, 5-dimethylamino-1[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine hydrochloride (OPC-31260) in the experimental SIADH rats receiving 1-deamino-8-D-arginine vasopressin (dDAVP) and a liquid diet (7).

Yamamura et al. (8) recently developed the orally effective, non-peptide AVP antagonist, OPC-31260, which blocks the binding of AVP to the plasma membranes of kidney in a competitive manner. We previously reported the in vivo diuretic effect of OPC-31260 in conscious rats and the therapeutic efficacy of OPC-31260 in the experimental SIADH and cirrhotic rats (7, 9, 10). In addition, both intravenous and oral administration of OPC-31260 produced an aquaretic effect in normal subjects (11, 12, 13).

The present study was undertaken to determine whether OPC-31260 produces water diuresis and improves hyponatremia in patients with SIADH.

	Subjects and Methods

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Subjects

Eleven patients with SIADH were studied at 7 separate hospitals by the same protocol described below. Profiles of the 11 patients are shown in Table 1. They were 9 males and 2 females whose ages ranged from 48–85 yr (64 ± 3.5 yr, mean ± SE). Serum sodium (Na) levels ranged from 113–134 mEq/L when the patients were admitted to the hospitals. Urinary excretion of Na increased and urinary osmolality (Uosm) was as high as 543 ± 57 mOsm/kg H₂O, despite of the decrease in serum osmolality (Sosm). Plasma AVP levels were 3.2 ± 1.2 pg/mL, which were not significantly different from those of 1.4 ± 0.2 pg/mL in control subjects aged 18–63 yr (n = 20) (14). Plasma AVP levels were detectable by RIA in all the patients, although Sosm was reduced as mentioned above. There was no abnormality in renal or adrenal function. Physical findings showed neither dehydration nor edema. All of the 11 patients were diagnosed as SIADH by the doctors who participated in the present protocol. SIADH occurred in 4 patients with disorders of the central nervous system, one patient with oat cell carcinoma of the lung, one patient with pulmonary tuberculosis, and 5 patients in whom the causes were considered idiopathic. Before initiation of the study, written informed consent was obtained from each subject, and the study was approved by the ethical committee of each hospital for the human studies.

The protocol was designed for completion of the study in 3 successive days. The duration of hyponatremia ranged from 18 days to 5 yr and 7 months (18 ± 7 months, mean ± SE) before starting the present protocol. The therapy for SIADH, which included water restriction (15–20 mL/kg/day) and, in part, high salt diet, was withdrawn. The patients were also prohibited from taking coffee, tea, or green tea, which could alter the diuretic effect. The patients were allowed free access to water. On day 1, they were observed without any diuretic agent, and blood collections were made at 1-h intervals for 4 h. Urine was initially collected for 2 h, and then 4 1-h urine collections were made. Urine volume, Uosm, and urinary excretions of sodium (Na), potassium (K), chloride (Cl), calcium (Ca), and phosphorus (P) were determined. Also, Sosm, serum Na, K, Cl, Ca, P, and plasma AVP were measured. On days 2 and 3, two doses of OPC-31260 (Otsuka Pharmaceutical Co., Osaka, Japan) were chosen from among 0.009, 0.017, 0.1, 0.25, 0.5, and 0.75 mg/kg, which were similar to the doses used in the study in normal volunteers (11), and at which an acute diuretic effect of OPC-31260 was evident. After a blood collection and one 2-h urine collection were made, the OPC-31260, dissolved in 5% glucose, was given intravenously in a total volume of 10 mL. Thereafter, blood and urine collections were made at 1-h intervals to determine the parameters described above. On principle, the lower dose of OPC-31260 should be given on day 2. During the study period, other diuretic agents were prohibited. Before the start of the study and at the end of the study, body weight, blood pressure, and pulse rate were determined each day. In addition, laboratory analysis of blood and urine were carried out for evaluating the safety of the drug.

Analytical measurements

Serum and urinary concentrations of Na, K, Cl, Ca, and P were measured with an autoanalyzer equipped with ion-specific electrodes. Sosm and Uosm were measured by the method of freezing-point depression. Blood was collected in chilled tubes containing EDTA-Na₂ (1 mg/mL blood) to measure plasma AVP levels. Plasma AVP levels were determined by RIA using AVP RIA kits (Mitsubishi Yuka, Tokyo, Japan) (15, 16). The normal value of plasma AVP is 0.2–2.2 pg/mL.

Free water clearance (C_H2O) was calculated using the following equation: C_H2O = Uv (1 - Uosm/Sosm).

Statistical analysis

All the values of urine volume, Uosm, urinary excretions of Na, K, Cl, Ca, and P, Sosm, serum levels of Na, K, Cl, Ca and P, and plasma AVP levels were analyzed by ANOVA for repeat measures based on a mixed model with the restricted maximum likelihood method, Dunnett’s test and Student’s paired t test. P < 0.05 was considered significant.

	Results

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Urine volume is shown in Fig. 1, which includes 3 doses of OPC-31260, because the other doses of 0.009, 0.017, and 0.75 mg/kg were used only on one or two occasions during the study period. Intravenous administration of 0.25 and 0.5 mg/kg OPC-31260 markedly increased urine volume, but 0.1 mg/kg of OPC-31260 had no effect on urine volume. An increase in urine volume was manifest in the first two 1-h urine collections as compared with the control. However, there was no difference in urine volume at the fourth 1-h urine collection. The cumulative urine volumes by 0.25 and 0.5 mg/kg OPC-31260 were 2.1- and 1.9-times greater than that of the control, respectively.

View larger version (19K): [in this window] [in a new window]   Figure 1. Alteration in urine volume after iv administration of OPC-31260 in patients with SIADH. Closed squares () show the control (n = 8). Open circles () show the group of 0.1 mg/kg OPC-31260 (n = 6). Open triangles () show the group of 0.25 mg/kg OPC-31260 (n = 4). Closed circles (•) show the group of 0.5 mg/kg OPC-31260 (n = 8). #P < 0.05 and ##P < 0.01 vs. the respective urine volume at the first urine collection, which was before the administration of OPC-31260. Values are means ±SEM.

View larger version (21K): [in this window] [in a new window]   Figure 2. Reduction in Uosm by iv administration of OPC-31260 in patients with SIADH. Closed squares () show the control (n = 8). Open circles () show the group of 0.1 mg/kg OPC-31260 (n = 5). Open triangles () show the group of 0.25 mg/kg OPC-31260 (n = 4). Closed circles (•) show the group of 0.5 mg/kg OPC-31260 (n = 7). #, P < 0.05 and ##, P < 0.01 vs. the respective Uosm at the first urine collection, which was before the administration of OPC-31260. Values are means ±SEM.

View larger version (16K): [in this window] [in a new window]   Figure 3. Increases in free water clearance (CH2O) following iv administration of OPC-31260 in patients with SIADH. Closed squares () show the control (n = 7). Open circles () show the group of 0.1 mg/kg OPC-31260 (n = 5). Open triangles () show the group of 0.25 mg/kg OPC-31260 (n = 4). Closed circles (•) show the group of 0.5 mg/kg OPC-31260 (n = 7). **P < 0.01 vs. the respective CH2O at the first urine collection, which was before the administration of OPC-31260. Values are means ±SEM.

View larger version (18K): [in this window] [in a new window]   Figure 4. Alteration in serum Na levels by iv administration of OPC-31260 in patients with SIADH. Closed squares () show the control (n = 9). Open circles () show the group of 0.1 mg/kg OPC-31260 (n = 6). Open triangles () show the group of 0.25 mg/kg OPC-31260 (n = 4). Closed circles (•) show the group of 0.5 mg/kg OPC-31260 (n = 8). *P < 0.05 and **P < 0.01 vs. serum Na level before the administration of OPC-31260. Values are means ± SEM.

Laboratory studies reveal that mild increases in glutamic-oxaloacetic transaminase, glutamic-pyruvic transaminase, alkaliphosphatase, and -guanosine 5'-triphosphate were found in a patient (patient 7), and an increase in glutamic-oxaloacetic transaminase was in the patient 9. However, these changes were not clinically significant.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The present study demonstrated an initial trial of the non-peptide AVP antagonist OPC-31260 in the patients with SIADH. It was designed to correspond to a previous study of intravenous administration of OPC-31260 in normal volunteers (11). The intravenous administration of OPC-31260 dose-dependently increased urine volume and free water clearance during the initial 4 hours and reduced Uosm in normal subjects. More than 0.5 mg/kg of OPC-31260 produced a significant water diuresis. Though OPC-31260 has been shown to be an orally effective antagonist to the antidiuretic action of AVP (8), we have studied the diuretic effect of OPC-31260 by administering parenterally to the patients with SIADH and monitoring several parameters of urine and blood samples during the 4-h observation period following a single injection of OPC-31260.

In the present study a single administration of 0.25 and 0.5 mg/kg OPC-31260 increased the 4-h cumulative urine volume and decreased Uosm to below 225 mOsm/kg H₂O. Such a diuretic effect of OPC-31260 was independent of any increase in urinary solute excretion, because C_H2O significantly increased, and urinary excretions of Na, K, and Cl remained to be changed during the observation period. However, the dosages of 0.009, 0.017, and 0.1 mg/kg had no diuretic action in the patients with SIADH (data not shown). Such a diuresis was closely related to increases in serum Na levels and Sosm. In fact, the administration of 0.5 mg/kg OPC-31260 significantly increased serum Na levels from 126.6 ± 3.2 mEq/L to 132.8 ± 2.4 mEq/L at 3 h and to 128.9 ± 3.4 mEq/L at 4 h. The diuretic effect was not so evident that there was any significant reduction in circulatory blood volume, as plasma AVP levels, mean blood pressure, and heart rate remained unchanged before and after the OPC-31260 administration. Both serum Na and Sosm seemed high on the control day, compared with those on the days when OPC-31260 was administered. We considered the possible reasons for this paradoxical evidence. Water intake may have been restricted before the start of the study, and the restriction may have been relaxed during the 3-day observation period. OPC-31260 (0.5 mg/kg) was effective in 3 patients (patient no. 5, 10, and 11) whose plasma AVP levels were below 0.3 pg/mL, an effect quite similar to that in the rest of patients with SIADH.

OPC-31260 was developed by Yamamura et al. (8). It blocks the binding of [³H]AVP to the plasma membrane preparations from rat kidney in a competitive manner. We found that, in cultured rat renal inner medullary collecting duct cells, OPC-31260 reduced the AVP-induced cellular cAMP production in a dose-dependent manner (17). Oral administration of OPC-31260 blocked the antidiuretic action of exogenous and endogenous AVP in conscious Sprague-Dawley and homozygous Brattleboro rats (10). We reported hyponatremic rats receiving 1-deamino-8-D-arginine vasopressin (dDAVP) subcutaneously and a liquid diet as an experimental model of SIADH (7). Chronic oral administration of OPC-31260 normalizes serum Na levels and serum osmolality in the experimental SIADH rats. In addition, the administration of OPC-31260 totally abolished the enhanced expression of water channel aquaporin-2 mRNA in the experimental SIADH rats (18). These studies support the results of the present clinical trial. The antagonism of OPC-31260 lasted for 4 h when it was given intravenously.

In summary, the present study demonstrated that intravenous OPC-31260 exerts a potent and safe aquaretic effect in the patients with SIADH. A single administration of OPC-31260 (0.5 mg/kg) significantly increased serum Na levels during the short observation period of 4 h. The present results indicate that OPC-31260 is an effective therapeutic agent for the hyponatremia associated with SIADH.

Received October 7, 1996.

Revised December 19, 1996.

Accepted December 31, 1996.

	References

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1. Schwartz WB, Bennet W, Curelop S, Bartter FC. 1957 A syndrome of renal sodium loss and hyponatremia probably resulting from inappropriate secretion of antidiuretic hormone. Am J Med. 23:529–542.[CrossRef][Medline]
2. Bartter FC, Schwartz WB. 1967 The syndrome of inappropriate secretion of antidiuretic hormone. Am J Med42 :790–806.
3. Cutting HO. 1971 Inappropriate secretion of antidiuretic hormone secondary to vincristine therapy. Am J Med. 51:269–271.[CrossRef][Medline]
4. Cooke CR, Turin MD, Walker WG. 1979 The syndrome of inappropriate antidiuretic hormone secretion: pathophysiologic mechanisms in solute and volume regulation. Medicine. 58:240–251.[Medline]
5. Hainsworth JD, Workman R, Greico A. 1983 Management of the syndrome of inappropriate antidiuretic hormone secretion in small cell lung cancer. Cancer. 5:161–165.
6. Ishikawa S, Okada K, Saito T. 1994 Vasopressin secretion in health and disease. In: Imura H, ed. The Pituitary Gland, 2nd ed. New York; Raven Press: pp. 331–350.
7. Fujisawa G, Ishikawa S, Tsuboi Y, Okada K, Saito T. 1993 Therapeutic efficacy of non-peptide ADH antagonist OPC-31260 in SIADH rats. Kidney Int 44:19–23.
8. Yamamura Y, Ogawa H, Yamashita H, et al. 1992 Characterization of a novel aquaretic agent, OPC-31260, as an orally effective non-peptide vasopressin V₂ receptor antagonist. Br J Pharmacol. 105:787–791.[Medline]
9. Tsuboi Y, Ishikawa S, Fujisawa G, Okada K, Saito T. 1994 Therapeutic efficacy of the non-peptide AVP antagonist OPC-31260 in cirrhotic rats. Kidney Int. 46:237–244.[Medline]
10. Tsuboi Y, Ishikawa S, Fujisawa G, Okada K, Saito T. 1994 In vivo diuretic effect of a new non-peptide arginine vasopressin antagonist, OPC-31260, in conscious rats. J Endocrinol. 143:227–234.[Abstract]
11. Ohnishi A, Orita Y, Okahara R, et al. 1993 Potent aquaretic agent: a novel nonpeptide selective vasopressin antagonist (OPC-31260) in men. J Clin Invest. 92:2653–2659.
12. Ohnishi A, Orita Y, Takagi N, et al. 1995 Aquaretic effect of a potent orally active, nonpeptide V₂ antagonist in men. J Pharmacol Exp Ther. 272:546–551.[Abstract/Free Full Text]
13. Shimizu K. 1995 Aquaretic effects of the nonpeptide V₂ antagonist OPC-31260 in hydropenic humans. Kidney Int. 48:220–226.[Medline]
14. Ishikawa S, Fujita N, Fujisawa G, et al. 1996 Involvement of arginine vasopressin and renal sodium handling in pathogenesis of hyponatremia in elderly patients. Endocrinol JPN. 43:101–108.
15. Sakurai H, Kurimoto F, Ohono H, et al. 1985 A simple and highly sensitive radioimmunoassay for 8-arginine vasopressin in human plasma using a reverse-phase C₁₈ silica column. Folia Endocrinol JPN. 61:724–736.
16. Ishikawa S, Saito T, Okada K, Tsutsui K, Kuzuya T. 1986 Effect of vasopressin antagonist on water excretion in inferior vena cava constriction. Kidney Int. 30:49–55.[Medline]
17. Ishikawa S, Okada K, Saito T. 1992 Effect of new non-peptide arginine vasopressin (AVP) antagonists OPC-31260 and OPC-21268 on cellular action of AVP in cultured rat renal papillary collecting tubule cells. J Am Soc Nephrol. 3:794.
18. Fujita N, Ishikawa S, Sasaki S, et al. 1995 Role of water channel AQP-CD in water retention in SIADH and cirrhotic rats. Am J Physiol. 269:F926–F931.

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Saito, T. Articles by Yoshida, S. Search for Related Content PubMed PubMed Citation Articles by Saito, T. Articles by Yoshida, S. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB SODIUM