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NPT 15392, a new synthetic immunomodulatory agent: Human, in vitro and in vivo (cancer patients) effects
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NPT-15392: IMMUNORESTOP~ATIVEEFFECTS IN TUMOR-SUPPRESSEDMICE. S. Sato and M. Tsurufuji Bio-science Laboratory, Mitsubishi Chem. Ind., Midori-ku Yokohama, JAPAN
NPT-15392 has been demonstrated to exhibit an immuno-modulating effect on SRBC induced IgM antibody using a PFC assay, mitogen induced lymphocyte proliferation and other immune functions in normal mice° In these studies we chose to investigate whether i t was possible to restore tumor suppressed immune functions in a variety of tumor-bearing mice. Preliminary studies showed that delayed type hypersensitivity (DTH), SRBC - PFC and Con A responses in Sarcoma 180, L-1210, Ehrlich's lung metastases, Ehrlich's ascites carcinoma and NF Sarcoma were s i g n i f i c a n t l y suppressed depending on the size of the tumor inoculum and the interval of testing after the implantation of tumor cells. The i . p . administration of NPT-15392, at doses ranging from 0.01 mg/kg to 10 mg/kg, exhibited a restoration to normal or near normal levels of the tumor-suppressed immune responses. Immunorestoration was noted in Sarcoma 180 (+DTH), L-1210 (+ DTH), Ehrlich's lung metastases (+ DTH, & + PFC) and in Ehlich's Ascites Carcinoma (+DTH, + PFC, & + Con A response). No effect was noted on the depressed immune response in NF Sarcoma implanted mice. With the consistent effects observed in these studies to increase tumor-depressed immunity, NPT-15392 w i l l be employed experimentally in these tumor systems both as sole therapy and in combination with chemotherapy or surgery as a sequential treatment in an e f f o r t to maximize the immunorestorative effects reported.
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NPT 15392: A PHARMACOLOGICAND TOXICOLOGICPROFILE Simon, L.N., S e t t i n e r i , R., Pfadenhauer, E.P., Jones~ C.~ Maxwell, K. and Glasky, A.J., Newport Pharmaceuticals International, Newport Beach, CA 92660, U.S.A. NPT 15392 is a novel nitrogen heterocyclic compound having immunomodulating properties in normal animals and humans as well as in tumor bearing subjects. Prior to entry into human c l i n i c a l t r i a l s , a pharmacologic p r o f i l e and toxicological evaluation was performed. Acute studies in mice revealed an oral LD50 of > 5,000 mg/kg and an i . p . LD50 of > l,O00 mg/kg. No CV, CNS or other general pharmacological effects were seen at doses up to lO0 mg/kg. Since the minimum effective immunomodulating dose (MED) of NPT 15392 in rodents has been shown to be O.OOl mg/kg, we conducted subacute t o x i c i t y studies in rats and dogs at 3 dose levels with the highest dosage used being 2,500 times the MED. After 90 days of oral dosing at O.l, l.O and 2.5 mg/kg, no mortality or signs of t o x i c i t y were observed. A transient decrease in body weight was seen in male rats but not in dogs; an elevated blood glucose in female rats and dogs was noted at the highest dosage level tested. No adverse histopathological findings due to drug administration were reported. Administration of a single dose of NPT 15392 by either the oral, intraperitoneal or subcutaneous route resulted in measurable blood levels within 15-30 minutes of administration, with a half l i f e of approximately 60 minutes. Using C-14 labeled NPT 15392, two major metabolites were found. The structure of these metabolites has not yet been determined. Because of the low blood levels anticipated at the human therapeutic dose levels (O.OOl - O.l mg/kg), an RIA procedure was developed and w i l l be discussed. In conclusion, on the basis of these preclinical studies NPT 15392 was found to have a therapeutic index in rodents of at least 500,000 and considered to be safe for administration to humans for further c l i n i c a l evaluation.
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NPT-15392: IMMUNORESTOP~ATIVEEFFECTS IN TUMOR-SUPPRESSEDMICE. S. Sato and M. Tsurufuji Bio-science Laboratory, Mitsubishi Chem. Ind., Midori-ku Yokohama, JAPAN
NPT-15392 has been demonstrated to exhibit an immuno-modulating effect on SRBC induced IgM antibody using a PFC assay, mitogen induced lymphocyte proliferation and other immune functions in normal mice° In these studies we chose to investigate whether i t was possible to restore tumor suppressed immune functions in a variety of tumor-bearing mice. Preliminary studies showed that delayed type hypersensitivity (DTH), SRBC - PFC and Con A responses in Sarcoma 180, L-1210, Ehrlich's lung metastases, Ehrlich's ascites carcinoma and NF Sarcoma were s i g n i f i c a n t l y suppressed depending on the size of the tumor inoculum and the interval of testing after the implantation of tumor cells. The i . p . administration of NPT-15392, at doses ranging from 0.01 mg/kg to 10 mg/kg, exhibited a restoration to normal or near normal levels of the tumor-suppressed immune responses. Immunorestoration was noted in Sarcoma 180 (+DTH), L-1210 (+ DTH), Ehrlich's lung metastases (+ DTH, & + PFC) and in Ehlich's Ascites Carcinoma (+DTH, + PFC, & + Con A response). No effect was noted on the depressed immune response in NF Sarcoma implanted mice. With the consistent effects observed in these studies to increase tumor-depressed immunity, NPT-15392 w i l l be employed experimentally in these tumor systems both as sole therapy and in combination with chemotherapy or surgery as a sequential treatment in an e f f o r t to maximize the immunorestorative effects reported.
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NPT 15392: A PHARMACOLOGICAND TOXICOLOGICPROFILE Simon, L.N., S e t t i n e r i , R., Pfadenhauer, E.P., Jones~ C.~ Maxwell, K. and Glasky, A.J., Newport Pharmaceuticals International, Newport Beach, CA 92660, U.S.A. NPT 15392 is a novel nitrogen heterocyclic compound having immunomodulating properties in normal animals and humans as well as in tumor bearing subjects. Prior to entry into human c l i n i c a l t r i a l s , a pharmacologic p r o f i l e and toxicological evaluation was performed. Acute studies in mice revealed an oral LD50 of > 5,000 mg/kg and an i . p . LD50 of > l,O00 mg/kg. No CV, CNS or other general pharmacological effects were seen at doses up to lO0 mg/kg. Since the minimum effective immunomodulating dose (MED) of NPT 15392 in rodents has been shown to be O.OOl mg/kg, we conducted subacute t o x i c i t y studies in rats and dogs at 3 dose levels with the highest dosage used being 2,500 times the MED. After 90 days of oral dosing at O.l, l.O and 2.5 mg/kg, no mortality or signs of t o x i c i t y were observed. A transient decrease in body weight was seen in male rats but not in dogs; an elevated blood glucose in female rats and dogs was noted at the highest dosage level tested. No adverse histopathological findings due to drug administration were reported. Administration of a single dose of NPT 15392 by either the oral, intraperitoneal or subcutaneous route resulted in measurable blood levels within 15-30 minutes of administration, with a half l i f e of approximately 60 minutes. Using C-14 labeled NPT 15392, two major metabolites were found. The structure of these metabolites has not yet been determined. Because of the low blood levels anticipated at the human therapeutic dose levels (O.OOl - O.l mg/kg), an RIA procedure was developed and w i l l be discussed. In conclusion, on the basis of these preclinical studies NPT 15392 was found to have a therapeutic index in rodents of at least 500,000 and considered to be safe for administration to humans for further c l i n i c a l evaluation.