Antrodin A from Antrodia camphorata modulates the gut microbiome and liver metabolome in mice exposed to acute alcohol intake.

This study aimed to investigate the protective effect of Antrodin A (AdA) from Antrodia camphorata (A. camphorata) mycelium on alcohol-induced gut microbiota and liver metabolomic disorders. In acute alcoholic liver injury mice, AdA ameliorated alcoholic exposure-induced hepatic lipid deposition (TC and TG), oxidative stress (MDA), inflammation (TNF-α, IL-1ß, IL-6, IL-17 and IFN-γ), and liver damage via modulating microbiome and metabolomic responses. AdA restored the composition of intestinal flora with an increase in the relative abundance of Lactobacillus and Dubosiella and a decrease in Clostridium_sensu_stricto_1, Lachnospiraceae_NK4A136_group, Prevotellaceae_NK3B31_group, and Prevotellaceae_UCG-001. Besides, AdA favorably regulated alcohol-induced metabolic disorders, including glutathione metabolism (S-(2-hydroxyethyl)glutathione and glutathione oxidized), ascorbate and aldarate metabolism (l-ascorbic acid), and taurine and hypotaurine metabolism (taurine). In conclusion, AdA in A. camphorata is a beneficial active ingredient to treat the microbiomic and metabolic disturbance induced by alcohol intake.

Multiple hepatic infarction after transcatheter arterial infusion with SMANCS.

We report a patient with hepatocellular carcinoma who developed multiple hepatic infarction after transcatheter arterial infusion (TAI) with a suspension of styrene maleic acid neocarzinostatin (SMANCS) and Lipiodol (SMANCS/Lipiodol). The parameters of hepatic functional reserve were apparently decreased after the second TAI with SMANCS/Lipiodol, and the patient died of hepatic failure 103 days after the second TAI. The autopsy liver specimen revealed multiple hepatic infarctions associated with peripheral arterial stenosis or occlusion, and portal thrombosis. It is speculated that both the arterial occlusion and the portal thrombosis caused the hepatic infarction, based on a long-term insufficiency of blood supply to the hepatocytes arising from toxic arteritis caused by SMANCS/Lipiodol.

Effect of arterial administration of a high molecular weight anti-tumor agent, styrene maleic acid neocarzinostatin, for multiple small liver cancer--a pilot study.

To assess the efficacy of the zinostatin derivative, the anti-tumor agent, styrene-maleic acid neocarzinostatin, in treating multiple small liver cancers, 29 patients with multiple hepatocellular carcinoma of 3 cm or less in diameter were treated with intraarterial injections of this high molecular weight agent, mixed with Lipiodol. Computed tomography 3 months after the first therapy showed complete deposition of Lipiodol in the entire area of the original tumor in 8 patients (27.6%), 50%-99% deposition in 4 (13.8%), 10%-49% in 10 (34.5%), and less than 10% in 7 (24.1%). After repeated injections, Lipiodol deposition in the entire area of the original tumor was found in 11 patients (37.9%). The degree of Lipiodol deposition depended on the angiographic vascularity of the tumor and on the images of the computed tomogram during arterial portography. Although complete deposition of Lipiodol was found in all tumors in 10 (58.8%) of the 17 patients with well demarcated round hypervascularity, only 1 (8.3%) of 12 patients with ill demarcated tumors showed complete deposition of Lipiodol in the tumors. Taking into account that hypervascularity on angiograms was closely correlated with the degree of Lipiodol accumulation on computed tomograms taken later, it appears that well demarcated round-shaped liver cancer is the best candidate for styrene-maleic acid neocarzinostatin therapy.

Tumor-targeted chemotherapy with lipid contrast medium and macromolecular anticancer drug (SMANCS) for renal cell carcinoma.

Twenty-five patients with renal cell carcinoma were treated with a lipophilic macromolecular drug, poly(stylene-co-maleic acid)-conjugated neocarzinostatin (SMANCS) dissolved in lipid contrast medium (Lipiodol). The drug was injected by catheterizing the renal artery and another feeding artery in 24 patients, and in the common hepatic artery in 1 patient with metastases to the liver after a radical nephrectomy. The procedure of selective arterial administration of 3-20 mg/mL of SMANCS/Lipiodol was simple to perform and was required once every two to three weeks. Total dose of SMANCS for each patient varied from 3 to 57 mg. Both SMANCS and Lipiodol accumulated more selectively in tumor than in any other tissue and remained in the neovasculature and extracapillary space for a long time. CT pattern of the remaining oil contrast medium in the tumor was characterized by the high-density area localized mainly in the periphery of the tumor around the central necrosis. When hyperviscosity Lipiodol (Lipiodol HV) was used as lipid contrast medium, it remained more persistently in the tumor and disappeared more slowly than Lipiodol. Moreover, the pronounced anticancer effect was recognized when SMANCS/Lipiodol HV was administered compared with only SMANCS/Lipiodol. Severe side effects, such as myelosuppression, unendurable pain, paralytic ileus, etc., were not observed. This targeting chemotherapy may be of great significance for advanced renal cell carcinoma.

Treatment of renal cell carcinoma with intra-arterial administration of SMANCS dissolved in Lipiodol.

Patients 1 with an unresectable clear-cell carcinoma of the kidney was treated by intra-arterial administration of SMANCS dissolved in an oily medium, Lioidol, (SMANCS/Lipiodol). It was previously shown that targeting chemotherapy could be achieved for hepatoma by the arterially administered SMANCS/Lipiodol. In this study, SMANCS/Lipiodol was administered for renal cancer and the selective remaining of SMANCS/Lipiodol in renal cancer was observed in this patient. Patient 1, after three years and five months of repeated arterial injection of the drug, the patient's physical condition recovered sufficiently, reduction in tumor size was observed and the tumor became resectable. Patient 2 with renal carcinoma (4 cm in diameter) was treated by intra-arterial injection of SMANCS/Lipiodol and resected for prevention of postoperative recurrence. More than 90% of the tumor showed necrosis. Definite anticancer effects of the preoperative arterial administration of SMANCS/Lipiodol can be observed both clinically and histologically.

[Principle and therapeutic effect of lipophilic anticancer agent [SMANCS/lipiodol]: selective targeting with oily contrast medium].

Lipiodol, an oily contrast medium, is utilized to deliver the anticancer agent SMANCS to the target tumor in which the tumor selective delivery of 2,500 fold more than plasma was confirmed with prolonged retention in the tumor tissue. This unique tumor targeting is accomplished by the arterial injection of the oily formulation of the drug. The method utilizes unique vascular properties of tumor tissue. SMANCS is a derivative of neocarzinostatin conjugated with copolymer of styrene and maleic acid. It has much propronounced lipophilicity, stability against various harsh environments and exerts a potent cytotoxicity. Therapeutic effect of the drug to unresectable primary hepatoma is much better than the conventional method. For Child A category patients with intrahepatic metastasis in no more than three area, a 3 yr survival rate is more than 87%. When the Child's A and B are combined with no distant metastasis, 1-, 2- and 3-year survival rates are 87%, 50%, and 35%, respectively. The side effect of this treatment [SMANCS/Lipiodol, i.p.] is minimal; transitory low grade fever is the commonest one (40-50% of cases) which can be controlled by a routine protocol. No liver or marrow toxicity was observed. Procedural limitations for the lung cancer etc. are discussed.

[A case of massive hepatoma which responded to SMANCS/Lipiodol regimen with intra-arterial infusion].

Transcatheter arterial chemotherapy (SMANCS/lipiodol) was applied to massive hepatoma, which had a high AFP 213,000 ng/ml, A-P shunt, tumor thrombosis and metastatic lung cancer. After 3 months, the AFP value reduced to 18 ng/ml, massive hepatoma and the A-P shunt disappeared, but AFP-negative nodular hepatoma recurred around initial hepatoma. Each time, we injected SMANCS/lipiodol to the recurring hepatoma. The therapy in the initial stage was not so effective. The portal vein was not observed in the initial stage, but appeared after the second dosage. Metastatic lung cancer was declining in the initial dosage and 23 months later disappeared after the third dosage. The massive hepatoma occupied entirely the rt. lobe of the liver. The patient lived for 4 years, had total admission periods of 190 days and could return to life in society. In this case, we considered that transcatheter arterial chemotherapy (SMANCS/lipiodol) had remarkable effects.

[Antitumor activities of oily suspended YM881 (SMANCS) against VX2 carcinoma].

YM881 (MW 15,000) is a conjugate protein preparation of two copolymer of styrene-maleic acid [SMA] (MW 1,500) and neocarzinostatin [NCS] (MW 12,000). Antitumor activities of YM881 and NCS with or without oily solvent injected arterially against VX2 carcinoma of rabbits were examined. Based on the growth and histological examination of the tumor, remarkable anti-tumor activities were observed with oily suspended YM881 but not with the other group. This results indicate that targeting of the anticancer agent to the tumor is most important for eliciting of antitumor activities.

Reduction of hepatic metastases in rabbits by administration of an oily anticancer agent into the portal vein.

We studied a prophylactic chemotherapy against hepatic metastases arising from the shedding of tumor cells into the portal circulation. The therapy was done with a lymphographic oily contrast medium, Lipiodol, and a high molecular weight anticancer agent named poly(styrene-maleic acid) copolymer conjugated neocarzinostatin (SMANCS), developed in our laboratory. SMANCS was dissolved in Lipiodol by sonication (SMANCS/Lipiodol, 1 mg of SMANCS in 1 ml of Lipiodol). Twelve rabbits were simply inoculated with the highly malignant carcinoma VX-2. Fifteen rabbits were given injections of SMANCS in glucose and Lipiodol into the portal vein and were subsequently inoculated with the tumor cells. Eighteen were given injections of SMANCS/Lipiodol and then the tumor cells. These rabbits were killed 12 days later. Thirteen were given injections of the tumor cells alone and were allowed to survive. Sixteen were given injections of SMANCS/Lipiodol and then with the tumor cells; they were allowed to survive. Rabbits given injections of SMANCS/Lipiodol before tumor inoculation had significantly fewer (P less than 0.001) metastases than those not treated or those given SMANCS in glucose and Lipiodol. Survival was significantly longer [P less than 0.005; 36.0 +/- 7.7 (SD) days] with SMANCS/Lipiodol before tumor inoculation than without treatment [23.5 +/- 3.0 days]. SMANCS/Lipiodol has a prolonged anticancer effect because it remains in the portal vein and allows sustained drug release from the oil (Lipiodol) to aqueous spaces. Hepatic metastases might be prevented by portal administration of the appropriate oily anticancer agent.

[Antiviral and immunostimulating effect of maleic anhydride copolymers in experimental neuroviral infections]. / Protivovirusnyi i immunostimuliruiushchii éffekt sopolimerov maleinovogo angidrida pri éksperimental'nykh neirovirusnykh infektsiiakh.

The virus-inhibiting and immunostimulating activity of Soviet preparations, maleic anhydride copolymers, was demonstrated in alpha-, flavi-, and bunyavirus infections. Positive results were obtained in subcutaneous and intraperitoneal inoculations of the preparations used in prophylactic and therapeutic-prophylactic schedules. Stimulation of vaccination immunity was observed after combined use of copolymers and the vaccine against Eastern equine encephalomyelitis.

[Interferon-inducing and antiviral activity of maleic anhydride copolymers]. / Interferonindutsiruiushchaia i protivovirusnaia aktivnost' sopolimerov maleinovogo angidrida.

Data on synthesis of new polymer compounds with potential interferon-inducing and antiviral activity are presented. Maleic anhydride (MA)-based alternating copolymers, in particular, copolymers of divinyl ether with MA containing five-member oxygen cycles in the chain, as well as furan copolymers with MA, were shown to be promising interferon inducers. The antiviral activity was found in copolymers based on allene hydrocarbons.

Use of oily contrast medium for selective drug targeting to tumor: enhanced therapeutic effect and X-ray image.

Highly malignant rabbit tumor (VX-2) was implanted at the periphery of the liver in 63 rabbits. Selective delivery of the anticancer agent copoly(styrenemaleic acid) conjugated to neocarzinostatin (SMANCS), which was dissolved in an oil contrast medium (Lipiodol), was performed by injection via the proper hepatic artery. The anticancer effect was also evaluated by various parameters. By using low-kVp X-ray examination of the resected rabbit liver, Lipiodol was found to distribute throughout the entire liver arterial lumina and was retained there for about 24 hr, but disappeared from the normal liver arterial lumina gradually. However, Lipiodol was retained in the tumor tissue and vessels for at least 7 days, whereas it was undetectable in any other organs. A radioactive analogue of Lipiodol, a chloroiodinated fatty acid, was prepared by using [14C]linoleic acid. This analogue was used in the study of the distribution by low-kVp X-ray examination, Sudan III staining, and autoradiography. Lipiodol remained in the tumor vessels as well as the tumor cells. The use of the radioisotope yielded a quantitative profile of Lipiodol accumulation in tumor tissues; approximately 1000 times more at 15 min and 100 times more at 3 days after the injection than that of most other organs or plasma. Its major excretion route appeared to be through the bile and then the feces. The biological activity of SMANCS was also determined and was found to be significant in both tumor and liver even 7 days after injection. No activity was found in any other organ or tissue. The relatively high biological activity of SMANCS in the nontumorous liver adjacent to the tumor may be the result of continuous drug release from SMANCS-Lipiodol in the tumor tissue. By histological examination, massive tumor necrosis and infiltration of the inflammatory cells were found in the rabbits treated with SMANCS-Lipiodol. In the rabbits treated with Lipiodol alone, necrosis of the tumor was only minimal, and no infiltration of inflammatory cells was observed. Survival periods of the treated rabbits (n = 14) were significantly longer than those of controls (n = 10); 23.1 +/- 5.5 (S.D.) days versus 16.1 +/- 2.9 days (p less than 0.005), respectively, even though only one injection was used for this highly malignant tumor. Mean tumor size for both groups at laparotomy was 163.3 +/- 83.0 sq mm and 160.5 +/- 76.5 sq mm, respectively (not significant).(ABSTRACT TRUNCATED AT 400 WORDS)