UMLS:C0038362 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038362 (stomatitis)
8,852 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this paper, we have investigated the effects of the pore-forming toxin aerolysin, produced by Aeromonas hydrophila, on mammalian cells. Our data indicate that the protoxin binds to an 80-kD glycosyl-phosphatidylinositol (GPI)-anchored protein on BHK cells, and that the bound toxin is associated with specialized plasma membrane domains, described as detergent-insoluble microdomains, or cholesterol-glycolipid "rafts." We show that the protoxin is then processed to its mature form by host cell proteases. We propose that the preferential association of the toxin with rafts, through binding to GPI-anchored proteins, is likely to increase the local toxin concentration and thereby promote oligomerization, a step that it is a prerequisite for channel formation. We show that channel formation does not lead to disruption of the plasma membrane but to the selective permeabilization to small ions such as potassium, which causes plasma membrane depolarization. Next we studied the consequences of channel formation on the organization and dynamics of intracellular membranes. Strikingly, we found that the toxin causes dramatic vacuolation of the ER, but does not affect other intracellular compartments. Concomitantly we find that the COPI coat is released from biosynthetic membranes and that biosynthetic transport of newly synthesized transmembrane G protein of vesicular stomatitis virus is inhibited. Our data indicate that binding of proaerolysin to GPI-anchored proteins and processing of the toxin lead to oligomerization and channel formation in the plasma membrane, which in turn causes selective disorganization of early biosynthetic membrane dynamics.
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PMID:A pore-forming toxin interacts with a GPI-anchored protein and causes vacuolation of the endoplasmic reticulum. 945 14

A new oral type of 5-fluorouracil (5-FU) derivative possessed of both potent antitumor activity and less gastrointestinal (GI) toxicity was investigated and developed in the form of a combination of tegafur (FT), a masked form of 5-FU, and its two peculiar biochemical modulators. One is 5-chloro-2,4-dihydroxypyridine (CDHP), a new potent inhibitor of 5-FU degradation in vivo, and another is potassium oxonate (Oxo), a characteristic inhibitor of 5-FU phosphorylation, which distributes much higher in GI tract after p.o. administration. 5-FU levels in blood of rats following administration of FT, were markedly elevated and persisted for a long-time by co-oral CDHP corresponding to over 0.4 molar ratio to FT, like the case in continuous infusion of 5-FU, which resulted in an augmentation of antitumor efficacy in Yoshida sarcoma-bearing rats, although severe GI toxicity simultaneously occurred. To reduce 5-FU-induced toxicities such as diarrhea and body weight loss and to maintain the augmented antitumor activity, 0.5 to 2 molar Oxo was orally given to rats with one molar FT plus 0.4 molar CDHP. As a result, both severe GI injury and body weight loss were markedly inhibited by coadministration of 0.5 to 1.0 molar Oxo while high antitumor efficacy (about 90% inhibition of tumor growth) was maintained. However, such almost complete antitumor effect was reduced to about 50% inhibition of tumor growth by over 2 molar Oxo combined with one molar FT plus 0.4 molar CDHP. Based on these results, a novel 5-FU derivative, named S-1, was composed of one molar FT, 0.4 molar CDHP and one molar Oxo. S-1 showed an antitumor activity over 3-fold stronger than UFT (one molar FT plus 4 molar uracil) against Yoshida sarcoma and Sato lung carcinoma in rats and human colon carcinoma (KM12C) xenografted in nude rats when its minimum toxic dose was administered. Co-oral Oxo also significantly reduced the incidence of diarrhea and stomatitis induced by administration of FT-CDHP in beagle dogs. These results suggest that high antitumor activity and less GI toxicity of S-1 was brought about by the elevation in blood and tumor tissues and by selective decrease of 5-fluoronucleotides, an active metabolite of 5-FU, in GI tract.
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PMID:[Invention of a tumor-selective 5-fluorouracil derivative named S-1 by biochemical modulation of 5-fluorouracil]. 949 31

In an effort to improve the therapeutic selectivity of 5-fluorouracil (FUra) against colorectal cancer, S-1, a combination agent including a prodrug of FUra with two modulators, was recently developed by Taiho Pharmaceuticals Co. S-1 is a combination of tegafur (FT), 5-chloro-2,4-hydroxypyridine, and potassium oxonate in the molar ratio of 1.0:0.4:1.0, with the latter two components as inhibitors of dihydropyrimidine dehydrogenase and phosphoribosylpyrophosphate transferase, respectively. In this study, the therapeutic selectivity and efficacy of S-1 (oral) was compared with FT (oral) and FUra (i.v. infusion) in rats bearing advanced colorectal cancer by using clinically relevant schedules. The maximum tolerated doses (MTDs) of S-1, FT, and FUra were 31.5, 200, and 25 mg/kg/d for 7 days and 22.5, 150, and 12.5 mg/kg/d for 28 days, respectively. The therapeutic index of S-1 was 4- to 5-fold higher than that of either FT or FUra. S-1 achieved 100% complete tumor regression (CR) at its MTD in both 7-day and 28-day schedules. Furthermore, the high incidences of stomatitis, alopecia, and diarrhea observed with FUra and FT, were not observed with S-1. In an attempt to understand the basis for the observed superior therapeutic selectivity with S-1, we studied pharmacokinetic analysis of FUra, drug-induced apoptosis, suppression of mitosis, and inhibition of thymidylate synthase (TS) after S-1, FUra, or FT administration. The peak plasma FUra concentrations derived from FUra or S-1 (FT) at comparable MTDs were similar, but the plasma level of FUra was higher with S-1 than with FUra. Induction of high and sustained apoptosis was achieved with S-1. Although the initial level of apoptosis induced by FUra was comparable to S-1, it was not sustained. The sustained level of apoptosis appears to correlate with tumor growth inhibition. Mitotic figures were more greatly suppressed with S-1 treatment than with FUra. Studies on TS inhibition indicated that, although both S-1 and FUra caused a 4- to 6-fold induction of total TS protein, single oral administration of S-1 was superior to 24-h infusion of FUra in suppressing free TS. The data are consistent with the observation that the therapeutic efficacy of S-1 (100% cure) over FUra is associated with high and sustained levels of drug-induced apoptosis, greater suppression of mitosis, and inhibition of free TS in tumor tissues.
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PMID:Persistent induction of apoptosis and suppression of mitosis as the basis for curative therapy with S-1, an oral 5-fluorouracil prodrug in a colorectal tumor model. 1003 74

Out of 938 parasitologically confirmed patients with visceral leishmaniasis treated with amphotericin B (1 mg/kg bodyweight daily infused in 2 h for 20 days), 935 were cured clinically, 933 parasitologically and 931 ultimately (no relapse within 6 months). Two parasitologically 'not cured' and 4 relapsed patients were cured with 25 infusions, and 1 with double relapse with 30 infusions. The treatment was started only when serum haemoglobin reached 5 g/dL, serum electrolyte imbalance was corrected and sodium stibogluconate-induced myocardial damage stabilized after 10 days' rest. Bronchopneumonia, cardiac failure and acute renal failure caused the death of 1 patient each. Nightblindness, angular stomatitis, neuritis, and petechial haemorrhages improved with appropriate treatment; 2 patients were given blood transfusion for post-treatment anaemia. Nausea and anorexia, and changes in serum creatinine and potassium, became normal in 2 weeks. Immediate withdrawal of the drug and restart after 10 days cured 2 patients who developed acute renal failure. Infusion-related toxicities--shivering, rigor and fever--were minimized but not eliminated by prior administration of hydrocortisone. Tuberculosis and visceral leishmaniasis were treated concurrently. Four pregnant patients were successfully treated without harmful effects on mother and child. It was concluded that the dosage of amphotericin B used was an effective and well-tolerated regimen and achieved 99% cure. Toxicity could be minimized with some precautions. All unresponsive and relapsed patients responded to more amphotericin and no resistance to the drug was seen.
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PMID:Amphotericin B deoxycholate treatment of visceral leishmaniasis with newer modes of administration and precautions: a study of 938 cases. 1049 70

The effects of three representative disinfectants, chlorine (sodium hypochlorite), iodine (potassium tetraglicine triiodide), and quaternary ammonium compound (didecyldimethylammonium chloride), on several exotic disease viruses were examined. The viruses used were four enveloped viruses (vesicular stomatitis virus, African swine fever virus, equine viral arteritis virus, and porcine reproductive and respiratory syndrome virus) and two non-enveloped viruses (swine vesicular disease virus (SVDV) and African horse sickness virus (AHSV)). Chlorine was effective against all viruses except SVDV at concentrations of 0.03% to 0.0075%, and a dose response was observed. Iodine was very effective against all viruses at concentrations of 0.015% to 0.0075%, but a dose response was not observed. Quaternary ammonium compound was very effective in low concentration of 0.003% against four enveloped viruses and AHSV, but it was only effective against SVDV with 0.05% NaOH. Electron microscopic observation revealed the probable mechanism of each disinfectant. Chlorine caused complete degeneration of the viral particles and also destroyed the nucleic acid of the viruses. Iodine destroyed mainly the inner components including nucleic acid of the viruses. Quaternary ammonium compound induced detachment of the envelope of the enveloped viruses and formation of micelle in non-enveloped viruses. According to these results, chlorine and iodine disinfectants were quite effective against most of the viruses used at adequately high concentration. The effective concentration of quaternary ammonium compound was the lowest among the disinfectants examined.
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PMID:Effects of chlorine, iodine, and quaternary ammonium compound disinfectants on several exotic disease viruses. 1067 96

We describe in this paper a therapeutic modality which is based on a self-rescuing concept (SRC) featuring dual activity, i.e., effect-enhancing activity and adverse reaction-reducing activity. We present the theory and practice of S-1, a novel oral fluoropyrimidine anticancer agent designed to enhance anticancer activity and reduce gastrointestinal toxicity through the deliberate combination of the following components: an oral fluoropyrimidine agent, tegafur (FT); a DPD inhibitor (CDHP: 5-chloro-2, 4-dihydroxypyridine) which is about 200-fold more potent than uracil used in UFT; and an ORTC inhibitor (Oxo: potassium oxonate) which is localized in the gastrointestinal tract. We devised a novel oral anticancer agent, S-1, as a combination drug with a molar ratio of 1:0.4:1 for FT, CDHP, and Oxo, respectively. To compare S-1, FT, and UFT in terms of their anticancer activity and adverse reactions, a colon cancer implantation model in rats was used for 4-week consecutive oral administration from the time when the postimplantation tumor weight become about 2 g. The tumor disappeared on day 16 at a given dose of S-1 (as 22.5 mg/kg FT), and the tumor did not reappear for at least three months. Antitumor activity was more marked with S-1 than FT and UFT. Adverse reaction, i.e., stomatitis, depilation, and weight loss, were less frequent in the S-1 group than in the other groups. A clinical pharmacology study examined blood concentrations of 5-FU after twice-a-day administration after meals of S-1 at a dose of 40 mg/m2. Blood concentrations of 5-FU were 60 to 200 ng/ml in all twelve patients examined. Late phase II clinical trials of S-1 were conducted in patients with advanced and recurrent stomach cancers, in the same regimen as for the clinical pharmacology study. It basically consisted in four cycles, each of which comprised 4-week, twice-a-day, consecutive oral administration with a 2-week withdrawal. The overall response rate was 44.6% (45/101). Median survival time (MST) was 224 days. S-1 was given manufacturing approval by the Ministry of Health and Welfare of Japan after a priority review, with indications for advanced and recurrent stomach cancers. A late phase II clinical study of S-1 in patients with advanced/recurrent head and neck cancer was conducted in 59 eligible patients. Objective responses were 4 complete response (CR) and 13 partial response (PR), for a response rate of 28.8% (17/59). MST was 344 days. Grade 4 hemoglobin decrease was observed in one case; however, this returned to normal after the termination of drug administration and blood transfusion. Therefore, this event was confirmed to be reversible. A late phase II clinical trial of S-1 was conducted to evaluate the efficacy and toxicities in patients with metastatic colorectal carcinoma. Sixty-three patients with measurable metastatic colorectal carcinoma were enrolled in this clinical trial. The overall response rate was 35.5% (22/62), and the MST was 378 days. The main adverse reactions were myelosuppression and GI toxicities. The incidence of neutropenia (Grade 3 or 4) was 13%, while the incidence of other adverse reactions was 10% or below. None of 53 outpatients required to be hospitalization due to adverse reactions. Late phase II clinical trials of S-1 are in progress for colorectal cancer, breast cancer and non-small cell lung cancer. To establish the standard therapeutic modality for cancers, including gastrointestinal cancers, in Japan, the conduction of clinical trials combining S-1 and other anticancer drugs holds promise for the future.
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PMID:[New oral anticancer drug, TS-1 (S-1)--from bench to clinic]. 1143 58

S-1 is a new oral formulation of 5-fluorouracil (5-FU) containing 1 M tegafur and 0.4 M 5-chloro-2,4-dihydroxypyridine (CDHP) and 1 M potassium oxonate (Oxo). It has been reported to have a high antitumor activity and low gastrointestinal toxicity in rats bearing murine and human tumors. We further studied the possible inhibition of the toxicities caused by the products of 5-FU metabolism with the use of CDHP, a new inhibitor of 5-FU degradation and Oxo, an inhibitor of 5-FU phosphorylation. In a model of pentylenetetrazole-induced convulsions in mice, intravenous injection of fluoroacetate (3 mg/kg), 2-fluoro-b-alanine (30 mg/kg) and 5-FU (over 300 mg/kg) significantly augmented the occurrence of convulsion. However coadministration of an equivalent dose of CDHP with 5-FU almost completely suppressed the 5-FU-augmented convulsions, suggesting that inhibition of 5-FU catabolism by CDHP may lead to a decreased risk of development of 5-FU neurotoxicity. Another advantage of the use of S-1 was protection through Oxo against the development of 5-FU-induced mucositis, which occurs frequently in cancer patients. When 6 mg/kg of S-1 was administered orally to beagle dogs for 5 days, the incidence of stomatitis decreased markedly compared to that in dogs receiving the same dose of S-1 not containing Oxo, in which severe stomatitis was frequently observed. One of the possible mechanisms of the decreased incidence of mucositis associated with oral S-1 administration is the decreased formation of 5-fluoronucleotides from 5-FU in the mucosal tissues of the oral cavity. These results suggest that oral S-1 could be employed for the treatment of cancer patients with marked reduction in the incidence of toxicities including encephalopathy, stomatitis and diarrhea.
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PMID:Possible regulation of 5-fluorouracil-induced neuro- and oral toxicities by two biochemical modulators consisting of S-1, a new oral formulation of 5-fluorouracil. 1149 50

We have constructed two retroviral vectors, one expressing multidrug resistance protein 1 (MRP1) alone (SF91MRP) and the other expressing MRP1 and gamma-glutamylcysteine synthetase (gamma-GCS), the rate-limiting enzyme of glutathione biosynthesis (SF91GCS-MRP). We have utilized the hybrid FMEV (Friend mink cell focus-forming/murine embryonic stem cell virus) backbone, previously shown to be efficient in early hematopoietic cells, even when coexpressing two distinct genes. In SF91GCS-MRP, the cDNAs were combined via an internal ribosomal entry site (IRES) sequence from poliovirus, resulting in a bicistronic mRNA produced via the long terminal repeat (LTR). Producer Fly-eco clones were established by trans-infection with vesicular stomatitis virus glycoprotein (VSV-G)-pseudotyped retroviral supernatants. Drug-resistant producer clones were subsequently selected with antimony potassium tartrate, a nonmutagenic MRP1 substrate. By RNA slot-blot and transduction of 3T3 fibroblasts, titers of both SF91MRP and SF91GCS-MRP were found to be greater than 10(6) viral particles/ml. The correct viral integration in the genome was established by Southern blotting. By flow cytometry, both MRP1 and bicistronic clones showed an increase in expression of the MRP1 protein. The bicistronic producer clones, as well as 3T3 cells transduced with SF91GCS-MRP, presented an increase in intracellular glutathione levels, compared with the parental counterparts. Producer cells, 3T3 fibroblasts transduced with either SF91MRP or SF91GCS-MRP, and primary murine myeloid progenitor cells transduced with SF91GCS-MRP were resistant to MRP1-effluxed drugs. However, only bicistronic producers, 3T3 fibroblasts transduced with SF91GCS-MRP, and primary murine myeloid progenitor cells transduced with SF91GCS-MRP were also resistant to alkylating agents. We conclude that the retrovirus SF91GCS-MRP has features that make it a suitable vector to induce bone marrow resistance to multiple classes of chemotherapeutic agents. The strategy of coexpressing gamma-GCS and MRP1 may help to design an effective in vivo selection for various clinical protocols of gene therapy.
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PMID:Novel bicistronic retroviral vector expressing gamma-glutamylcysteine synthetase and the multidrug resistance protein 1 (MRP1) protects cells from MRP1-effluxed drugs and alkylating agents. 1156 Jul 71

Although 5-fluorouracil (5-FU) was first introduced in 1957, it remains an essential part of the treatment of a wide range of solid tumors. 5-FU has antitumor activity against epithelial malignancies arising in the gastrointestinal tract and breast as well as the head and neck, with single-agent response rates of only 10%-30%. Although 5-FU is still the most widely prescribed agent for the treatment of colorectal cancer, less than one-third of patients achieve objective responses. Recent research has focused on the biomodulation of 5-FU to improve the cytotoxicity and therapeutic effectiveness of this drug in the treatment of advanced disease. As all the anticancer agents, 5-FU leads to several toxicities. The toxicity profile of 5-FU is schedule dependent. Myelotoxicity is the major toxic effect in patients receiving bolus doses. Hand-foot syndrome (palmar-plantar erythrodysesthesia), stomatitis, and neuro- and cardiotoxicities are associated with continuous infusions. Other adverse effects associated with both bolus-dose and continuous-infusion regimens include nausea and vomiting, diarrhea, alopecia, and dermatitis. All these reasons explain the need for more effective and less toxic fluoropyrimidines. In the first part of this review, we briefly present the metabolic pathways of 5-FU responsible for the efficacy and toxicity of this drug. This knowledge is also necessary to understand the target(s) of biomodulation. The second part is devoted to a review of the literature on three recent prodrugs of 5-FU, i.e., capecitabine, UFT (ftorafur [FTO] plus uracil), and S-1 (FTO plus 5-chloro-2,4-dihydroxypyridine plus potassium oxonate). The pharmacological principles that have influenced the development of these new drugs and our current knowledge of the clinical pharmacology of these new agents, focusing on antitumor activity and toxicity, are presented. The literature was analyzed until March 2002. This review is intended to be as exhaustive as possible since it was conceived as a work tool for readers wanting to go further.
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PMID:Clinical studies of three oral prodrugs of 5-fluorouracil (capecitabine, UFT, S-1): a review. 1218 93

Antimony is a poisonous element with toxic properties that mimic those of arsenic. Numerous reports describe gastrointestinal complications of vomiting, diarrhea and stomatitis associated with antimony exposure. However, antimony toxicity from the use of tartar emetic as a treatment for alcohol abuse has never been described previously. A 19-y-o man with a history of alcohol abuse ingested a 10 mL bottle of "Soluto Vital" (tartar emetic, 50 mg/mL), produced in Guatemala for treatment of alcohol abuse. He presented 60 min after ingestion with severe vomiting, abdominal cramps, diarrhea, weakness and orthostasis. Initial laboratory evaluations were remarkable for creatinine of 2.5 mg/dL, potassium 6.1 mEq/L, and 60% hematocrit. He was given activated charcoal, iv saline and antiemetics. Over the next 48 h his creatinine normalized to 1.1 mg/dL and the hematocrit returned to 53%; urine had an antimony concentration of 1200 mcg/L (normal = < 10 mcg/L). It is important to recognize that foreign alcohol therapies aversive therapy other than disulfiram may be used, the contents of such a foreign product should be identified.
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PMID:Antimony toxicity from the use of tartar emetic for the treatment of alcohol abuse. 1558 54

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