Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027497 (nausea)
 23,468 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CL 246,738 is a synthetic heterocyclic of the acridine class that has immunomodulating, interferon (IFN)-inducing, and antitumor activity by the oral route in mice. We have completed a phase I ascending dose trial to determine the maximum tolerated oral dose and biologic modifying effects. Twenty-three patients received CL 246,738 orally at five dose levels, escalating from 5 to 50 mg/kg. The major side effects were gastrointestinal disturbances such as nausea, vomiting, and diarrhea. No hematologic, hepatic, or symptomatic dose-limiting toxicities were encountered. The mean half-life of CL 246,738 in whole blood was at least 300 h and remained relatively constant over the dose range studied. Higher doses resulted in increased whole blood levels. Biologic response modification included stimulation of the IFN-induced proteins, 2',5'-oligoadenylate synthetase and beta 2-microglobulin, at higher doses of CL 246,738, and enhanced T-cell proliferation to alloantigens at lower doses. Increases in lymphocytes bearing the Leu-7 phenotypic marker were observed and some patients had enhanced natural killer (NK) cell cytotoxicity. Enhanced NK cell cytotoxicity was demonstrated in vitro. Thus, CL 246,738 was orally relatively well tolerated and has immunomodulating properties in humans.
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PMID:Biological and clinical effects of the oral immunomodulator 3,6-bis(2-piperidinoethoxy)acridine trihydrochloride in patients with malignancy. 169 Jul 88

Forty-five patients with proved gastrointestinal amyloidosis were examined to study the clinical and pathological features and to determine the correlation with amyloid fibril proteins. The examinations included physical examination, laboratory study, plain X-ray film of the abdomen, gastrointestinal radiography, gastrointestinal endoscopy, endoscopic biopsy, surgery, and autopsy. The results were as follows: 1) Amyloid fibril proteins consisted of amyloid light chain protein (AL) in 7 patients, amyloid A protein (AA) in 36, beta 2-microglobulin (AH) in one, and prealbumin (AF) in one. 2) At the time of examination, gastrointestinal symptoms were present in 43 (96%) of the 45 patients. The incidence of diarrhea and gastrointestinal bleeding was higher in patients with the AA type than in those with other types, whereas abdominal distension, nausea, and vomiting were more frequently evident in patients with the AL type. 3) The incidence of hypoalbuminemia, hypokalemia, and positive occult blood was higher in patients with the AA type, whereas abnormal electrocardiogram and cardiac failure were more frequently observed in patients with the AL type. The thyroid gland was enlarged in 7 patients with the AA type, and the macroglossia was evident in only 2 patients with the AL type. 4) The frequency of radiographic abnormalities in the gastrointestinal tract was as follows: 79% of the patients in the jejunum and ileum, 61% in the duodenum, 53% in the stomach, 32% in the colorectum, and 14% in the esophagus. Fine granular shadows were most frequently seen in patients with the AA type, whereas multiple polypoid protrusions and thickening of the folds were characteristic in patients with the AL type. 5) Endoscopic abnormalities were found as follows: 82% in the duodenum, 81% in the jejunum, 73% in the stomach, 42% in the colorectum, and 20% in the esophagus. Endoscopy revealed fine granular appearance in 31 (86%) of the 36 patients with the AA type, whereas multiple polypoid protrusions and thickening of the folds were evident in 5 (71%) of the 7 patients with the AL type. 6) On the histological examination of the biopsy specimens, amyloid deposition was found in the duodenum in 98% of the 45 patients studied, in the jejunum in 96% of the 26 patients, in the antrum in 93% of the 41 patients, and in the rectum in 86% of the 43 patients. 7) Histological findings of the biopsy and autopsy specimens revealed that the the degree of amyloid deposition was the highest in the duodenum and jejunum of the gastrointestinal tract.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Diagnosis of gastrointestinal amyloidosis with special reference to the relationship with amyloid fibril protein]. 178 55

Tumor necrosis factor (TNF) is a cytokine with pleiotropic biological and antitumor effects in vitro and in mouse models. The immunological effects of the molecule as a single agent, however, have not been well studied clinically. We conducted a Phase I trial of TNF in 53 patients with advanced malignancies in order to determine the biological and clinical effects of TNF when administered as a 30-min i.v. infusion three times/week. Dose levels of TNF ranged from 5 to 275 micrograms/m2; doses of TNF were escalated between patient groups. The most common clinical toxicities of TNF consisted of rigors, anorexia, headache, and fatigue. Dose-limiting toxicity consisted of hypotension, fatigue, and nausea. Four patients treated at the maximally tolerated dose of 225 micrograms/m2 received dexamethasone to determine whether the toxicities of TNF could be ameliorated. No significant differences in hypotension or subjective symptomatology were observed in those patients receiving dexamethasone and those who did not or between injections in which dexamethasone was administered and when it was not. One patient with colorectal carcinoma treated with 50 micrograms/m2 had a partial response lasting about 9 months. Biological responses were evaluated in 8 patients treated at the maximally tolerated dose before therapy and 24 h afterward. TNF significantly (P less than 0.05 for all) enhanced serum beta 2-microglobulin, serum neopterin, and serum interleukin-2 receptor (Tac antigen) levels. Indoleamine 2,3-dioxygenase activity was also increased 24 h following the administration of TNF, although this increase was only of borderline statistical significance (P = 0.07). TNF did not enhance granulocyte bactericidal activity. The expression of cell surface proteins on monocytes, including HLA-DR, HLA-DQ, beta 2-microglobulin, and the Fc receptor, and serum interleukin-1 activity also were not significantly increased by the administration of TNF. Thus, in humans TNF caused biological response modulation with evidence of HLA Class I (beta 2-microglobulin) increase and T-cell (Tac antigen) and monocyte (neopterin) activation.
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PMID:Biological and clinical effects of intravenous tumor necrosis factor-alpha administered three times weekly. 199 56

Twenty-eight evaluable patients with metastatic cancer refractory to standard therapy received escalating doses of muramyl tripeptide phosphatidylethanolamine (MTP-PE) (.05 to 12 mg/m2) in phosphatidylserine (PC):phosphatidylcholine (PS) liposomes (lipid:MTP-PE) ratio 250:1). Liposomal MTP-PE (L-MTP-PE) was infused over 1 hour twice weekly; doses were escalated within individual patients every 3 weeks as tolerated for a total treatment duration of 9 weeks. Routine clinical laboratory parameters, acute phase reactants and various immunologic tests were monitored at various time points during treatment. Toxicity was moderate (less than or equal to grade II) in 24 patients with chief side effects being chills (80% of patients), fever (70%), malaise (60%), and nausea (55%). In four patients L-MTP-PE treatment was deescalated due to severe malaise and recurrent fever higher than 38.8 degrees C. The maximum-tolerated dose (MTD) was 6 mg/m2. Significant (P less than .05) increases in WBC count, absolute granulocyte count, ceruloplasmin, beta 2-microglobulin, c-reactive protein, monocyte tumoricidal activity, and serum IL-1 beta were found. Significant decreases in serum cholesterol were also observed. Clearance of intravenously (iv)-infused technetium-99 (99mTc)-labeled liposomes containing MTP-PE in four patients was biphasic; gamma camera scans revealed uptake of radiolabel in liver, spleen, lung, nasopharynx, thyroid gland, and tumor (two patients). No objective tumor regression was seen. In view of its definite immunobiologic activity and lack of major toxicity, additional phase II and adjuvant trials of L-MTP-PE are warranted.
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PMID:Phase I trial of liposomal muramyl tripeptide phosphatidylethanolamine in cancer patients. 247 21

The safety and tolerability of 1 gm imipenem and cilastatin given together every 6 hours for 10 days was evaluated in a randomized, double-blind, placebo-controlled trial in normal subjects. Nausea was more common in the drug-treated group (five of six subjects) than in the control group (two of six subjects). No consistent changes in hepatic function indices were noted. Although beta 2-microglobulin excretion showed a significant trend of rising over time in the drug group, there were no differences between groups with regard to 24-hour urinary excretion of either N-acetyl-beta-glucosaminidase or beta 2-microglobulin. Urinalysis did not reveal any casts and serial creatinine clearance determinations showed no change in renal function in either the drug- or placebo-treated groups. Pure tone audiograms were performed before and after dosing in 11 of 12 subjects; no changes were noted. We conclude that the combination of imipenem and cilastatin was well tolerated and safe.
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PMID:Safety and tolerability of multiple doses of imipenem/cilastatin. 388 56

In a phase I/II study, 7 levels of 3TC therapy (from 0.5 to 20.0 mg/kg/day) were studied in 104 asymptomatic and mildly symptomatic human immunodeficiency virus-infected patients with CD4 cell counts < or = 400 x 10(6)/L. Mild and transient episodes of diarrhea, headache, fatigue, nausea, and abdominal pain were the most frequent events reported. No dose-limiting toxicities were observed. Small and transient increases in CD4 cell counts were detected during the first 4 weeks of treatment. These were followed by progressive declines during prolonged therapy. Sustained decreases in beta 2-microglobulin, neopterin, and p24 antigen levels were seen over the 52-week study. There was no consistent dose-response correlation for any surrogate marker. Penetration of 3TC into cerebrospinal fluid (CSF) was in the same range as reported for ddC and ddI; the mean CSF-to-serum ratio was 0.06. These findings indicate that 3TC exhibits an excellent safety profile and has antiretroviral activity at the dosages studied.
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PMID:Evaluation of safety and efficacy of 3TC (lamivudine) in patients with asymptomatic or mildly symptomatic human immunodeficiency virus infection: a phase I/II study. 775 91

Imiquimod is an orally active interferon inducer with anti-tumour activity in experimental animals. In this study the tolerability, toxicity and biological effects of daily oral imiquimod administration were investigated in 21 patients with refractory cancer. Patients were treated with doses of 25 mg, 50 mg, 100 mg or 200 mg on a projected 112 day course. Only three patients completed the course, all at the 50 mg dose. Treatment toxicities were dose related and mainly comprised flu-like symptoms, nausea and lymphopenia. Of the 21 patients, five received dose reductions and in five treatment was discontinued because of treatment-related toxicity. The biological activity of imiquimod was confirmed by significant and sustained rises in peripheral blood mononuclear cell (PBMC) 2-5A synthetase (2-5AS) levels at all doses. At 100 mg and 200 mg these occurred within the first 24 h of administration. Levels of neopterin and beta 2-microglobulin (beta 2M) were also significantly elevated when assessed after three weeks' treatment. Interferon production was not demonstrated within the first 24 h of the initial dose but, following repeated doses, ten of the patients developed detectable serum interferon concentrations with a maximum value of 5600 IU ml-1 recorded. Administration of imiquimod did not have any significant effect on serum levels of tumour necrosis factor (TNF) or interleukin 1 (IL-1), nor did it lead to development of detectable levels of antibodies to interferon. One mixed clinical response was observed after 4 weeks' treatment at 100 mg in a patient with renal cell cancer. Daily administration of imiquimod causes activation of the interferon production system but at higher doses results in unacceptable toxicity. Further investigation of imiquimod as an interferon-inducing agent in cancer patients is suggested at either the lower dose levels or employing alternative dosing schedules.
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PMID:A phase I clinical trial of imiquimod, an oral interferon inducer, administered daily. 891 49

Fifteen patients with stage II, IIIA, and IIIB non-small cell lung cancer (NSCLC) received subcutaneous (s.c.) recombinant, glycosylated, human interferon-beta 1a (Rebif; rHuIFN-beta 1a) on each day of conventionally fractionated radiation therapy (RT) given in 2.0 Gy fractions to 60 Gy in 6 weeks. The rHuIFN-beta 1a was generated in CHO cells by recombinant DNA technology and is identical to natural IFN-beta produced by fibroblasts in primary sequence and glycosylation. Cohorts of three patients each were treated with escalating doses of rHuIFN-beta 1a: 1.5, 3, 6, 12, and 24 MIU/m2 per treatment day. Acute toxicity was assessed according to modified WHO criteria; late toxicity was graded using RTOG late toxicity criteria. The maximum tolerated dose (MTD) of rHuIFN-beta 1a was defined as the dose level immediately below that in which dose-limiting toxicity occurred in > or = two of six patients. Immunomodulatory effects and antigenicity of rHuIFN-beta 1a were assessed by 2-5A synthetase, beta 2-microglobulin, and neopterin levels and by measurement of anti-rHuIFN-beta antibodies, respectively. Fourteen of fifteen patients experienced grades 1-3 acute (early) toxicity (< or = 90 days), which was primarily gastrointestinal: dysphagia/esophagitis (14/15), nausea/vomiting (12/15), anorexia (7/15), and liver transaminasemia (6/15). One of three patients treated with 24 MIU/m2 per treatment day (total rHuIFN-beta 1a dose 672 MIU) died of complications secondary to pneumonia, sepsis, adult respiratory distress syndrome (ARDS), and radiation pneumonitis. Twelve patients were evaluable for late toxicity (> 90 days). Maximum toxicity was grade 0 in five patients, grade 1 in four patients, and grade 5 in one patient (radiation pneumonitis). Clinical responses from the combination were 1/15 CR, 6/15 PR, 6/15 stable disease, and 1/15 progressive disease. The MTD of rHuIFN-beta 1a has been estimated at 12 MIU/m2 per treatment day when given daily during conventional RT to 60 Gy in 6 weeks. Biologic response by rHuIFN-beta 1a alone was reflected by significant and dose-related increases in 2-5A synthetase, beta 2-microglobulin, and neopterin. Radiation therapy alone had no effect on these immune response parameters and did not diminish their augmentation by rHuIFN-beta 1a. There was no association of biologic modulation with clinical response or survival.
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PMID:Recombinant human interferon-beta (rHuIFN-beta) and radiation therapy for inoperable non-small cell lung cancer. 893 64