Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018681 (headache)
 56,091 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tiazofurin, an investigational antimetabolite, is undergoing clinical evaluation in leukemia. We analyzed the data base of 198 patients entered in Phase I trials to characterize the incidence and severity of toxicities associated with tiazofurin according to dose and schedule. Severe myelosuppression occurred infrequently, and was not dose-dependent. A five day bolus schedule had a higher incidence of severe or life-threatening neutropenia than other schedules. Tiazofurin produced lymphopenia which was not dose-dependent in the range of 23-36% decrease from baseline, and the effect on lymphocyte count was generally greater than the decline in neutrophil count. Non-hematologic toxicity of a moderate or worse severity (greater than or equal to grade 2) included nausea and vomiting (18% of all courses), serum transaminase elevations (SGOT, 16%; SGPT, 9%), rash (9%), stomatitis (3%), conjunctivitis (3%), headache (10%), other signs of central nervous system toxicity (8%), and cardiac toxicity, primarily pleuropericarditis (4%). Dose-related cutaneous toxicity, headache, and nausea and vomiting were evident in the five day bolus schedule, and myalgia was more frequently reported at higher doses on the single dose schedule. The five day continuous infusion (CI) schedule had a higher incidence of neurotoxicity, cardiac toxicity, SGPT elevations and ocular toxicity than the daily for five days bolus schedule, but none of these differences attained statistical significance. Although the peak plasma concentrations of tiazofurin achieved with the five day bolus schedule were 3-fold higher than the steady-state plasma levels seen with an equal dose given by CI, the area under the concentration-time curve (AUC) was approximately 1.6-fold higher with CI. These observations suggest that both high peak plasma concentrations (above 400 microM) and prolonged exposure to plasma levels exceeding 50 microM may result in a higher incidence of serious non-hematologic toxicity.
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PMID:Clinical toxicity associated with tiazofurin. 220 Jul 59

A therapeutic committee was established in Toulouse Regional University Hospital in order to prescribe zidovudine in patients suffering from AIDS. Using an informatic card, the side effects were evaluated in the 125 patients treated by Zidovudine since the creation of the Committee (from July 1987 to January 1989). Zidovudine was prescribed from May 1987 to June 1988 at the total dose of 1,200 mg daily from June 1988 at 900 mg daily. The most frequent side effects were hematologic: zidovudine used alone (or associated with non hematotoxic drugs) elicited in 21.2% of patients a neutropenia (defined as a number of neutrophils less than 1,000/mm3), in 2.4% anaemia (haemoglobin less than or equal to 9 g/100 ml) and in 4.8% neutropenia associated with anaemia. When zidovudine was administered with hematotoxic drugs, neutropenia, anaemia or the association of both were observed in 12.0%, 3.2% and 2.4% of patients respectively. These hematologic side effects were always regressive after drug cessation. However, it is important to underline the low incidence of hematological side effects on red cells of zidovudine in the present study. This result is unexpected. The other side effects of Zidovudine (used alone) did not led to modification in drug treatment: gastrointestinal disturbances (30.4%), headaches (16.8%), insomnia (13.6%), somnolence (6.4%).... These side effects appeared during the four first months and decreased with the continuation of drug treatment. Their imputation was difficult to define and differentiate to evolution of the disease.
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PMID:[Evaluation of the pharmacovigilance follow-up of zidovudine]. 226 33

In desperation, we have used retrovir in five hemophilic children (10-16 years old) over the past 22 months. All had presented with various clinical manifestations of acquired-immune-deficiency-syndrome (AIDS)-related complex or AIDS. Our decision to treat with retrovir was based on clinical manifestations and very low numbers of CD4 cells (less than 200). The most common clinical presentation was recurrent oral moniliasis. Other significant findings included recurrent herpes zoster, thrombocytopenia, growth failure, and biliary tract infection. Initially, all five children received the full adult dosage of retrovir (200 mg q 4 h x 6 doses/day). This dosage had to be reduced in four children because of toxicity. The most commonly observed toxic side effects were anemia and neutropenia. Alanine aminotransferase (ALT) levels rose to 4-10 times the upper limit of normal in four of five children. One was on concomitant ketokonazole prior to the rise in ALT level. Myalgia and headache were reported by two patients. Improvement in clinical and immunological status was observed in all children initially. After 12-18 months of retrovir therapy, infectious complications secondary to prolonged neutropenia were seen in these immunocompromized children. However, compared to historic controls, these children have had fairly stable disease. We feel that all hemophilic children with symptomatic human immunodeficiency virus infection should be offered this drug, even though the optimal dosage for children is not yet established.
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PMID:Retrovir therapy in hemophilic children with symptomatic human immunodeficiency virus infection: efficacy and toxicity. 237 12

The genes for a number of growth factors that stimulate human hematopoietic and lymphoid cells in vitro have recently been cloned and recombinant molecules provided for clinical trials. For three of these (erythropoietin, G-CSF, and GM-CSF), phase I and II studies have been completed and promising results have been obtained. Of particular relevance to the field of bone marrow transplantation (BMT) has been the finding that G-CSF and GM-CSF could shorten the period of neutropenia in patients treated with chemotherapy, including regimens requiring BMT support. Doses of up to 240 micrograms/m2 of GM-CSF have been well tolerated and have increased the peripheral blood neutrophil count in a dose-dependent manner. At higher doses, eosinophils and monocytes were also increased. A continuous infusion over at least 2 h was found to be superior to bolus administration in terms of both efficacy and reduced side effects. These have usually been mild, but bone pain, headache, fatigue and elevated temperature have been encountered. The rise in neutrophil numbers shortly after initiating treatment with GM-CSF is probably due to neutrophil demargination. After a few days increased bone marrow cellularity has also been noted. In addition to these effects on cell numbers, enhancement of granulocyte and monocyte functions has been documented. However, a major concern with the use of G-CSF and GM-CSF in cancer patients, particularly those with hematopoietic malignancies, is the potential of these molecules to stimulate malignant cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Colony stimulating factors. 245 88

The in vivo effect of yeast-derived recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) was investigated in 29 patients with advanced malignancy in phase Ib trial. Patients were treated at six different dose levels (30-1000 micrograms/m2/day) with either daily intravenous bolus injection or 24 hours continuous infusion for 5 days or 2 weeks. Administration of rh GM-CSF resulted in a broad spectrum of dose-, route-, and schedule-dependent hematopoietic effects. Sustained infusion of rh GM-CSF elicited a maximum 17-fold average peak increase of the total white blood cell (WBC) count with mainly neutrophils, eosinophils, and monocytes accounting for this rise, and increases in bone marrow cellularity with a shift to immature myeloid elements. Elevation of lymphocytes, platelets and reticulocytes was not induced. Within one week after discontinuation of treatment the leukocytosis had disappeared. Adverse reactions encountered with rh GM-CSF seen in 65% of the patients studied were never life-threatening and always reversible. They included mild myalgias, facial flushing, low-grade fever, headache, bone discomfort, nausea, dyspnoea and transient decline of platelet counts. These results suggest that rh GM-CSF can be safely administered at the doses and schedules employed and that it can induce in vivo some of the biological effects reported in in vitro studies. Although no objective antitumour responses have been seen, the ability of rh GM-CSF to increase turnover and function of leukocytes in vivo may prevent neutropenia and infections, when GM-CSF is adjunctively added to cytotoxic cancer therapy.
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PMID:Yeast-expressed granulocyte-macrophage colony-stimulating factor in cancer patients: a phase ib clinical study. 246 45

Recombinant alpha-interferon (IFN-R) was given to 17 patients with non-A, non-B chronic hepatitis (NANB-CH) and to 11 patients with B chronic hepatitis (B-CH). Fever (100.4 to 102.2 Fahrenheit) was observed in every patient during the early phase of treatment. Other side-effects included rigors, myalgia, headache and laboratory changes such as leucopenia, neutropenia and, in some cases, thrombocytopenia. However, the tolerance was considered acceptable and treatment had to be interrupted in only one patient presenting generalized mucosal lesions attributed to a hypersensitivity reaction. The response to IFN-R in NANB-CH was considered positive when serum aminotransferase levels became normal or below two times the upper normal limit. Out of eight patients who completed the treatment, four were considered as responders but one of them, treated during five months, showed a relapse after three months. On the other hand, in one patient treated for twelve months, a persistent normalization of serum amino-transferases was observed: a liver biopsy showed a striking decrease of the inflammatory changes. As to the B-CH. 3 out of 8 patients who completed the treatment showed a disappearance of HBeAg and DNA-polymerase and were considered as responders. These preliminary results show that IFN-R is a promising drug but only multicenter controlled trials will establish its value in the treatment of viral chronic hepatitis.
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PMID:[Recombinant alfa interferon in the treatment of chronic B and non-A, non-B hepatitis: preliminary results]. 251 13

The in vivo effect of yeast-derived recombinant human granulocyte-macrophage colony-stimulating factor (rh GM-CSF) was investigated in 30 patients with advanced malignancy in a phase Ib trial. Patients were treated at four different dose levels (120 to 1,000 micrograms/m2/d) by either daily intravenous (IV) bolus injection or 24-hour continuous infusion. Administration of rh GM-CSF resulted in a broad spectrum of dose- and schedule-dependent hematopoietic effects. Sustained infusion of rh GM-CSF elicited a maximum 17-fold average peak increase of the total WBC count with mainly neutrophils, eosinophils, and monocytes accounting for this rise, and increases in bone marrow cellularity with a shift to immature myeloid elements. Elevation of lymphocytes, platelets, and reticulocytes was not induced. Within five days after discontinuation of treatment the leukocytosis had disappeared. Adverse reactions encountered with rh GM-CSF seen in 65% of the patients studied were never life-threatening and always rapidly reversible. They included mild myalgias, facial flushing, low-grade fever, headache, bone discomfort, nausea, dyspnea, and transient decline of platelet counts. These results suggest that rh GM-CSF can be safely administered at the doses and schedules used and that it can induce in vivo some of the biological effects reported in in vitro studies. Although no objective antitumour responses have been seen, the ability of rh GM-CSF to increase number and function of leukocytes in vivo may prevent neutropenia and infections when GM-CSF is added to cytotoxic cancer therapy.
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PMID:Hematopoietic responses in patients with advanced malignancy treated with recombinant human granulocyte-macrophage colony-stimulating factor. 264 95

Dipyridamole (DP) blocks nucleoside salvage by inhibiting uptake at the cell membrane. At the usual oral doses DP has no cytotoxic activity, but when combined with an antimetabolite, it results in synergistic cell kill in vitro. In this study, 45 patients with advanced solid tumors were treated with oral DP and i.v. or i.m. methotrexate (MTX) to define the toxicity of this combination. The DP dose was 75 mg b.i.d. in the first 16 patients, 150 mg b.i.d. in the next 2, and 75 mg q.i.d. in the remaining 27 patients. MTX was given weekly at an initial dose of 10-30 mg/m2 and increased weekly by 5-10 mg/m2 to the maximum tolerable dose (MTD) or a maximum of 60 mg/m2; thereafter that dose was given every other week. DP levels ranged from 2.76 to 11.46 microM, with a mean of 5.67 microM in four patients taking 75 mg q.i.d. The combination of oral DP and MTX was generally well tolerated and did not appear to result in any more myelotoxicity or mucositis than that expected for MTX alone. One patient experienced severe headaches related to DP, ten patients experienced grade 3 or 4 neutropenia and/or thrombocytopenia, and four patients had grade 3 mucositis. Although this trial was not designed as a phase II study, one partial remission was observed in a patient with metastatic pleomorphic adenoma of the parotid gland and seven patients showed significant improvement.
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PMID:Oral dipyridamole and methotrexate in human solid tumors: a toxicity trial. 264 13

Zidovudine (azidothymidine) is a thymidine analogue antiretroviral drug active against human immunodeficiency virus (HIV). In acquired immunodeficiency syndrome (AIDS) and AIDS-related complex (ARC) patients, orally and intravenously administered zidovudine is effective in reducing the incidence of opportunistic infections and neoplasms, increasing helper T lymphocyte numbers, and improving survival rates and quality of life. Adverse effects include serious haematological abnormalities and severe headache, abdominal discomfort, nausea, myalgia and insomnia. In addition, neutropenia and other anaemias frequently limit zidovudine therapy and may result in a need for multiple blood transfusions, dose reductions or withdrawal of the drug. However, despite these problems and the lack of information about some aspects of zidovudine use, zidovudine provides a major hope for HIV-infected patients, and it has rapidly become the standard therapy for improving the quality and duration of the lives of AIDS and ARC patients.
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PMID:Zidovudine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy. 266 Nov 94

Fifteen patients with metastatic malignant melanoma, including 10 who had not previously received systemic therapy, were treated with recombinant alpha2-interferon (IFN-alpha 2) in a dose of 20 million IU/m2 by 30-min i.v. infusion daily for 5 days each 14 days. Evaluable metastatic sites included lung, subcutaneous tissue, liver, nodes, adrenals, and bone. Subjective toxicity was generally mild to moderate, with fever (38.2-40.2 degrees C), occasional rigors, fatigue, myalgia, headache, and nausea. Objective toxicity included transient neutropenia and elevation of hepatic enzymes, particularly gamma-glutamyl transpeptidase. In 1 of the 10 patients receiving more than one cycle, IFN dosage was reduced because of toxicity, but later reescalated. All patients were evaluated for response. No overall partial or complete responses were observed, but two site responses (lung and subcutaneous tissue) were seen. Median survival from start of IFN treatment was 19 weeks. High doses of IFN were reasonably well tolerated in this study, but the results suggest little activity against malignant melanoma.
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PMID:Phase-II study of recombinant alpha 2-interferon in advanced malignant melanoma. 287 Nov 16


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