Gene/Protein Disease Symptom Drug Enzyme Compound
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 51,768 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Antiretroviral therapy, although successful in reducing HIV load and accordingly decreasing the incidence of HIV infection-related symptoms, has its drawbacks in the form of severe side effects. Recognized drug-related side effects are, for example, nausea, fatigue, lactic acidosis, neuropathy, lipodystrophy, and myopathy. Because not all patients experience these side effects, genetic factors could be involved. It is believed that the main toxicity of nucleoside analog drugs is due to a decrease in mitochondrial function, possibly by inhibition of mitochondrial DNA (mtDNA) replication. mtDNA is replicated by a multienzyme complex, the main component of which is the nuclear-encoded DNA polymerase gamma. Presently, the only known variation in the DNA polymerase gamma gene is variation in the number of CAG repeats in the second exon. To investigate whether CAG repeat expansion or mutations in the DNA polymerase gamma (POLG) gene could predispose to peripheral neuropathy or lactic acidosis, we have sequenced part of the second exon of the DNA polymerase gamma gene, containing the CAG repeat, of 59 drug-treated HIV-infected patients, 11 of whom experienced drug-induced neuropathy, and 3 of whom died from lactic acidosis. No correlation was found between numbers of CAG repeats and any of the symptoms. The coding regions of the POLG gene from the three lactic acidosis patients were then completely sequenced, but no mutations were found. In addition, no variation was detected in exons 3, 8, and 19 of seven neuropathy patients and three control subjects without symptoms. These exons were the only sites of amino acid changes between human and chimpanzee POLG genes, and were chosen as targets of tolerated variation.
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PMID:Lack of correlation between length variation in the DNA polymerase gamma gene CAG repeat and lactic acidosis or neuropathy during antiretroviral treatment. 1203 82

Thalidomide--banned from clinical use in the 1960s because of severe teratogenicity--is now back in clinical practice as an effective agent in the treatment of relapsed and refractory multiple myeloma. Several clinical trials have determined that thalidomide is active in 25-35% of patients with relapsed myeloma. The role of thalidomide in early-stage myeloma is being actively investigated. Thalidomide has antiangiogenic and immunomodulatory properties and is an effective inhibitor of TNF-alpha. However, the mechanism of its action in myeloma remains unclear. Major toxicities of thalidomide include constipation, sedation, skin rash, fatigue and peripheral neuropathy. This paper summarizes the current status of thalidomide in multiple myeloma.
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PMID:Thalidomide in the treatment of multiple myeloma. 1211 24

We investigated the clinical activity of the farnesyl transferase inhibitor R115777 in 22 patients with chronic myelogenous leukemia (CML) in chronic, accelerated, or blastic phase and in 8 patients with myelofibrosis (MF) and 10 patients with multiple myeloma (MM). R115777 was administered at 600 mg orally twice daily for 4 weeks every 6 weeks. Seven patients with CML (6 in chronic phase, 1 in advanced phase) achieved complete or partial hematologic response. Four of them had a minor cytogenetic response. Responses were transient, with a median duration of 9 weeks (range, 3-23 weeks). Two patients discontinued therapy because of toxicity while in complete hematologic response. Two MF patients had a significant decrease in splenomegaly, one had normalization of white blood cell count and differential, and one became transfusion independent. One patient with MM had a reduction in monoclonal protein of 34%. Adverse events included nausea in 22 patients (55%; all grade 2 or lower) and fatigue in 19 (48%; grade 3 or higher in 1). Other grade 3 or 4 toxicities included skin rash (4 patients, 10%), peripheral neuropathy (2 patients, 5%), and liver toxicity (2 patients, 5%). Patients who responded to therapy had significantly higher plasma vascular endothelial growth factor (VEGF) concentrations prior to treatment than nonresponders. Plasma concentrations decreased significantly during therapy among responders. R115777 showed clinical activity in patients with CML and MF. The effect on VEGF needs to be further investigated to determine whether this might be a possible mechanism of action of R115777.
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PMID:Efficacy of the farnesyl transferase inhibitor R115777 in chronic myeloid leukemia and other hematologic malignancies. 1241

5-Fluorouracil-based combination chemotherapy is commonly used in patients with advanced gastric cancer, but results with such therapy are fairly modest. Evaluation of newer agents is therefore required in this disease. Paclitaxel has shown promising activity as a single agent in gastric cancer. In vitro, paclitaxel exhibits sequence-dependent synergy with platinum compounds against gastric cancer. This study was conducted to evaluate the efficacy and toxicity of combination carboplatin and paclitaxel in patients with advanced gastric cancer. Twenty-seven patients with measurable or evaluable advanced gastric cancer were enrolled on the study from April 1996 to July 2000. Patients were treated with paclitaxel 200 mg/m intravenously during 3 hours followed by carboplatin at projected area under the curve 5 mg x h x ml (as per the Calvert formula). Twenty-six patients were assessable for toxicity, and 25 patients were assessable for objective response. Nine of the 27 enrolled patients had a major response for an objective response rate of 33% (95% CI 0.17-0.54) by intention-to-treat analysis. The median response duration was 4.9 months (95% CI 2.8-7.3), and median survival was 7.5 months. The 1-year survival rate was 23%. One hundred seventeen courses were administered with a median of four courses per patient administered. The major toxicity was neutropenia, with grade III to IV neutropenia observed in 9 patients (33%) and neutropenic fever in only 1 patient. Grade III peripheral neuropathy developed in two patients, and grade III myalgia and grade III fatigue developed in one patient each. There were no treatment-related deaths. The combination of carboplatin and paclitaxel is a highly tolerable, regimen with activity comparable to that of other regimens in advanced gastric cancer. This regimen needs to be further evaluated in combination with other agents and as a component of multimodality therapy in gastric cancer.
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PMID:Phase II study of paclitaxel and carboplatin in patients with advanced gastric cancer. 1257 22

This presentation represents consensus recommendations on prognostic markers and criteria to initiate therapy in patients with Waldenstrom's macroglobulinemia (WM), which were prepared in conjunction with the Second International Workshop held in Athens, Greece during September 2002. The panel recommended that initiation of therapy should not be based on the IgM level per se since this may not correlate with the clinical manifestations of WM. The consensus panel agreed that initiation of therapy was appropriate for patients with constitutional symptoms such as recurrent fever, night sweats, fatigue due to anemia, or weight loss. The presence of progressive, symptomatic lymphadenopathy or splenomegaly provide additional reasons to begin therapy. The presence of anemia with a hemoglobin value of <or= 10 g/dL or a platelet count < 100 x 10(9)/L due to marrow infiltration also justifies treatment. Certain complications such as hyperviscosity syndrome, symptomatic sensorimotor peripheral neuropathy, systemic amyloidosis, renal insufficiency, or symptomatic cryoglobulinemia may also be indications for therapy. Recommendations for follow-up of watch-and-wait patients are that those with monoclonal gammopathy of undetermined significance (MGUS) should have serum protein electrophoresis repeated each year. Patients with asymptomatic (smoldering) macroglobulinemia should be evaluated every 6 months. Regarding prognostic markers, hemoglobin and beta(2)-microglobulin levels at diagnosis are important prognostic markers in WM: they influence the timing of treatment and survival. Age is a consistently important prognostic factor for survival. However, the panel felt that current data are inadequate to support the use of any prognostic marker to select the timing and type of therapy, and called for studies on the application of prognostic markers in WM.
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PMID:Prognostic markers and criteria to initiate therapy in Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom's Macroglobulinemia. 1272 Jan 19

Experimental studies have demonstrated that thalidomide (Thal), a drug developed as a sedative, has antitumoural properties. The possible antitumour mechanisms of action involve: inhibition of angiogenesis, cytokine-mediated pathways, modulation of adhesion molecules, inhibition of cyclooxygenase-2 and stimulation of immuno response. Therefore, Thal is under clinical evaluation in oncology. This paper provides an overview of the data currently available in literature regarding, in terms of activity and toxicity, the use of Thal in cancer patients. Multiple myeloma is so far the most responsive malignancy. A moderate activity has been documented in certain solid tumours: glioblastoma multiforme, renal cell carcinoma and malignant melanoma. Tolerability is generally satisfactory with peripheral neuropathy being the most relevant dose-dependent toxicity. The more frequent, but moderate side effects are: somnolence, constipation, dizziness and fatigue. More studies are needed to properly evaluate the anticancer activity of Thal alone or in combination with other anticancer treatments. Preliminary studies suggest promising results of Thal in combinations with corticosteroids and cytotoxic drugs as front-line therapy of multiple myeloma. Regarding therapy of solid tumours in the adult, combination with chemotherapy, radiation therapy and molecular-targeting compounds are under investigation.
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PMID:Thalidomide: a new anticancer drug? 1283 55

Symptom recognition is critical for patient care but has been little studied in older HIV-infected individuals. The authors examined differences in symptom expression between younger (younger than age 50 years) and older (older than age 50 years) HIV-infected individuals. The authors analyzed data from two cross-sectional studies of HIV-infected individuals: 2864 individuals from the HIV Cost and Service Utilization Study (HCSUS) and 881 individuals from the Veterans Aging Cohort 3 Site Study (VACS 3). The authors compared the prevalence of eight symptoms common to both studies and 10 symptoms examined only in the VACS 3 population, stratified by age and race. Disease severity was assessed by CD4 count and 18 HIV-related diseases reported. Multivariate logistic regression models were used to account for demographics and severity differences. VACS 3 versus HCSUS participants were more likely nonwhite and older. In unadjusted comparisons, older nonwhites were less likely to report experiencing symptoms than younger whites. They reported the fewest total number of symptoms and the fewest individual symptoms common to both studies (headache, fever, nausea/vomiting, and diarrhea) or in the VACS 3 only (dizziness, sleeping difficulty, fatigue, rashes, bloating, and myalgias/arthalgias). Multivariate regression estimates suggest older age predicts a greater likelihood of reporting peripheral neuropathy, weight loss, or hair loss, but a lower likelihood of reporting headaches, depressed mood, white oral patches, or diarrhea. Nonwhites appeared less likely to report symptoms. Age is a determinant of reporting certain symptoms in HIV disease but may be masked or accentuated by other factors such as race.
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PMID:Differences in symptom expression in older HIV-positive patients: The Veterans Aging Cohort 3 Site Study and HIV Cost and Service Utilization Study experience. 1285 57

Acute human immunodeficiency virus (HIV) seroconversion illness is a difficult diagnosis to make because of its nonspecific and protean manifestations. We present such a case in an adolescent. A 15-year-old boy presented with a 5-day history of fever, sore throat, vomiting, and diarrhea. The patient also reported a nonproductive cough, coryza, and fatigue. The patient's only risk factor for HIV infection was a history of unprotected intercourse with 5 girls. Physical examination was significant for fever, exudative tonsillopharyngitis, shotty cervical lymphadenopathy, and palpable purpura on both feet. Laboratory studies demonstrated lymphopenia and mild thrombocytopenia. Hemoglobin, serum creatinine, and urinalysis were normal. The following day, the patient remained febrile. Physical examination revealed oral ulcerations, conjunctivitis, and erythematous papules on the thorax; the purpura was unchanged. Serologies for hepatitis B, syphilis, HIV, and Epstein-Barr virus were negative. Bacterial cultures of blood and stool and viral cultures of throat and conjunctiva showed no pathogens. Coagulation profile and liver enzymes were normal. Within 1 week, all symptoms had resolved. The platelet count normalized. Repeat HIV serology was positive, as was HIV DNA polymerase chain reaction. Subsequent HIV viral load was 350 000, and the CD4 lymphocyte count was 351/mm3. HIV is the seventh leading cause of death among people aged 15 to 24 in the United States, and up to half of all new infections occur in adolescents. Our patient presented with many of the typical signs and symptoms of acute HIV infection: fever, fatigue, rash, pharyngitis, lymphadenopathy, oral ulcers, emesis, and diarrhea. Other symptoms commonly reported include headache, myalgias, arthralgias, aseptic meningitis, peripheral neuropathy, thrush, weight loss, night sweats, and genital ulcers. Common seroconversion laboratory findings include leukopenia, thrombocytopenia, and elevated transaminases. The suspicion of acute HIV illness should prompt virologic and serologic analysis. Initial serology is usually negative. Diagnosis therefore depends on direct detection of the virus, by assay of viral load (HIV RNA), DNA polymerase chain reaction, or p24 antigen. Both false-positive and false-negative results for these tests have been reported, further complicating early diagnosis. Pediatricians should play an active role in identifying HIV-infected patients. Our case, the first report of acute HIV illness in an adolescent, emphasizes that clinicians should consider acute HIV seroconversion in the appropriate setting. Recognition of acute HIV syndrome is especially important for improving prognosis and limiting transmission. It is imperative that we maintain a high index of suspicion as primary care physicians for adolescents who present with a viral syndrome and appropriate risk factors.
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PMID:Acute human immunodeficiency virus syndrome in an adolescent. 1452 19

The purpose of this report is to summarize information on oxaliplatin, a drug recently approved by the U.S. Food and Drug Administration. Information provided includes regulatory history, study design, efficacy and safety results, and pertinent literature references. A single, multicenter, randomized trial, enrolling 463 patients with metastatic colorectal carcinoma whose disease had recurred or progressed during or within 6 months of completion of therapy with the combination of bolus 5-fluorouracil (FU)/leucovorin (LV) and irinotecan, was submitted. Study arms included infusional 5-FU/LV alone (arm A), oxaliplatin alone (arm B), and the combination of oxaliplatin and infusional 5-FU/LV(arm C). Oxaliplatin, at a dose of 85 mg/m2, was administered to patients in arms B and C intravenously over 2 hours in 250-500 ml of dextrose 5% in water (D5W) on day 1 only. A 200-mg/m2 dose of LV was administered simultaneously to arm C patients, in a separate bag using a Y-line, or alone to arm A patients, by i.v. infusion, over 2 hours. 5-FU was then administered to arms A and C patients, first as a bolus injection over 2-4 minutes at a dose of 400 mg/m2, then as a continuous infusion in 500 ml of D5W over 22 hours at a dose of 600 mg/m2. LV was repeated on day 2 of the cycle (arms A and C) followed by a 400-mg/m2 5-FU bolus and a 600-mg/m2 22-hour infusion. Treatment was repeated every 2 weeks. Response rate was the prespecified end point for accelerated approval. Time to progression (TTP) was a secondary end point. The prespecified primary comparison was between the 5-FU/LV regimen and the 5-FU/LV/ oxaliplatin combination regimen. The three arms were well balanced for patient prognostic factors. There were no complete responders. The partial response rates were 0%, 1%, and 9% for the 5-FU/LV, oxaliplatin, and oxaliplatin plus 5-FU/LV treatments, respectively (p = 0.0002, arm C versus arm A). The median times to radiographic tumor progression, based on available radiographs, were 2.7 months, 1.6 months, and 4.6 months, respectively (p < 0.0001, arm C versus arm A). Common adverse events associated with the combination treatment included peripheral neuropathy, fatigue, diarrhea, nausea, vomiting, stomatitis, and abdominal pain. Neutropenia was the major hematologic toxicity. Adverse events were similar in men and women and in patients <65 and > or =65 years of age, but older patients may have been more susceptible to dehydration, diarrhea, hypokalemia, and fatigue. Oxaliplatin in combination with infusional 5-FU/LV was approved for the treatment of patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed during or within 6 months of completion of first-line therapy with the combination of bolus 5-FU/LV and irinotecan. Approval was based on response rate and on an interim analysis of TTP. No results are available, at this time, that demonstrate a clinical benefit, such as improvement in disease-related symptoms or survival.
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PMID:FDA drug approval summaries: oxaliplatin. 1475 10

Advances in the treatment of gynecologic cancer have extended the duration of survival of many patients. However, these patients frequently experience a variety of treatment- and disease-related side effects that diminish their quality of life (QOL) during and after treatment; among these are pain, nausea and vomiting, anemia, fatigue, peripheral neuropathy, emotional distress, and sexual dysfunction. Given the gains in survival time, patient care is being expanded to include enhancement or preservation of QOL in addition to early diagnosis and disease treatment, thus treating the whole person. In parallel with this evolution in cancer care, supportive measures are being increasingly recognized as crucial to effective patient management. This paper reviews some of the potential causes of diminished QOL in gynecologic cancer patients and basic treatment strategies for their control, with a focus on short-term QOL issues. It is important that clinicians monitor QOL during the course of the disease and its treatment, utilize procedures and therapeutic agents that take patient preferences and QOL into account, and proactively prevent and treat relevant symptoms.
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PMID:Quality of life in patients receiving treatment for gynecologic malignancies: special considerations for patient care. 1476 77


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