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)

Malignant gliomas continue to be a significant source of mortality in young and middle aged adults. The introduction of new treatment strategies and multidisciplinary approaches has improved the outcome of patients with these tumors only slightly. Because retinoic acid has growth inhibitory activity against glioma and neuroblastoma cells in cultures, we assessed the efficacy of all-trans-retinoic acid in the treatment of recurrent cerebral gliomas. Thirty-six patients with recurrent cerebral gliomas were entered in the study and treated with 120 or 150 mg/ m2/day of all-trans-retinoic acid as a single agent. The drug was given for 3 weeks followed with one week of rest. Two blocks of 4 weeks constituted one course of treatment. One (3%) of 34 evaluable patients had a minor response and 14 (41%) had stable disease. In the rest of the patients (56%), tumors continued to progress despite treatment. The median time to progression of all evaluable patients was 8 weeks, and for the responders was 17 weeks. The higher dose level (150 mg/m2) was associated with high incidence of headache, which responded to dose reduction. The lower dose level was very well tolerated, with mild, mainly dermatological toxicity. All-trans-retinoic acid as a single agent has no significant activity against recurrent cerebral gliomas.
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PMID:The treatment of recurrent cerebral gliomas with all-trans-retinoic acid (tretinoin). 921 61

The Radiation Therapy Oncology Group enrolled 30 patients with recurrent malignant astrocytomas onto a phase II study (RTOG 91-13). Patients were treated with all-trans-retinoic acid at a starting dose of 120 mg/m2 per day orally continuously until disease progression. Fourteen patients had glioblastoma, 14 had anaplastic astrocytoma, and 2 had other histologies; 53% were under 50 years of age. All patients had failed radiation therapy and/or at least one chemotherapy regimen. All patients had a Karnofsky performance status score of at least 70, but only 37% had a KPS of 90-100. Forty percent had a neurologic function status of grade 1 (able to work). A minimum of 4 weeks of all-trans-retinoic acid defined adequate treatment. Twenty-five patients received adequate therapy. Most common toxicities were dry skin, cheilitis, anemia, and headache; 3 patients had grade 3 headache requiring suspension of all-trans-retinoic acid. No grade 3 hematologic toxicity was observed. Of 25 adequately treated patients, 3 showed objective regression of tumor on magnetic resonance imaging and computed tomography scans, 3 patients remained stable, and 19 patients had disease progression. The median time to tumor progression was 3.8 months and the median survival time was 5.7 months. This study suggests that this dose of single agent all-trans-retinoic acid has modest clinical activity against recurrent malignant gliomas with tolerable side effects. A response rate of 12% and a stabilization rate of 12% are lower than expected. Future studies with higher dosage or in combination with biological response modifiers or chemotherapy may be warranted.
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PMID:All-trans-retinoic acid: a phase II Radiation Therapy Oncology Group study (RTOG 91-13) in patients with recurrent malignant astrocytoma. 921 68

A double-blind, placebo-controlled, randomized study using single ascending oral doses of 5 mg, 15 mg, 40 mg, 80 mg, and 150 mg of 9-cis-retinoic acid was performed to assess the single-dose pharmacokinetics, tolerability, and pharmacodynamic effects of 9-cis-retinoic acid in healthy men. Forty participants received treatment (six taking the active treatment and two taking placebo for each dose level). The pharmacokinetics of 9-cis-retinoic acid were linear over the dose range studied. Peak plasma concentrations were achieved within 3 to 4 hours on average. The half-life was in the range of 1.3 to 2.4 hours. Metabolism was the major pathway of elimination. 4-Oxo-9-cis-retinoic acid, one of four metabolites measured, which included all-trans-retinoic acid and 13-cis-retinoic acid, was the main metabolite in plasma, achieving peak plasma levels of 41% to 83% of those of 9-cis-retinoic acid. Dose-/concentration-dependent reductions of retinol in plasma, with a maximum of 30% from baseline, were observed 24 hours after administration. Baseline levels were recovered after 5 days. Concentrations of retinol binding protein remained unchanged. Overall, the drug was well tolerated at all dose levels. Adverse events observed were consistent with findings of other retinoids (all-trans-retinoic acid and 13-cis-retinoic acid) and included headache and xeroderma at high dose levels.
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PMID:Pharmacokinetics and pharmacodynamics of 9-cis-retinoic acid in healthy men. 924 49

A 51 year-old male admitted with petechiae and headache. Acute promyelocytic leukemia (APL) with disseminated intravascular coagulation (DIC) was diagnosed. He received all-trans retinoic acid (ATRA) with enocitabine and daunomycin for induction chemotherapy, and supportive therapy for DIC. On 2nd day after admission, subacute subdural hematoma was confirmed with CT scan. He had anisocoria and disturbance of consciousness, and was treated with neurosurgical operation for his life saving on the 3rd day. Although DIC was continued at this time, the operation was done without problem. The recurrence of hematoma has not occurred after the operation. Furthermore, the findings of DIC disappeared by the day 6 following induction therapy. He achieved a complete remission including cytogenetic findings on 35th day after administration of ATRA and received 3 times of combination chemotherapy as consolidation therapy. It may be difficult to do neurosurgical treatment in the setting of DIC. However, we should consider whether the indications for surgery operation according to the condition of each patient.
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PMID:[Successful treatment of subdural hematoma with operation in a patient with acute promyelocytic leukemia]. 924 31

An intermittent and cyclic regimen with All-Trans Retinoic Acid (ATRA) and intensive chemotherapy was conducted due to pharmacokinetic studies on ATRA for acute promyelocytic leukemia (APL) in children. We have treated 17 children with APL using ATRA for remission induction followed by an intermittent schedule of ATRA plus intensive chemotherapy (APL-ATRA protocol). There were 10 males and 7 females. The median age was 9.0 years old. The median baseline white blood cell count was 12.1 x 10(3)/microliter, hemoglobin 7.8 g/dl, platelet 4.5 x 10(4) microliters at diagnosis. Sixteen patients showed t(15; 17) translocation. RT-PCR analysis was available in 15 patients and showed PML/RAR alpha rearrangement in all patients. Overall, 13 or 17 newly diagnosed patients (88%) achieved complete remission and EFS was 67%. Compared to the control (same chemotherapy without ATRA regimen), remission induction and EFS were significantly increased. The toxicity of ATRA consisted of retinoic acid syndrome in 1 and pseudotumor cerebli in another. Other toxicities included headache, chelitis, gastrointestinal trouble and bone pain. These results suggest that intermittent and cyclic regimen with ATRA and intensive chemotherapy (APL-ATRA protocol) is highly effective for APL patients.
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PMID:[Treatment results of intermittent and cyclic regimen with ATRA and chemotherapy in childhood acute promyelocytic leukemia. Children's Cancer and Leukemia Study Group]. 942 34

All-trans retinoic acid (ATRA) induces complete remission (CR) in most cases of acute promyelocytic leukemia (APL). Toxicity of ATRA has been shown to be mild and consist of headache, dry skin, dermatitis, gastrointestinal disorders, and hypertriglyceridemia. We report three patients with APL treated with ATRA in combination with chemotherapy, who developed scrotum exfoliative dermatitis with ulceration. Their age was 33 years (range, 25 to 37). All three cases developed scrotum erosions, and many small ulcers after 9 to 17 days of ATRA treatment. The scrotum exfoliative dermatitis with ulceration occurred repeatedly, but gradually resolved in about 8 weeks time. They developed no dryness of the lip or skin apart from the scrotum. All three cases continued to receive 45 mg/m2 of ATRA daily throughout induction therapy, and achieved CR. We suspected the scrotum exfoliative dermatitis with ulceration to be a side effect of ATRA. The scrotum lesions, which have been already reported may be common in patients receiving ATRA.
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PMID:[Scrotum exfoliative dermatitis with ulcers associated with treatment of acute promyelocytic leukemia with all-trans retinoic acid]. 949 53

Because tamoxifen and all-trans-retinoic acid (ATRA) have additive antitumor effects in preclinical systems, we performed a Phase I/II clinical trial of this combination in patients with advanced breast cancer. Patients with potentially hormone-responsive advanced breast cancer were enrolled. All received 20 mg of tamoxifen by mouth daily. Consecutive cohorts of 3-6 patients were treated on odd-numbered weeks with ATRA at doses of 70, 110, 150, 190, or 230 mg/m2/day. Twenty-six patients were entered in this trial; 25 were evaluable. A dose of 230 mg/m2 ATRA produced unacceptable headache and dermatological toxicity, but doses < or = 190 mg/m2 were tolerable. Two of 7 patients with measurable disease responded. Seven of 18 patients with evaluable, nonmeasurable disease achieved disease stability for more than 6 months. Plasma AUCs on day 1 of successive weeks of treatment were stable over time. A nonsignificant decrease in serum insulin-like growth factor I levels was noted during treatment, but this trend was similar to that observed in three "control" patients treated with tamoxifen alone. When given with daily tamoxifen, the maximum tolerated dose of ATRA that could be given on alternate weeks was 190 mg/m2/day. This schedule of ATRA resulted in repeated periods of exposure to potentially therapeutic concentrations of ATRA. Declines in the serum insulin-like growth factor I concentrations observed in patients treated with tamoxifen and ATRA were similar to those observed in patients treated with tamoxifen alone. Objective responses were observed, some in patients who had previously progressed while receiving tamoxifen, suggesting that further studies would be of interest.
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PMID:Phase I/II trial of all-trans retinoic acid and tamoxifen in patients with advanced breast cancer. 953 31

9-cis-Retinoic acid (9-cis-RA) and all-trans-RA (ATRA) are naturally occurring hormones. The nuclear receptors that mediate the effects of retinoids are the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). ATRA binds RAR with high affinity but does not bind to RXR, whereas 9-cis-RA, an isomer of ATRA, is a ligand that binds and transactivates both RARs and RXRs. The goals of this study were to determine the safety, tolerability, pharmacokinetics, and metabolic profile of 9-cis-RA in advanced cancer patients. Forty-one patients received oral 9-cis-RA (ALRT1057; Panretin capsules) at doses ranging from 5-140 mg/m2/day. Twenty-six patients were treated once daily with up to 140 mg/m2; a subsequent cohort of 15 patients were treated twice daily (b.i.d.) at 100-140 mg/m2/day (50, 60, and 70 mg/m2 b.i.d.) to evaluate a b.i.d. dosing regimen. Headache was the most frequent adverse event and was dose limiting in 3 of 41 patients. Skin toxicity was the next most common toxicity and was seen in 11 of 41 patients; it was typically mild and limited to skin dryness and erythema. Other toxicities included conjunctivitis, flushing, diarrhea, transaminitis, hypercalcemia, and asymptomatic hypertryglyceridemia. Toxicities were typically dose related, occurred primarily above 83 mg/m2/day, and were not ameliorated by b.i.d. dosing. No tumor responses were observed. The mean day 1 area under the plasma concentration-time curve and peak plasma concentration values were dose-proportional over all dose levels, whereas day 15 area under the plasma concentration-time curve and peak plasma concentration values were nonlinear above 83 mg/m2/day, suggesting that 9-cis-RA induced its own metabolism at doses equal to and above 140 mg/m2/day. 9-cis-RA is a retinoid receptor pan agonist with a more favorable pharmacokinetic and toxicity profile than that observed with previously studied retinoids and merits further investigation.
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PMID:Phase I study of 9-cis-retinoic acid (ALRT1057 capsules) in adults with advanced cancer. 962 60

We report a rare case of pseudotumor cerebri associated with all-trans retinoic acid (ATRA) treatment of acute promyelocytic leukemia (APL). An 18-year-old male was admitted to our hospital complaining of palpitations and shortness of breath; he was found to have APL. The administration of ATRA and chemotherapy was started. After 23 days, he complained of nausea, headache and double vision. Computed tomography and magnetic resonance imaging of the head showed no intracranial abnormalities. Bilateral papilledema, a symptom of increased intracranial pressure, was noted. A diagnosis of pseudotumor cerebri was made. Symptoms were improved by administration of glycerin and the discontinuation of ATRA. After 29 days, a complete remission was achieved.
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PMID:Pseudotumor cerebri in a patient with acute promyelocytic leukemia during treatment with all-trans retinoic acid. 967 91

The use of all-trans retinoic acid (RA) for remission induction markedly increases survival of patients with acute promyelocytic leukemia (APL) compared to patients treated solely with cytotoxic chemotherapy. However, clinical resistance to this agent develops rapidly, which has been associated with a progressive decline in plasma drug concentrations. Previous studies suggested that 9-cis RA, a retinoid receptor 'pan agonist' did not induce its own catabolism to the same extent as all-trans RA. Therefore, we conducted a dose-ranging study of this compound in patients with both relapsed and newly diagnosed APL. We treated 18 patients with morphologically diagnosed APL (13 relapsed, five newly diagnosed). The daily dose of 9-cis RA ranged from 30 to 230 mg/m2/day given as a single oral dose. Four of 12 (33%) relapsed patients (three of whom were previously treated with all-trans RA) and four of five (80%) newly diagnosed patients achieved complete remission. The sole failure in the newly diagnosed group died early from an intracranial hemorrhage. One other patient with t(9;12) translocation had substantial hematologic improvement. The drug was generally well tolerated; headache and dry skin were the most common adverse reactions. Three patients were treated with corticosteroids for signs of incipient 'RA syndrome.' These preliminary data suggest that 9-cis RA is an effective agent for remission induction and deserves further investigation in patients with retinoid-sensitive APL.
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PMID:Clinical study of 9-cis retinoic acid (LGD1057) in acute promyelocytic leukemia. 976 93


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