Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027947 (neutropenia)
 17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The studies reviewed herein support the precept that "systemic dose-intensity" (i.e., systemic exposure) may be more informative than "administered dose-intensity" for certain anticancer drugs. This does not mean that the administered dose-intensity should be ignored; in fact these data indicate the importance of documenting and assessing administered dose-intensity as an initial step toward identifying those situations where systemic dose-intensity may be most important. The studies described in this review were selected as representative examples of successful clinical pharmacodynamic studies; other published examples include vincristine AUC versus severity of neurotoxicity, etoposide systemic exposure versus leukopenia, red cell concentration of mercaptopurine metabolites versus neutropenia in children with ALL, and ARA-CTP retention in leukemic blasts versus clinical response in acute non-lymphocytic leukemia. As is the case with other types of clinical trials in cancer patients, there are also examples of negative pharmacodynamic studies (i.e., no relationship found between concentration and effects). There are several possible reasons for such negative findings, including the lack of such a relationship for some drugs, measuring the inappropriate drug moiety (e.g., failure to measure all active metabolites), measuring drug concentrations in the wrong biological fluid, evaluating systemic exposure over too narrow a range (i.e., all patients have either sub- or supra-therapeutic systemic exposure), selecting inappropriate sampling times or pharmacokinetic parameters, inadequately assessing drug toxicity or response, or simply studying an inadequate number of patients or patients with drug-resistant cancers. Therefore, negative findings in some pharmacodynamic studies should not deter the investigation of other drugs and/or other malignant diseases, just as negative therapeutic trials do not preclude subsequent clinical trials in oncology. Also, finding a relation between systemic exposure and drug toxicity, in the absence of a clear relation to antitumor effects, is potentially of great clinical utility. Such data should allow more objective escalation of drug dosages in individual patients, to ensure maximum dose-intensity while avoiding host toxicity. Obviously, if such dose escalation could be guided by more easily measured patient characteristics (e.g., age, weight, CrCl, shoe size, etc.), then using drug concentrations in individual patients might be obviated.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Clinical pharmacodynamics of anticancer drugs: a basis for extending the concept of dose-intensity. 328 32

The drugs concerned by this review are cytarabine (ara-C), gemcitabine and fludarabine. Seventy-eighty per cent of a dose of ara-C are excreted under the form of ara-U (main metabolite). Plasma concentrations of ara-C are not related to drug pharmacodynamics (response to treatment) in contrast to intracellular levels of ara-CTP (active metabolite) which are associated with cytotoxic activity. Gemcitabine is able to autoactivate its own mechanism of action. Gemcitabine is characterized by a short half-life of elimination (15-20 min) and plasma pharmacokinetics of the drug are not linked to pharmacodynamics. Prolonged administration of gemcitabine is pharmacokinetically and pharmacologically justified and should deserve more intense clinical investigations. Total body clearance of F-ara-A (main circulating metabolite of fludarabine) is linked to creatinine clearance and drug-related neutropenia are more frequent in patients with creatinine clearance below 50 mL/min. So far there are no relationships between intracellular levels of F-ara-CTP and response to treatment.
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PMID:[Clinical pharmacology of nucleoside analogues]. 1244 33

Cladribine has single-drug activity in acute myeloid leukaemia (AML), and may enhance the formation of the active metabolite (ara-CTP) of cytosine arabinoside (ara-C). To evaluate the feasibility of adding intermittent cladribine to intermediate-dose ara-C (1 g/m2/2 h) b.i.d. for 4 d with idarubicin (CCI), we performed a 2:1 randomized phase II trial in AML patients aged over 60 years. Primary endpoints were time to recovery from cytopenia and need for supportive care following the first course. Sixty-three patients (median 71 years, range 60-84 years) were included, constituting 72% of all eligible patients. Toxicity was limited, with no differences between the treatment arms. The early toxic death rate was 11%. The median time to recovery from neutropenia and thrombocytopenia was 22 and 17 d from the start of course no. 1, respectively, and the requirement for platelet and red cell transfusions was four and eight units respectively. Patients had a median of 8 d with fever over 38 degrees C, and 17 d with intravenous antibiotic treatment. The overall complete remission (CR) rate was 62%, with 51% CR from one course of CCI in comparison with 35% for the two-drug therapy (P = 0.014). The median survival with a 2-year follow-up was 14 months, and the 2-year survival was over 30%, with no differences between the treatment arms. Considering the median age and our population-based approach, the overall results are encouraging.
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PMID:Increased remissions from one course for intermediate-dose cytosine arabinoside and idarubicin in elderly acute myeloid leukaemia when combined with cladribine. A randomized population-based phase II study. 1463 71

Thalidomide has direct antimyeloma and immunomodulatory effects. In addition, both thalidomide and metronomic chemotherapy inhibit angiogenesis. The synergy of such a combination may decrease toxicity while maintaining efficacy. The Hoosier Oncology Group conducted a phase II trial of oral cyclophosphamide (50 mg b.i.d. for 21 days), thalidomide (200 mg/day), and prednisone (50 mg q.o.d.) (CTP) per 28-day course in patients with relapsed multiple myeloma (MM). Of the 37 patients enrolled, 16 had prior stem cell transplantation. The median follow-up time was 25.3 months (95% confidence interval [CI] 23.2-27.7). Of 35 patients treated, 22 patients (62.9%) responded: 7 (20.0%) complete responses, 2 (5.7%) near-complete responses, and 13 (37.1%) partial responses. Eight patients (22.9%) had stable disease, and three (8.6%) had disease progression. Two patients withdrew from the study early due to reasons unrelated to progression or toxicity and were treated as nonresponders. The median time to best response and time to progression were 3.6 months (95% CI 2.8-10.9) and 13.2 months (95% CI 9.4-21.0), respectively. The median number of treatment cycles was seven (range 1-12 cycles). Grade III to IV toxicities included leukopenia (42.9%; febrile neutropenia, 11.4%), hyperglycemia (20%), sensory neuropathy (11.4%), thromboses (8%), and motor neuropathy (5.7%). No patient withdrew from the study due to toxicity. The efficacy and low toxicity of the CTP regimen support the future development of such an approach in MM.
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PMID:Final report of toxicity and efficacy of a phase II study of oral cyclophosphamide, thalidomide, and prednisone for patients with relapsed or refractory multiple myeloma: A Hoosier Oncology Group Trial, HEM01-21. 1722 4

In 1992-1993, synergistic interaction of ribonucleotide reductase inhibitors (fludarabine, cladribine) and cytarabine (Ara-C) increasing Ara-CTP concentration in myeloblasts was proved. Based on these findings and encouraging results of the addition of cladribine to standard daunorubicin+Ara-C induction regimen (DAC) in acute myeloid leukemia (AML), the Polish Adult Leukemia Group (PALG) conducted a pilot study on the administration of cytarabine, daunorubicin, and fludarabine (DAF) as a reinduction treatment of AML to assess tolerance, toxicity, and early outcome. The DAF regimen consisted of daunorubicine 60 mg m(-2) day(-1) iv on days 1-3 and fludarabine 25 mg m(-2) day(-1) iv on days 1-5 given before cytarabine 200 mg m(-2) day(-1) in ci on days 1-7. Thirty-four AML patients with median age 39, 24% relapsed and 76% refractory, were included into the study between September 2003 and August 2004. Achieved response rate in the whole study population was 56%; n = 16 patients with complete remission (CR), and n = 3 patients with partial remission (PR). Fifteen of 16 patients achieved CR after the first course of therapy. Only 9% of total population died before the assessment of remission. All patients developed severe neutropenia. Serious infections were observed in 47% of the cases. Severe thrombocytopenia was observed in 72% of the patients. All patients required substitution of platelet concentrates (median 4), and PRBC (median 5). Severe alopecia, mucositis, vomiting were of low frequency. Liver, kidney, or circulatory failure, diarrhea, or polyneuropathy were not observed. The probability of overall survival (OS) for 1 year for the whole study population (34 patients) and the group of 16 patients in CR was: 44% (95% confidence interval [CI] 36-52%) and 69% (95% CI 55-83%), respectively. The probability of leukemia-free survival (LFS) for 1 year was 38% (95% CI 22-54%). Summarizing, DAF regimen used as the induction therapy in relapsed/refractory AML was well tolerated with acceptable toxicity and early efficacy.
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PMID:Daunorubicin, cytarabine and fludarabine (DAF) for remission induction in relapsed or refractory acute myeloid leukemia. Evaluation of safety, tolerance and early outcome--Polish Adult Leukemia Group (PALG) pilot study. 1807 33