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)

A single-agent dose-escalating Phase I and pharmacological study of the polyamine synthesis inhibitor SAM 486A was performed. A dosing regimen of four weekly infusions followed by 2 weeks off therapy was studied. Fifty patients were entered into the study. Dose levels studied were 1.25, 2.5, 5, 8, 16, 32, 48, 70, 110, 170, 270, and 325 mg/m2/week. Pharmacokinetic sampling was done on day 1, and trough samples were taken weekly during the first treatment cycle. Pharmacodynamic sampling was done on days 1 and 22. At 325 mg/m2/week, dose-limiting toxicity was seen (one patient each with grade 4 febrile neutropenia, grade 3 neurotoxicity, and grade 3 hypotension with syncope and T-wave inversions on electrocardiogram). The recommended dose for further testing was set at 270 mg/m2/week. Infusion time was increased from 10 to 180 min due to facial paresthesias and flushing and somnolence. Drug exposure increased linearly with dose. Mean +/- SD t1,2 at 70-325 mg/m2 doses was 61.4+/-26.2 h, with a large volume of distribution at steady state. In peripheral blood leukocytes, a clear relationship between dose and inhibitory effect on S-adenosylmethionine decarboxylase or changes in intracellular polyamine pools was not recorded. SAM 486A can be administered safely using a dosing regimen of four weekly infusions followed by 2 weeks off therapy. The recommended dose for Phase II studies using this regimen is 270 mg/m2/week.
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PMID:Phase I and pharmacological study of weekly administration of the polyamine synthesis inhibitor SAM 486A (CGP 48 664) in patients with solid tumors. European Organization for Research and Treatment of Cancer Early Clinical Studies Group. 1081 92

We administered the anti-angiogenic drug thalidomide to 21 patients (12 men) with myelofibrosis with myeloid metaplasia (MMM), who were not responsive to standard treatment. Patients received thalidomide at an escalating dose from 100 to 400 mg/d. Administration of the drug was discontinued before the planned 6 months of treatment in 19 patients (90.5%), mainly because of somnolence and/or fatigue, neurological symptoms or neutropenia. Of the 13 evaluable patients (who received more than 30 d of therapy), anaemia improved in three out of seven (43%) who were treated because of anaemia; thrombocytopenia improved in two out of three (66.6%) who were treated because of thrombocytopenia; splenomegaly was reduced in four (30.8%). Undesired increases in white blood cell and platelet counts were observed in three (23.1%) and five (38.5%) patients respectively. A severity score, indexed on haematological and clinical parameters, improved in two patients (15.4%), but worsened in five (38.5%). In conclusion, standard-dose thalidomide in MMM patients is burdened with a high rate of side-effects, which prevent prolonged treatment. Because the drug is effective in improving anaemia and thrombocytopenia and in reducing splenomegaly, low-dose therapy warrants evaluation. The unexpected observation of leucocytosis and thrombocytosis suggests biological studies and better criteria for selection of patients for treatment.
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PMID:Safety and efficacy of thalidomide in patients with myelofibrosis with myeloid metaplasia. 1147 48

We conducted a clinical trial of thalidomide as initial therapy for asymptomatic smoldering (SMM) or indolent multiple myeloma (IMM). Sixteen patients were studied. Thalidomide was given orally at a dose of 200 mg/day for 2 weeks, and then increased as tolerated by 200 mg/day every 2 weeks to a maximum dose of 800 mg/day. Bone marrow microvessel density (MVD) and angiogenesis grading were estimated using CD34 immunostaining. Six patients had a confirmed response to therapy with at least 50% or greater reduction in serum and urine monoclonal (M) protein. When minor responses (25-49%) decrease in M protein concentration) were included, 11 of 16 patients (69%) responded to therapy. Major grade 3-4 toxicities included two patients with somnolence, and one patient each with syncope and neutropenia. Pre-treatment MVD was not a significant predictor of response to therapy, median MVD 4 and 12 in responders and non-responders respectively, P = 0.09. We conclude that thalidomide has significant activity in the treatment of newly diagnosed SMM/IMM. However, we do not recommend treatment with thalidomide at this stage since some patients with SMM/IMM can be stable for several months or years without any therapy. Additional randomized trials are needed to determine if thalidomide will delay progression to active multiple myeloma.
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PMID:Thalidomide for previously untreated indolent or smoldering multiple myeloma. 1148 May 71

Recent reports showed that thalidomide has anti-angiogenic activity and is effective for the treatment of refractory multiple myeloma (MM). We examined the relationship between the clinical efficacy and adverse effects of thalidomide and the plasma concentrations of this drug as well as angiogenic growth factors in refractory MM. Ten out of twenty-four evaluable patients (42%) showed more than 25% reduction of M-protein, and eight (33%) achieved more than 50% reduction. These changes were associated with restoration of anemia and recovery of normal immunoglobulin level. Somnolence and headache, constipation, peripheral neuropathy and skin rash were frequently observed, but were well tolerated. However, grade 2 - 4 severe neutropenia was also observed in nine cases. These adverse effects other than neutropenia occurred more frequently in the patients with higher plasma concentrations of thalidomide (2.0 microg/ml at 12 h after the last administration) and were readily alleviated by dose reduction. In contrast, neutropenia developed regardless of the plasma concentration. Plasma concentrations of angiogenic growth factors were frequently elevated before treatment. After thalidomide treatment, these growth factor levels tend to decrease to near-normal ranges in responders but were still high in most non-responders. After thalidomide treatment, plasma vascular endothelial growth factor (VEGF) level was significantly reduced in responders (P = 0.025), but not in non-responders (P = 0.37). Reduction of plasma VEGF level might be an important indicator for anti-myeloma effect of thalidomide.
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PMID:Thalidomide for the treatment of refractory multiple myeloma: association of plasma concentrations of thalidomide and angiogenic growth factors with clinical outcome. 1235 57

The objective of this study was to monitor the long-term effect of clozapine administered to Parkinson's disease (PD) patients with psychosis. Confusion, visual hallucinations, and psychosis are major dose-limiting factors for long-term dopaminergic management of PD. Classic neuroleptic agents exacerbate the motor symptoms of the disease. For this reason, the introduction of atypical antipsychotic drugs has been a major advancement for the management of psychosis in patients with PD. Of them, clozapine is one of the most effective. Thirty-two patients (mean age, 73 years; mean disease duration, 12.2 years) with PD and psychosis (DSM-IV), 14 of them with dementia (DSM-IV), were followed for 5 years with periodic clinical evaluation, Mini Mental State Examination (MMSE), and Parkinsonian Psychosis Rating Scale (PPRS) administered before and following the study (at least once in 6 months). Periodic blood count was performed for tracking neutropenia. Nineteen patients (8 with dementia) have continued to receive clozapine (mean daily dose, 50 mg). Thirteen patients stopped medication: 9 because symptoms improved and did not return after weaning off clozapine; 3 patients because of somnolence; and 1 because of personal reasons. The average duration of treatment in those in whom medication was stopped was 8.5 months (range, 1-24 months). No correlation was found between age, sex, duration, and severity of disease (Yahr scoring), the presence of dementia, and the response to clozapine. Also, the PPRS scoring did not influence clozapine response. No case of neutropenia was found. According to the experience accumulated and the results of the present study, the authors believe clozapine is the best therapeutic choice currently available for the management of psychosis in patients with PD.
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PMID:Clozapine in Parkinson's disease psychosis: 5-year follow-up review. 1256 58

Thalidomide as a single agent (200-400 mg/day) was administered in fourteen cases of refractory myeloma, from March 2001 till February 2002. The median age was 71 years (range 58 to 85 years), and the efficacy of thalidomide was observed in cases receiving treatment for at least three consecutive months. Response was evaluated in February 2002, according to the criteria for assessment of response described by Kakimoto et al. At the time of evaluation, two cases were in the PR2 state, one in PR3, two were stable, and three were PD. Evaluation of the response was not possible in six cases in whom treatment had to be discontinued due to intolerable side effects. The response to thalidomide was variable, with some cases responding well even to a low dose (200 mg/day) while a few others showed an early relapse due to the refractory nature of the disease in its response to the drug. The efficacy of treatment seemed to be correlated with the maturation pattern of myeloma cells. Side effects included neurological complications like somnolence, physiological symptoms such as constipation and so on, etc but all were relieved with symptomatic treatment. The drug was well tolerated in geriatric patients. Neutropenia was a dose limiting factor with half of the cases (7/14) presenting with severe neutropenia (grade 3-4), but a response was observed in all of them on administration of G-CSF. Thromboembolism occurred in two cases, the cause of which is not clear. These results suggest that thalidomide is a well tolerated drug and can be considered as a mainstay in the therapy of refractory myeloma.
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PMID:[Single-agent thalidomide for advanced and refractory multiple myeloma]. 1288 14

Thalidomide, an antiemetic administered in 60th of the 20th century to pregnant women, has become notorious for a range of adverse effects which led to its taking off market. In recent years, its antimyeloma effect was discovered. The aim of the work was to evaluate the incidence of adverse reactions to thalidomide. Its therapeutic effect has not been assessed because of a short period of monitoring and diversity of a sample. The assessed sample consisted of 17 patients with diagnosis of multiple myeloma (10 men and 7 women). An average age of patients was 62.9 +/- 9.4. An average time elapsed from making the diagnosis to starting the treatment with thalidomide was 51.0 +/- 23.7 months. An average length of therapy was 20.1 +/- 9.6 weeks. An average daily maximum therapeutic dose was 138.3 +/- 83.2 mg. Data were collected from outpatient physicians reports, regular laboratory tests, and direct interviews with patients. To classify severity of adverse drug effects (grades 0-4) we used WHO criteria, Cancer and Leukemia Group B criteria, and in cases where certain adverse effects were not included in the above mentioned criteria, we defined our own criteria. The most frequent adverse effects included: leucopenia or neutropenia in 12 (70.6%) patients, altered state of consciousness in 11 (64.7%) patients, obstipation in 10 (58.8%) patients, skin alterations in 9 (52.9%) patients, dizziness in 8 (47.1%) patients, peripheral neuropathy in 7 (41.2%) patients, spasms and spasmodic convulsions in 7 (41.2%) patients, and altered liver tests in 6 (35.3%) patients. From the perspective of necessity to interrupt treatment or reduce the dose the most severe disorders included: peripheral neuropathy in 2 patients (inability to control lower extremities), altered consciousness in 1 patient (protracted somnolence during a day), skin alteration in 1 patient (generalized toxoalergic reaction), leucopenia or neutropenia in 1 patient (1.0 resp < 0.5 x 10(9)/l), altered vision in 1 patient (blurred vision), hypothyroidism in 1 patient, and altered mood in 1 patient (subjective feeling of depression). This work proved thalidomide to be beneficial for the patients with multiple myeloma but it also shoved necessity to intensively monitor its adverse effects and to adjust its doses.
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PMID:[Desirable and undesirable effects of thalidomide in patients with multiple myeloma]. 1468 82

Thalidomide has shown promise in the treatment of newly diagnosed multiple myeloma and relapsed/refractory disease, but side effects such as somnolence, constipation, and neuropathy limit its use. CC-5013, an immunomodulatory drug (IMiD), is more potent than thalidomide. CC-5013 has various immunomodulatory effects, including growth arrest or apoptosis of drug-resistant myeloma cell lines and inhibition of binding of myeloma cells to bone marrow stromal cells. Clinically, 17 of 24 patients (71%) with relapsed/refractory disease experienced a reduction of paraprotein of > or = 25% following treatment with CC-5013, including 11 who had a history of treatment with thalidomide. Another two experienced stable disease. Median time to best response was 2 months (range, 1 to 11) and median duration was 6 months (range, 2 to 18). Grade 3 thrombocytopenia was seen in 20% of patients; grade 3 neutropenia was seen in 60%; and grade 4 neutropenia was seen in 16%. CC-5013 use was not associated with somnolence, constipation, or neuropathy. This article reviews thalidomide in multiple myeloma, the effects of thalidomide analogues IMiDs, and the preclinical and clinical data on CC-5013 in relapsed/refractory multiple myeloma.
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PMID:The role of immunomodulatory drugs in multiple myeloma. 1501 93

Although thalidomide was withdrawn in the 1960s after its teratogenic property was recognized, it was subsequently found that this drug possesses immunomodulatory and anti-inflammatory effects. Recent studies have also demonstrated that thalidomide has antineoplastic activity via an antiangiogenic mechanism. Observations in the late 1990s that the microenvironment in the bone marrow plays a role in tumor progression in multiple myeloma provided an impetus to use thalidomide for the treatment of this disease. It is known that thalidomide monotherapy is effective in one-third of refractory cases, and in combination with glucocorticoids and/or antineoplastic drugs, thalidomide provides a response rate of more than 50%. Thus, thalidomide therapy is considered a standard approach for the treatment of relapsed and refractory myeloma. The exact mechanism of the antimyeloma effect of thalidomide is not yet clearly understood. Anti-angiogenic effects, direct activity in tumor cells such as the induction of apoptosis or G1 arrest of the cell cycle, the inhibition of growth factor production, the regulation of interactions between tumor and stromal cells, and the modulation of tumor immunity have been considered as possible mechanisms. In addition to its teratogenicity, the adverse effects of thalidomide have been general symptoms such as somnolence and headache, peripheral neuropathy, constipation, skin rash, and other symptoms. Although these adverse effects are generally reversible and mild, grade 3 and 4 toxicities such as peripheral neuropathy, deep venous thrombosis, neutropenia, and toxic dermal necrosis have occasionally been reported. The application of thalidomide therapy in patients with multiple myeloma is being broadened to include not only cases of refractory myeloma, but also previously untreated cases, as well as for maintenance therapy after hematopoietic stem cell transplantation and for the treatment of other hematological diseases. The safe use of this drug will depend on the establishment of diagnostic and treatment guidelines. In addition, the establishment of a nation-wide regulation system is urgently needed in Japan.
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PMID:Thalidomide for the treatment of multiple myeloma. 1532 81

Thalidomide represents a recent and innovative therapeutic approach in multiple myeloma. Main toxicity usually consists in somnolence, constipation, peripheral neuropathy and deep vein thrombosis, but, unlike alkylating agents, thalidomide is reported to rarely induce severe hematologic toxicity. The majority of patients developing neutropenia are heavily pretreated with three or more lines of chemotherapy. Here, we report, for the first time, clinical and laboratory data of a 66-year-old female patient with multiple myeloma at diagnosis who, after 4 weeks of thalidomide treatment, developed a grade 4 WHO neutropenia with septicemia. A brief review of the literature and suggestions for possible predictive factors of this toxicity are made.
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PMID:Low-dose thalidomide-induced agranulocytosis in a multiple myeloma patient treated at diagnosis. 1626 90


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