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PubMedDate not supplied

Macrophage colony-stimulating factor for cancer therapy.

Macrophage colony-stimulating factor (M-CSF) is a homodimeric glycoprotein which stimulates differentiation of progenitor cells to mature monocytes and enhances production of hemopoietic growth factors from mature monocytes such as granulocyte-macrophage CSF, granulocyte CSF and megakaryocyte potentiator, suggesting that M-CSF administration enhances production of monocytes, neutrophils and platelets. Since the commercial availability of M-CSF in 1991, serial M-CSF infusions at a daily dose of 8 million units have been performed in patients with acute myeloid leukemia in complete remission after combination chemotherapy. Although M-CSF infusion reduced the duration of neutropenia in 3 of 5 patients, it reduced the duration of pyrexia over 37 degrees C in all patients, and that over 38 degrees C in 4 of 5 patients. Average durations of pyrexia and parenteral antibiotic injections were significantly shorter in M-CSF than in control courses. Although M-CSF infusion reduced the duration of thrombopenia in 2 of 5 patients, it reduced total platelet units transfused in 4 of 5 patients. The average number of platelet units transfused after combination chemotherapy was significantly lower in M-CSF than in control courses. In mice, M-CSF injection increased the serum concentration of reactive nitrogen intermediates which inhibited the growth of L1210 cells, and increased the survival rate of mice previously injected with them. These results indicate that M-CSF may be a promising agent not for improving patients' quality of life after cancer chemotherapy, but also in cancer immunotherapy.

Adolescent↗
PubMed1990

Role of immunoglobulins G1 and G2 in anaphylactic shock in the guinea pig.

Heating serum from actively sensitised guinea pigs did not remove its ability to sensitise recipient animals in vivo and parenchymal lung strips in vitro to anaphylaxis. Thermoresistant antibodies should thus account for the transferable sensitising effect, which persists for at least 9 days. IgG1 and IgG2, contained in the serum, were separated by affinity chromatography to determine the importance and the participation of these subclasses in passive anaphylactic shock. IgG1, present in smaller amounts than IgG2, was more effective in sensitising isolated lung strips. The intravenous administration of ovalbumin to guinea pigs, which had been injected with 0.8 mg/kg of IgG1 or 2 mg/kg of IgG2 9 days beforehand, induced an intense bronchoconstriction with leucopenia and moderate thrombopenia, suggesting an as yet undescribed role for IgG2 in passive tissue sensitisation. The use of mepyramine, an antagonist of the histamine H1 receptor, WEB 2086, an antagonist of platelet-activating factor, and nordihydroguaiaretic acid, a dual inhibitor of cyclooxygenase and lipooxygenase, alone or associated, demonstrated that the anaphylactic contraction of lung strips from guinea pigs sensitised by IgG1 is mediated by histamine and arachidonate derivatives, whereas that of lung strips from guinea pigs sensitised with IgG2 is mostly mediated by histamine. In addition, the association of the three potential antagonists slightly reduced the anaphylactic contraction of lung strips provided by guinea pigs sensitised by serum. Our results, using a sensitisation procedure considered until now to involve exclusively IgE antibodies, indicate that IgG1 and IgG2 are in fact the essential antibodies for passive anaphylactic shock in the guinea pig.

Anaphylaxis↗
PubMedDate not supplied

Antenatal diagnosis of brain damage in the survivor after the second trimester death of a monochorionic monoamniotic co-twin: case report and literature review.

At 28 weeks of amenorrhea, 1 fetus of a monoamniotic twin pregnancy died. Ultrasound and Doppler investigations of the surviving twin were normal. Three weeks later, endovaginal ultrasound and magnetic resonance imaging revealed massive bilateral cerebral ischemic necrosis in the surviving twin. In utero fetal blood sampling carried out before the termination did not reveal either anemia or thrombopenia. Current data suggest that cerebral or renal ischemic complications could set in immediately after the death of the first twin as a result of a period of acute hypotension. At least 2 weeks are necessary for them to be identifiable by ultrasound. It seems that they cannot be prevented by prompt delivery of the second twin.

Abortion, Spontaneous↗
PubMed1993

Intraperitoneal carboplatin in advanced ovarian carcinoma.

24 patients with advanced epithelial ovarian cancer, who demonstrated a clinical complete or partial response to the induction of intravenous chemotherapy, underwent implantation of a subcutaneous semipermanent port-and-catheter system (Port-A-Cath) for intraperitoneal chemotherapy, which consisted of carboplatin 300 mg/m2 every 4 weeks. The median survival was 27.4 months for minimal residual disease versus 8 months for bulky disease (p = 0.0054). The median progression-free interval was 15.7 months for minimal residual disease versus 1.8 months for bulky disease (p = 0.008). There were 3 complications (12.5%) related to the catheter: 1 perforation of the large bowel and 2 catheter inflow obstructions. Myelosuppression, especially a grade 3 leucopenia in 5 patients (25%) and a grade 4 thrombopenia in 3 patients (15%), was the dose-limiting toxicity. Even with maximum cytoreductive surgery and second-line intraperitoneal carboplatin-based chemotherapy, the 5-year progression-free survival (4.1%) remains very small.

Aged↗
PubMed1992

Higher pentamidine levels in AIDS patients with hypoglycemia and azotemia during treatment of Pneumocystis carinii pneumonia.

Trimethoprim-sulfamethoxazole (TMP-SMZ) and pentamidine are both licensed for the treatment of Pneumocystis carinii pneumonia (PCP). However, their use is associated with various adverse side effects. In this prospective study, 26 AIDS patients with 32 episodes of PCP were treated with pentamidine (4 mg/kg/d). Each patient was treated for 12 to 21 days, depending on the rapidity of onset of the clinical response. During the 32 PCP episodes, hypoglycemia occurred in 16 instances, azotemia in 12, liver toxicity in 10, and leukopenia in 8. The occurrence of thrombopenia, leukopenia, and liver toxicity was not related to age, pentamidine levels, or other complications. However, patients who had hypoglycemia during pentamidine treatment had higher serum pentamidine levels than patients who did not have hypoglycemia (107 +/- 40 versus 70 +/- 26 ng/ml, p less than 0.004). In addition, we observed that patients with azotemia showed higher pentamidine levels during treatment (120 +/- 35 versus 64 +/- 22 ng/ml, p less than 0.001). In fact, 100% (11/11) of patients with serum pentamidine concentration greater than 100 ng/ml had fasting hypoglycemia and/or azotemia, while 33% (7/21) of those with pentamidine levels less than 100 ng/ml had these side effects (p less than 0.001). The relative risk of these complications with pentamidine levels greater than 100 ng/ml was 3 (95% confidence interval, 1.6 to 5.5). Fine-tuning the dose of pentamidine may eventually prove useful to avoid toxicity and optimize therapy.

Acquired Immunodeficiency Syndrome↗
PubMedDate not supplied

A combination of cyclophosphamide, methotrexate, vincristine and VP 16-213 (NSC 141 540) in the treatment of bronchogenic carcinoma.

Thirty patients with bronchogenic carcinoma were treated with an 8-week induction therapy consisting of cyclophosphamide, methotrexate, vincristine and VP 16-213 (NSC 141 540). Those who achieved objective remission of tumor stabilization were then placed on an intermittent treatment schedule with the same drugs. Of the 30 patients, 17 had an objective response, 5 remained without change, and 8 progressed. Responses were more frequent among anaplastic (13/19) than epidermoid or adenocarcinoma (4/11). The toxicity consisted mainly of leucopenia, thrombopenia, alopecia, nausea and vomiting. The implications of these findings in the planning of further chemotherapeutic programs are discussed.

Alopecia↗
PubMed1997

In vitro toxicity of trichothecenes on human erythroblastic progenitors.

Trichothecenes are mycotoxins produced by various species of fungi which can occur on various agricultural products. Among these compounds, T-2 toxin, HT-2 toxin, diacetoxyscirpenol (DAS) and deoxynivalenol (DON) are the most naturally encountered and potent trichothecenes. Consumption of trichothecene contaminated foods by farm animals and humans leads to mycotoxicoses. Trichothecenes are known to induce haematologic disorders such as neutropenia, thrombopenia, and aplastic anemia in human and animals. The aim of our investigations is to explore the effects of trichothecenes on the haematopoietic progenitors. The four trichothecenes previously demonstrated to be strongly cytotoxic for human CFU-GM have been tested on human BFU-E. For this purpose, a culture model of human erythroblastic progenitors (BFU-E) optimized for toxicological studies was used to determine the effects of T-2, HT-2, diacetoxyscirpenol (DAS) and deoxynivalenol (DON) on red blood cell precursor proliferation and differentiation. Results showed that human BFU-E are as sensitive to trichothecenes as human CFU-GM, except for DON, in the range of concentrations tested. Differentiation of erythroblastic progenitors could be perturbed by these mycotoxins. Human erythroblastic progenitors are also a target of trichothecenes.

Cell Differentiation↗
PubMed1996

Platelets and antiphospholipid antibodies.

The involvement of platelets in the antiphospholipid syndrome is complex and the full pathogenic significance is not fully understood. The binding of aPL antibodies to the platelet membrane may result in the thrombopenia and further haemostatic activation.

Antibodies, Antiphospholipid↗
PubMed2002

Germline FAS gene mutation in a case of ALPS and NLP Hodgkin lymphoma.

FAS germline mutations have been associated with the development of autoimmune lymphoproliferative syndrome (ALPS). Occurrence of Hodgkin lymphoma (HL) has been reported in 2 families with ALPS. In both families an uncle of the index patient developed HL. A 15-year-old boy with autoimmune thrombopenia, lymphadenopathy, and splenomegaly for 6 years was studied. In an axillary lymph node biopsy nodular lymphocyte predominant (NLP) HL was diagnosed; in the areas between the nodules a proliferation of double-negative blastic T cells were present, suggestive of ALPS. Analysis for the presence of a FAS gene mutation using the denaturing gradient gel electrophoresis technique indicated a mutation in exon 9. Direct sequence analysis revealed a mutation causing a substitution of arginine with glutamine at codon 234. Because ALPS and NLP HL are both highly infrequent conditions, the occurrence in at least 3 families suggests a causative relationship between germline FAS gene mutations and NLP HL.

Adolescent↗
PubMed1989

Hemorrhagic cystitis following high-dose chemotherapy and bone marrow transplantation in children with malignancies: incidence, clinical course, and outcome.

Two hundred ninety-one courses of high-dose chemotherapy (HDC) with bone marrow transplantation (BMT) in children with malignancies were reviewed in order to assess the incidence, clinical course, outcome, and predisposing factors of hemorrhagic cystitis. Hemorrhagic cystitis occurred in 19 HDC courses (6.5%). Three patients had grade I hematuria linked to thrombopenia, nine had grade II hematuria despite platelet levels greater than 50 x 10(9)/L, and seven had grade III hematuria with clots and bladder obstruction. Severe complications occurred in grade III patients, but no deaths were directly linked to the cystitis. Fourteen patients recovered within two to 120 days of onset. The other patients died before the cystitis resolved, either of a relapse of the malignancy or of infection. Predisposing factors were age (increased incidence in older children), conditioning regimen containing cyclophosphamide, previous vesical irradiation, association with prolonged aplasia, and hepatic complications. The role of busulfan was also probable. No viral agent was found.

Adolescent↗
PubMed1997

Intensive sequential chemotherapy with repeated blood stem-cell support for untreated poor-prognosis non-Hodgkin's lymphoma.

PURPOSE: To demonstrate the feasibility and efficacy of six ambulatory high-dose sequential chemotherapy courses that include three intensified cycles supported by stem-cell infusion in high-risk and high-intermediate-risk untreated non-Hodgkin's lymphoma (NHL) patients. PATIENTS AND METHODS: A pilot nonrandomized study included 20 untreated patients aged less than 60 years with aggressive histologically identified NHL and two or three adverse-prognosis criteria (International Index). Patients received an ambulatory regimen with high-dose chemotherapy supported by granulocyte colony-stimulating factor (G-CSF) and repeated peripheral-blood stem-cell (PBSC) infusion. The median age was 39 years (range, 20 to 59), with 13 men and seven women. Chemotherapy consisted of one cycle every 21 days for a total of six cycles. The first three cycles (A1, A2, and A3) consisted of cyclophosphamide (Cy) 3,000 mg/m2, doxorubicin (Doxo) 75 mg/m2, and vincristine 2 mg (plus corticosteroids). The last three cycles (B4, B5, and B6) consisted of the same drug combination plus etoposide 300 mg/m2 and cisplatin 100 mg/m2. For an expected duration of 18 weeks, the projected dose-intensity was 25 mg/m2/wk for Doxo and 1,000 mg/m2/wk for Cy. G-CSF 300 micrograms was administered from day 6 following each cycle until neutrophil reconstitution. Two aphereses were performed at approximately day 13 after each A cycle, and PBSCs were injected at day 4 of each B cycle. Radiotherapy on tumor masses > or = 5 cm was scheduled after completion of the last cycle. RESULTS: The median duration of grade 4 neutropenia was 1 day (range, 0 to 7) for each A cycle and 4 days (range, 1 to 10) for each B cycle (P = .02). The median duration of grade 4 thrombopenia was 0 days (range, 0 to 8) for each A cycle and 6 days (range, 1 to 21) for each B cycle (P < .001). Hospitalization for febrile neutropenia was required for 18% and 44% of patients during cycles A and B, respectively (P < .01). Only three patients did not complete the protocol: one due to emergency surgery after cycle B4, one who died after cycle B5 from interstitial pneumonia, and one with delayed hematologic reconstitution after cycle B4. Chemotherapy delivery was optimal (median actual relative dose-intensity, 97%; range, 66 to 100). The median total dose administered over 18 weeks was 18,000 mg Cy (range, 12,000 to 18,000), 450 mg Doxo (range, 300 to 450), 900 mg etoposide (range, 300 to 900), and 300 mg cisplatin (range, 100 to 300). Evaluation of response after six courses showed 13 complete remissions ([CRs] 65%), four partial remissions (PRs), two nonresponses (NRs), and one toxic death. With a median follow-up period of 25 months (range, 16 to 43), 15 patients are alive, with 12 in continuous first CR; five patients relapsed (four of four PRs and one of 13 CRs). Two-year survival and failure-free survival (FFS) rates are 73% and 56%, respectively. The disease-free survival (DFS) rate for the CRs is 86%. CONCLUSION: PBSC support contributes to the feasibility of first-line, very-high-dose, ambulatory chemotherapy delivery in poor-risk NHL and is associated with a high rate of remission and FFS.

Adult↗
PubMed1998

Toxicity of fluorouracil in patients with advanced colorectal cancer: effect of administration schedule and prognostic factors.

PURPOSE: Fluorouracil (5-FU) continuous infusion is superior to 5-FU bolus in patients with advanced colorectal cancer, but the survival difference between the two treatments is small and, therefore, the difference in toxicity profile is crucial in choosing a treatment for individual patients. MATERIALS AND METHODS: We conducted a meta-analysis of all randomized trials that compared 5-FU bolus with 5-FU CI, based on individual data from 1,219 patients, to compare the toxicity of the two schedules of 5-FU administration and to identify predictive factors for toxicity. The toxicities considered were World Health Organization (WHO) grade 3 to 4 anemia, thrombopenia, leukopenia, neutropenia, nausea/vomiting, diarrhea, mucositis, and hand-foot syndrome. RESULTS: Hematologic toxicity, mainly neutropenia, was more frequent with 5-FU bolus than with 5-FU CI (31% and 4%, respectively; P < .0001). Hand-foot syndrome was less frequent with 5-FU bolus than with 5-FU CI (13% and 34%, respectively; P < .0001). There was no difference between the two treatment groups in terms of other nonhematologic toxicities. Independent prognostic factors were age, sex, and performance status for nonhematologic toxicities, performance status, and treatment for hematologic toxicities, and age, sex, and treatment for hand-foot syndrome. CONCLUSION: Based on a large data set, this study confirmed and quantified the toxicity profile of the two schedules of administration of 5-FU and allowed the identification of clinical predictors of toxicity.

Colorectal Neoplasms↗
PubMed1998

Phase II trial of oxaliplatin as first-line chemotherapy in metastatic colorectal cancer patients. Digestive Group of French Federation of Cancer Centers.

PURPOSE: To evaluate the objective tumor response rate and safety profile of oxaliplatin when administered to patients with previously untreated metastatic colorectal adenocarcinoma. PATIENTS AND METHODS: A total of 39 patients were entered onto this phase II trial. One patient was excluded for having had a second cancer, so the study was based on 38 patients. Patients were treated with oxaliplatin 130 mg/m2 as a 2-hour infusion on day 1, every 21 days. Patients were assessed for response every three courses. All clinical and radiologic data were reviewed by an external panel of experts, with their assessment being considered definitive. RESULTS: Nine partial responses (PRs) were observed (response rate, 24.3%; 95% confidence interval, 11.8% to 41.2%). The median duration of response was 216+ days. Fifteen patients (40.5%) had stable disease and 13 (35.2%) had progressive disease. The median progression-free survival time for all patients was 126+ days (range, 21 to 447+). The main toxicity was peripheral sensory neuropathy. Grade 3 neurotoxicity (National Cancer Institute common toxicity criteria [NCI-CTC]) was reported in 13%. Hematologic and gastrointestinal toxicities were mild. The incidence of grade 3 neutropenia was 5.2%, while that of grade 3 or 4 thrombopenia was 7.9%. Vomiting (grade 3 or 4) occurred in 7.9% of patients and grade 3 diarrhea in 2.6%. CONCLUSION: This phase II study provides clear evidence of the safety and efficacy of oxaliplatin monotherapy at this dose and schedule in patients with previously untreated metastatic colorectal carcinoma.

Adenocarcinoma↗
PubMed2003

Repeated bone-targeted therapy for hormone-refractory prostate carcinoma: tandomized phase II trial with the new, high-energy radiopharmaceutical rhenium-188 hydroxyethylidenediphosphonate.

PURPOSE: We investigated the effect of repeated bone-targeted therapy with rhenium-188 hydroxyethylidenediphosphonate (HEDP) in patients with progressive, hormone-resistant prostate carcinoma and bone pain. The aim of this study was to determine the pain palliation and the antitumor effect of rhenium-188 HEDP treatments. PATIENTS AND METHODS: Sixty-four patients were randomly assigned to one of two groups for radionuclide therapy with rhenium-188 HEDP; patients of group A received a single injection, patients of group B received two injections (interval, 8 weeks). After therapy, patients were followed-up by assessment of pain palliation and clinical outcome until death. RESULTS: In both groups, toxicity was low, with moderate thrombopenia and leukopenia (maximum common toxicity criteria grade of 2). The effectiveness of rhenium-188 HEDP for pain palliation was better in the repeated treatment group (group B), with a response rate and time of response of 92% and 5.66 months, respectively (P =.006 and P =.001). In group B, 11 (39%) of 28 patients had a prostate-specific antigen decrease of more than 50% for at least 8 weeks, compared with two (7%) of 30 patients in the single-injection group (group A). The median times to progression of group A and group B were 2.3 months (range, 0 to 12.2 months) and 7.0 months (range, 0 to 24.1 months), respectively (P =.0013), and the median overall survival times were 7.0 months (range, 1.3 to 36.7 months) and 12.7 months (range, 4.1 to 32.2 months), respectively (P =.043). CONCLUSION: Compared with single-injection therapy, repeated bone-targeted therapy with rhenium-188 HEDP administered to patients with advanced progressive hormone-refractory prostate carcinoma enhanced pain palliation and improved progression-free and overall survival. Larger studies are justified to further evaluate the use of rhenium-188 HEDP.

Aged↗
PubMed1999

Treatment of the Kasabach-Merritt syndrome with pegylated recombinant human megakaryocyte growth and development factor in mice: elevated platelet counts, prolonged survival, and tumor growth inhibition.

Kasabach-Merritt Syndrome (KMS) is seen in children with large vascular tumors. KMS is characterized by very low platelet counts and a consumption of coagulation factors causing life-threatening complications. It has been proposed that thrombopenia in these patients is caused by intratumoral trapping of platelets. The truncated form of the cMpl-receptor ligand thrombopoietin, pegylated human megakaryocyte growth and development factor (Peg-rHuMGDF), is an agent that stimulates platelet production. We hypothesized that stimulation of the platelet production would prevent the life-threatening complications of patients with KMS owing to low platelet counts. In a mouse model of KMS, with tumors derived from a hemangioendothelioma cell line, we studied the effect of Peg-rHuMGDF. Treatment with Peg-rHuMGDF (10 microg/kg/day intraperitoneally) increased platelet counts by 7-8-fold compared with control tumor-bearing mice after 11 d of treatment (p < 0.001, n = 8). Survival was significantly increased, with 50% of treated animals alive at 1 mo versus 0% in untreated controls. Interestingly, we also observed an inhibition of tumor growth by 75% (p < 0.001, n = 8). Hematoxylin and eosin staining showed fresh fibrin clots in the treated tumors, suggesting that higher platelet counts caused intravascular thrombosis of tumor vessels. We conclude that increased platelet production in this model of KMS resulted in an antivascular tumor effect via platelet trapping. Further, we propose that thrombopoietin may be of critical value in preventing life-threatening complications from KMS.

Animals↗
PubMed2006

Phase II trial of a simultaneous radiochemotherapy with cisplatinum and paclitaxel in combination with hyperfractionated-accelerated radiotherapy in locally advanced head and neck tumors.

BACKGROUND: Simultaneous radiochemotherapy (RCT) is the treatment of choice for locally advanced head and neck cancers. In order to evaluate the toxicity and the survival rates, we investigated the use of a very aggressive combination protocol that included cisplatinum and paclitaxel combined with hyperfractionated-accelerated radiotherapy. The final results of the phase II study are listed below. METHODS: For the phase II trial 32 patients (29 male, 3 female) with histologically diagnosed locally advanced non-metastatic squamous cell carcinoma of the head and neck in stage III/IV were treated from 1999 to 2003. Radiotherapy was administered as hyperfractionated-accelerated to a total dose of 70.6 Gy. The chemotherapy regime included administering cisplatinum on d 1-5 and on d 29-33 at doses of 20 mg/m(2) and during the entire course of treatment paclitaxel was administered twice a week at doses of 25 mg/m(2). RESULTS: The 5-yr overall and disease-free survival rates were 48% and 43%. Twenty-two (69%) patients reached a clinically complete response and 8 (25%) a partial response (for two of the patients the response rate is not known). Two (6%) patients died during the treatment. Seven (22%) patients developed local recurrences and six of these patients have in the meantime died. With regards to the four (12%) patients who developed distant metastases, three of them have in the meantime died and two (6%) patients have died as a result of secondary malignancies. Seven out of 25 (28%) patients developed grade 3 erythema and 22 out of 31 (71%) patients developed grade 3 mucositis. No cases of grade 4 mucositis were observed; however, one patient out of 25 (4%) was classified with grade 4 dermatitis. One out of 24 (4%) patients developed grade 2 liver toxicity and 1 out of 22 patients (5%) developed grade 3 thrombopenia. Seven out of 25 patients (28%) developed a grade 3 leukopenia, and 2 out of 25 patients (8%) experienced a grade 4 eutropenic infection. Dysphagia was a significant late toxicity. Out of 24 patients, 4 (17%) developed a grade 3 dysphagia and 1 (4%) patient developed a grade 3 xerostomia. An osteoradionecrosis was seen in 2 out of 24 (8%) patients. CONCLUSION: This very aggressive radiochemotherapy protocol yielded excellent response and overall survival rates; however it is associated with a very high rate of acute toxicity. Therefore, in such cases where acute toxicity resulted, extensive supportive care is required.

Adult↗
PubMed2006

Mitochondrial disease in the offspring as a result of antiretroviral therapy.

Nucleoside analogue reverse transcriptase inhibitors (NRTIs) have substantially lowered the risk of the mother-to-child transmission of HIV. Evidence of mitochondrial toxicity in vitro, in animal models and in adult HIV-infected patients, has raised concern about the perinatal safety of these antiretrovirals. In zidovudine-exposed, but HIV-uninfected infants, transient anaemia and additional long-term blood abnormalities (neutropenia, thrombopenia and lymphopenia) and hyperlactatemia have been documented. The overall risk of mortality and congenital abnormalities does not appear to be increased, but rare mitochondrial events cannot be excluded for lack of statistical power. French data suggest an above background incidence of mitochondrial symptomatology. Preclinical data demonstrate zidovudine also to be a carcinogen. Long-term systematic follow-up of exposed babies in large cohorts is needed, as are randomised trials with NRTIs carrying a lower risk of mitochondrial toxicity.

Animals↗
PubMed2003

Utilisation and safety of low molecular weight heparins: prospective observational study in medical inpatients.

AIMS: Low molecular weight heparins (LMWHs) are widely used as curative or preventive treatments of thromboembolic diseases. The aim of our study was to: investigate the pattern of prescription of LMWHs in different departments of French teaching hospitals; andestimate the incidence of adverse drug reactions (ADRs) induced by LMWHs and associated risk factors for the occurrence of bleeding events. METHODS: This prospective study was performed in two teaching hospitals in Toulouse (south-western France) in March 1999 in different medical wards. All patients receiving a prescription for a LMWH were included in the survey. All data were prospectively recorded in each ward. RESULTS: A total of 334 patients were included. Sex ratio (male/female) was 1.25 and mean age was 72.5 +/- 16.3 years (extremes:18-101). 450 prescriptions for LMWHs were collected (1.34 prescription per patient) and involved mainly enoxaparin (61%), which was more frequently used than tinzaparin in patients over 75 years old (71.7 vs 28.3%; p < 0.0001). Ninety-nine patients received a LMWH for curative treatment (corresponding to 127 prescriptions of which 99 were for enoxaparin and 28 were for tinzaparin [p < 0.0001]). Indications included therapy for deep venous thrombosis, pulmonary embolism, acute coronary syndrome, unstable angina pectoris, non-Q-wave myocardial infarction. Serious renal insufficiency was significantly more frequent in patients from the geriatrics department (p < 0.00001). Enoxaparin was prescribed more frequently in patients with serious or moderate renal insufficiency than tinzaparin (72 vs 61%, p < 0.05). The incidence of LMWHs-induced ADRs was 10.5% occurring in 22 cases during preventive treatment of deep venous thrombosis and in 13 cases during curative therapy. ADRs were classified as 'serious' in 11 cases (31.4%). Reported ADRs were bleeding events (n = 15), thrombocytosis (n = 13), thrombopenia (n = 4) and hepatic cytolysis (n = 1). The mean delay for the occurrence of bleeding effects was 8.0 +/- 9.1 days (range 1-40). Multivariate analysis of the influence of several criteria on the occurrence of haemorrhagic effects showed that the decrease of creatinine clearance (10 ml/min) was associated with an increased haemorrhagic risk (relative risk [RR] = 1.34, 95% CI 1.12-1.65; p < 0.05). Moreover, the risk of adverse bleeding effects increased for patients with a creatinine clearance <20 ml/min (RR = 2.8; 95% CI 1.00-7.8). CONCLUSION: Our data firstly show a different pattern of LMWHs prescription in different clinical wards. Secondly, the risk of bleeding ADRs in patients treated by LMWHs increases significantly with renal function impairment for the two LMWH preparations studied. More pharmacoepidemiological studies are necessary in patients with several risk factors, particularly in elderly people who often have renal impairment, in order to determine the optimal pattern use of each LMWH.

Adolescent↗