Hematopoietic stem cell allografts using a non-myeloablative conditioning regimen can be safely performed on an outpatient basis: report of four cases.

Using a non-myeloablative, immunosuppressive, fludarabine-based conditioning regimen, we performed allogeneic peripheral blood stem cell transplants totally on an outpatient basis in four patients (two with chronic myelogenous leukemia, one with acute myelogenous leukemia and one with thalassemia major). The median granulocyte recovery time to 0.5 x 109/l was 10 days and the lowest absolute neutrophil count was 0.064 x 109/l; only one patient developed thrombocytopenia below 20 x 109/l. No patient required red blood cell transfusions and one was given a single prophylactic platelet transfusion. All patients are alive at 210-390 (median 285) days and have definite evidence of chimerism; one developed biopsy-proven GVHD on day 50, with a limited cutaneous rash. The procedure is less costly than its counterpart using myeloablative conditioning regimens and may represent another approach in the management of patients requiring an allogeneic stem cell transplant. Bone Marrow Transplantation (2000) 25, 131-133.

Effect of inhaled cyclosporin on the rat airway: histologic and bronchoalveolar lavage assessment.

Airway inflammation plays a pivotal role in asthma. Over the last 10 years, evidence has accumulated for the potential role of lymphocytes in airway inflammation. Since cyclosporin A (Cyc-A) can profoundly influence lymphocyte activation, it is appropriate to consider this drug as a novel antiasthmatic. The effect of inhalation of low doses of Cyc-A on airway inflammation remains unclear. The purpose of this study was to investigate the bronchoalveolar lavage (BAL), peripheral blood cell profiles, and lung biopsy specimens in Cyc-A-pretreated rats. Twenty-nine rats (8 controls, 10 ovalbumin sensitized, and 11 Cyc-A inhaling and ovalbumin sensitized) were included in the study. A commercial intravenous Cyc-A solution was given as a single dose of 20 mg/kg 1 h prior to inhalation of ovalbumin via nebulizer. The total number of BAL cells significantly increased in rats inhaling Cyc-A when compared with ovalbumin-sensitized rats (2.37 +/- 2.34 x 10(6)/ml and 1.01 +/- 0.49 x 10(6)/ml respectively, p < 0.05). There was a significant increase in the percentage of lymphocytes (14.5 +/- 8.5 versus 27.4 +/- 7.4%, p < 0.03), a nonsignificant increase in the percentage of eosinophils (0.8 +/- 1.0 versus 3.0 +/- 4.6%), and a significant decrease in the percentage of polymorphonuclear leukocytes (9.4 +/- 6.9 versus 3.4 +/- 3.8%, p < 0.01) and macrophages (75.4 +/- 5.1 versus 50.2 +/- 11.8%, p < 0.02) in BAL in the ovalbumin-sensitized group as compared with controls. Differential cell counts revealed a higher percentage of neutrophils and macrophages in the BAL of Cyc-A-pretreated rats than in that of the ovalbumin-sensitized group (26.3 +/- 26.8 versus 3.4 +/- 3.8%, p < 0.01 and 66.1 +/- 7.7 versus 50.2 +/- 11.8%, p < 0.02). There was a nonsignificant decrease of lymphocytes and eosinophils in the Cyc-A-pretreated group when compared with the ovalbumin-sensitized group (27.4 +/- 7.4 versus 21.1 +/- 12.4 and 3.0 +/- 4.6% versus 2.4 +/- 2.6%). The peripheral blood total white blood cell count decreased in the ovalbumin-sensitized and Cyc-A-pretreated groups as compared with the control group (2,520 +/- 1,098/mm3, 3,591 +/- 2,251/mm3, and 5,975 +/- 2,787/mm3, respectively, p < 0.01). In addition, peripheral eosinophilia was detected in the Cyc-A-pretreated group when compared with controls and the ovalbumin-sensitized group (6.9 +/- 4.7, 2.4 +/- 1.1, and 2.6 +/- 2.4%, respectively, p < 0.01). Light-microscopic examination of the airways revealed prominent eosinophilia in tracheal, bronchial, and bronchiolar sections in the ovalbumin-sensitized group: counts were 1.8 +/- 2.3/HPF, 10.3 +/- 11.4/HPF, 63.3 +/- 45.0/HPF, respectively. Cyc-A resulted in a decrease of the eosinophil counts/HPF to 0/HPF in trachea (p < 0.05), to 4.3 +/- 9.4/HPF in bronchi (p < 0.02), to 19.4 +/- 38.4 in bronchioles (p < 0.004). In conclusion, the present study supports the theory that locally administered inhaled low-dose Cyc-A is effective on inflammatory cells of sensitized airways and peripheral cells. It may therefore be useful in elucidating the inflammatory mechanisms involved in asthma.

Pharmacokinetic and pharmacodynamic assessment of bioavailability for two prodrugs of methylprednisolone.

AIMS: The aim of this study was to establish whether pharmacokinetic differences between two pro-drugs of methylprednisolone (MP) are likely to be of clinical significance. METHODS: This study was a single-blind, randomized, crossover design comparing the bioequivalence of MP released from the pro-drugs Promedrol (MP suleptanate) and Solu-Medrol (MP succinate) after a single 250 mg (MP equivalent) intramuscular injection to 20 healthy male volunteers. Bioequivalence was assessed by conventional pharmacokinetic analysis, by measuring pharmacodynamic responses plus a novel approach using pharmacokinetic/pharmacodynamic modeling. The main measure of pharmacodynamic response was whole blood histamine (WBH), a measure of basophil numbers. RESULTS: The MP Cmax was less for MP suleptanate due to a longer absorption halflife of the prodrug from the intramuscular injection site. The bioavailability of MP was equivalent when based on AUC with a MP suleptanate median 108% of the MP succinate value (90% CI: 102-114%). For Cmax the MP suleptanate median was 81% of the MP succinate value (90% CI: 75-88%). The tmax for MP from MP suleptanate was delayed relative to MP succinate. The median difference was 200% (90% non-parametric CI: 141-283%). The area under the WBH effect-time curve (AUEC) and the maximum response (Emax) were found to be equivalent (90% CI: 98-113% and 93-109% respectively). The maximum changes in other white blood cell counts, blood glucose concentration and the parameters of the pharmacodynamic sigmoid Emax model (EC50, Emax and gamma) were also not significantly different between prodrugs. CONCLUSIONS: MP suleptanate is an acceptable pharmaceutical alternative to MP succinate. The use of both pharmacokinetic and pharmacodynamic response data together gives greater confidence in the conclusions compared with those based only on conventional pharmacokinetic bioequivalence analysis.

Assessment of lymphocyte subsets and neutrophil leukocyte function in chronic psychiatric patients on long-term drug therapy.

1. Lymphocyte subsets and neutrophil function were studied in chronic psychiatric patients on long-term multiple drug therapy, and the correlation with disease and drug treatments was also investigated. 2. Patients showed decreased CD4+ percentage, CD4+/CD8+ ratio, B lymphocyte percentage, increased absolute and percentage NK, and impaired neutrophil chemotaxis, phagocytosis, and oxidative metabolism. Correlations were found between: patient status and lower CD4+ percentage, CD4+/CD8+ ratio, neutrophil chemotaxis, phagocytosis, and oxidative metabolism; schizophrenia and higher absolute and percentage NK, and neutrophil random migration; benzodiazepines and higher CD8+ absolute number and lower NBT reduction frequency; carbamazepine and higher NK percentage, neutrophil chemotaxis, phagocytosis, stimulated O2-production, and lower microbicidal activity. 3. The present study provides direct evidence for the existence of immunologic abnormalities in a population of chronic psychiatric patients on long-term drug therapy. Although a possible role by other factors could not be excluded, such abnormalities are strongly associated with chronic administration of benzodiazepines and carbamazepine. Further investigations are warranted to confirm these findings and disclose the possible mechanism(s) involved.

Clinical toxicity and laboratory effects of granulocyte-colony-stimulating factor (filgrastim) mobilization and blood stem cell apheresis from normal donors, and analysis of charges for the procedures.

BACKGROUND: Apheresis of granulocyte-colony-stimulating factor (filgrastim)-mobilized blood stem cells from normal donors is now being used in place of a marrow harvest in transplantation. How the adverse effects of and charges for this procedure compare with those of the standard marrow harvest is not known. STUDY DESIGN AND METHODS: Forty consecutive normal subjects who received filgrastim 96 micrograms/kg) subcutaneously twice daily for 4 to 6 days in preparation for apheresis were monitored prospectively by clinical and laboratory evaluation. RESULTS: Sixty-two percent of the subjects required oral analgesics. None discontinued filgrastim prematurely. Bone pain (82%), headache (70%), fatigue (20%), and nausea (10%) were reported. Filgrastim caused a mean eightfold increase in neutrophil counts, a mean twofold increase in lymphocyte counts, a mean twofold rise in alkaline phosphatase and lactate dehydrogenase levels, and minor changes in serum potassium, magnesium, and uric acid. Adverse events and laboratory effects resolved within 7 days after apheresis. No apheresis stem cell donor required transfusion or hospitalization, and only one required an additional clinic visit after completion of apheresis. By comparison, a retrospective analysis of 33 normal marrow donors demonstrated that all received transfusion(s), 3 were hospitalized, 3 required additional clinic visits after the marrow harvest. The median total charges related to the two procedures were comparable (p = 0.43), although the charges were significantly lower for donors requiring only one apheresis procedure (p = 0.002). CONCLUSION: Filgrastim mobilization and apheresis of blood stem cells constitute a safe, well-tolerated, and comparable or less expensive alternative to the traditional marrow harvest.

Five-day course of granulocyte colony-stimulating factor in patients with prolonged neutropenia after adjuvant chemotherapy for breast cancer is a safe and cost-effective schedule to maintain dose-intensity.

PURPOSE: To analyze the safety and efficacy of a short course of granulocyte colony-stimulating factor (G-CSF) to maintain dose-intensity of subsequent cycles of chemotherapy after a prior episode of prolonged neutropenia, without febrile complications, in patients receiving adjuvant treatment for breast cancer. PATIENTS AND METHODS: Thirty-two patients undergoing adjuvant cyclophosphamide, methotrexate, and fluorouracil (CMF) or doxorubicin-CMF for stages I to II breast cancer were included after having chemotherapy delays due to neutropenia (absolute neutrophil count [ANC] < 1.5 x 10(9)/L) on day 22. G-CSF was administered subcutaneously on days 15 to 19 of each subsequent cycle. RESULTS: None of the patients included in this study had to be admitted to the hospital for fever and neutropenia. The median percentage of the projected dose-intensity for CMF or doxorubicin-CMF on an intent-to-treat basis was 0.994, which was significantly higher than the delivered dose-intensity before the start of G-CSF treatment (P < .0001). Patients who received concomitant G-CSF and radiotherapy achieved a similar dose-intensity as patients who did not undergo radiotherapy. Seven patients discontinued G-CSF treatment due to musculoskeletal pain. These patients had more subsequent cycle delays because of day 22 neutropenia than the 25 patients who followed the G-CSF schedule (P = .0028). CONCLUSION: A 5-day course of G-CSF in patients with prior chemotherapy delays due to prolonged neutropenia seems to be a safe and cost-effective schedule to maintain CMF or doxorubicin-CMF dose-intensity in the adjuvant treatment of breast cancer.

An assessment of the systemic effects of single and repeated doses of inhaled fluticasone propionate and inhaled budesonide in healthy volunteers.

The systemic effects of single and multiple doses of inhaled fluticasone propionate (FP) and budesonide were examined in 24 healthy male volunteers (age range 18-29 years). The study was of an open, placebo-controlled, randomized, three-way crossover design. On each study day, multiple blood samples were taken over a 20 h period after drug administration (after a single dose and after the last of seven doses) and area under the curve (AUC(0-20)) for plasma cortisol and white blood cell (WBC) counts was calculated. RESULTS. The present study shows that multiple dosing with FP 1.0 mg b.i.d. for 3.5 days (seven doses) resulted in a marked cortisol suppression from placebo which, at 55%, was more than double that seen with a single dose (25% suppression). Multiple dosing with budesonide 0.8 mg b.i.d. resulted in a 34% suppression in plasma cortisol compared with a suppression of 26% with a single dose. The increase in systemic activity of FP after multiple dosing is confirmed by both the number of subjects with 0800 hours plasma cortisol values below normal limits and by the changes in WBC and differential counts. CONCLUSION. The results of the present study confirm previous findings with regard to the more marked systemic effect of FP following multiple dosing as compared with a single dose. This increase in systemic effect from single dosing to multiple dosing is significantly greater for FP than for budesonide.

Economic study of neutropenia induced by myelotoxic chemotherapy.

This article describes the economic and social impact of neutropenia induced by myelotoxic chemotherapy in patients with cancer during the period 1 January-31 December 1991. Neutropenia is a life-threatening complication of chemotherapy in patients with cancer. The episodes of fever and infections originating from neutropenia require hospitalization of the patient until the granulocyte levels are restored. The calculation of the economic cost was based on the following parameters: length of stay in hospital, analytical tests performed on the patient, type and cost of drug therapy administered, blood transfusions performed, health assistance received, cost of isolation and absence from work. The overall economic cost of neutropenia in patients with cancer reached 329,775 pesetas ($2,893). Cost of the health-care staff was the largest budget item in relation to the total health resources estimated.

Early health effects and biological monitoring in persons occupationally exposed to tetraethyl lead.

Dependent on the level of occupational exposure to tetraethyl lead, the occurrence of early signs of toxicity and the urinary excretion of triethyl lead, diethyl lead and total lead compounds were investigated. This was done in the following cohorts in the province of Hubei, China: 277 workers at gasoline depots exposed to gasoline, 36 traffic policemen exposed to automobile exhaust and 342 public office workers (virtually non-exposed controls). Mean external tetraethyl lead exposure concentrations were 84.8 micrograms/m3 (as Pb) for the gasoline depot workers, 5.2 micrograms/m3 for traffic police and 1.1 microgram/m3 for the controls. No significant subclinical indications of organic lead toxicity were found in the group of traffic policemen compared with the controls. In the cohort of gasoline workers, however, there was a statistical increase (vs controls) in the frequency of appearance of tremor and of sinus bradycardia. When the cohort of gasoline workers was divided into subgroups of different ranges of exposure, dose-dependence was noted. In general, the urinary excretion of triethyl lead was very low compared to that of diethyl lead, which appears to be a sensitive and specific indicator of exposure to tetraethyl lead; total lead excretion did not correlate well with actual external tetraethyl lead exposure. On the basis of these data it seems that current occupational exposure limits for tetraethyl lead are inadequate and need to be revised. In addition, a biological limit, based on urinary diethyl lead excretion, may be proposed.

Assessment of the immunotoxic potential of the fungicide dinocap in mice.

The immunotoxic potential of dinocap was evaluated in female C57BL/6J mice following in vivo and in vitro exposure to this fungicide. In in vivo studies, groups of mice were dosed by gavage with technical grade dinocap at dosages ranging from 12.5 to 50 mg/kg per day for 7 or 12 days and selected immune functions examined. Mice dosed at 50 mg/kg per day dinocap died after 4 days of dosing. Twelve days of dosing with dinocap at 25 mg/kg per day resulted in decreased thymus weights and cellularity, and increased spleen weights. No changes were observed in body weight, absolute differential peripheral leukocyte counts, the lymphoproliferative responses to B- or T-cell mitogens, the mixed lymphocyte reaction, or natural killer (NK) cell activity of spleen cells from mice exposed to dinocap. Lymphoproliferative responses to concanavalin A (Con A) and phytohemagglutinin (PHA), however, were reduced in thymocytes from mice dosed at 25 mg/kg per day dinocap. The cytotoxic T lymphocyte (CTL) response to P815 mastocytoma cells was enhanced in mice exposed for 7 days to 25 mg/kg per day dinocap. Exposure of mice for 7 days to 25 mg/kg per day dinocap also caused a significant reduction in the IgM and IgG plaque-forming cell (PFC) response to sheep red blood cells (SRBC). A time-course study indicated that dinocap-induced suppression of the IgM PFC response was due to a delay in the peak PFC response to SRBC. In vitro studies using murine thymocytes cultured with dinocap (10 micrograms/ml for 72 h) resulted in suppression of the proliferative response to Con A and PHA. Exposure of thymocytes to dinocap in vitro for as little as 30 min resulted in suppression of the mitogen-stimulated response in the absence of any apparent direct cytotoxic effect. These results suggest that dinocap alters the immune system of the mouse, however, these effects are relatively modest in terms of adverse immune function and are only seen at relatively high exposure levels.

Feeding differently processed soya bean. Part 2. An assessment of haematological responses in the chicken.

The use of differently processed soya bean as a major source of dietary protein was evaluated in a haematological study using broiler chickens in which groundnut cake (GNC), raw soya bean (RSB), roasted soya bean (RtSB), cooked soya bean (CSB) and soya bean oil cake (SBC) were fed on equi-protein basis. The results showed that: 1. Red blood cell (RBC) count and haemoglobin content of blood significantly (P less than 0.05) increased in chicks fed RSB relative to the other soya bean diets. Feeding differently processed soya bean significantly (P less than 0.05) influenced mean cell haemoglobin (MCH) and mean corpuscular volume (MCV) while the mean corpuscular haemoglobin concentration (MCHC) was not significantly influenced. 2. Both the total white blood cell (WBC) count and the monocytes were significantly (P less than 0.05) influenced by the dietary treatments. Chicks fed processed soya bean generally had higher number of monocytes. 3. Physical properties determined were specific gravity and erythrocyte sedimentation rate. The latter was significantly (P less than 0.05) lower in all the processed soya bean-fed chicks. 4. Minerals determined in blood were Na, K, Ca, Mg, Fe, Cu and P. Of all these, chicks fed RSB had significantly (P less than 0.01) lower levels of blood Mg and marked decrease in Ca.

Assessment of posttraumatic polymorphonuclear leukocyte accumulation in rat brain using tissue myeloperoxidase assay and vinblastine treatment.

Polymorphonuclear leukocytes (PMN) are implicated in the pathogenesis of traumatic brain injury. We tested the following hypotheses: (1) leukocyte accumulation is present in brain tissue 24 h posttrauma, (2) leukocyte accumulation represents PMN, and (3) prior systemic PMN depletion attenuates brain tissue PMN accumulation. Trauma was induced in exposed right parietal cortex by weightdrop in anesthetized Wistar rats (n = 24). Of the traumatized rats, 12 were PMN-depleted with vinblastine sulfate i.v. Controls were 12 normal rats and 5 sham-operated rats (craniotomy). Sections of traumatized and contralateral hemispheres were analyzed for myeloperoxidase (MPO) activity. Brain MPO activity was increased fivefold at 24 h posttrauma, but only in the traumatized hemisphere (0.448 +/- 0.133 U/g vs 0.090 +/- 0.022 U/g in trauma vs normal, respectively, p < 0.05, mean +/- SEM). PMN depletion attenuated this increase in MPO activity and decreased circulating PMN counts (0.07 +/- 0.032 x 10(9)/L vs 0.894 +/- 0.294 x 10(9)/L PMN-depleted-trauma vs trauma rats, respectively, p < 0.05). Leukocyte accumulation in the brain posttrauma was confirmed by MPO assay. Inhibition of MPO activity in the PMN-depleted group and the specificity of vinblastine treatment for depletion of circulating PMN suggest that leukocyte accumulation in the brain at 24 h posttrauma is largely due to PMN.

Assessment of neonatal avian inflammatory macrophage function following embryonic cyclophosphamide exposure.

Inflammatory macrophage recruitment and function were examined in 4-5-week-old chickens which had received two doses of cyclophosphamide (CP) or vehicle (dH2O) during late embryogenesis (18 and 19 days of incubation). Mononuclear leukocyte chemotaxis to N-formyl-methionyl-leucyl-phenylalanine (FMLP) and hematological parameters were unchanged in CP-treated vs control chickens. Peritoneal exudate cells (PECs) elicited in response to intraperitoneal (i.p.). Sephadex injection did not differ in CP-treated vs control chickens with respect to cell number, cell type, superoxide anion production, or cell surface expression of Ia and transferrin receptor (TfR) antigens. The CP-treated chickens did exhibit the expected decrease in bursa weight; male chickens exposed to CP also had inhibited testes growth. Although embryonic exposure to CP at this dose results in irreversible bursal damage and subsequent impaired humoral immunity, it appears that there are no long-lasting effects on avian inflammatory macrophage function.

Toxicological assessment of chlorinated diphenyl ethers in the rat, Part II.

Chlorinated diphenyl ethers (CDE's) are environmental contaminants that have been found in Great Lakes fish. Because of the paucity of toxicity data and potential for human exposure, the present short-term study was conducted to assess their potential toxic effects. Groups of 10 male and 10 female rats were administered the three CDE congeners (2,2',4,4',5-pentachlorodiphenyl ether (PCDE), 2,2',4,4',5,5'-hexachlorodiphenyl ether (HCDE), 2,2',3,4,4',6,6'-heptachlorodiphenyl ether (HPCDE] in diets at levels of 0.5, 5.0, 50 or 500 ppm for a period of 4 weeks. Decreased food consumption was observed with male and female rats fed the diet containing 500 ppm HPCDE. Treatment with the three isomers at the highest dose level produced an increase in liver weight in both sexes. While administration of PCDE produced an increase in hepatic aminopyrine demethylase activity, HCDE caused a significant increase in aminopyrine demethylase, aniline hydroxylase and ethoxyresorufin de-ethylase activities. HPCDE caused a significant increase in ethoxyresorufin de-ethylase activity. HPCDE at the highest dose level also caused a significant reduction in circulating lymphocytes in male rats. The 3 CDE's produced mild and adaptative histological changes in the liver and thyroid, but only HPCDE elicited mild changes in the thymus, bone marrow, and spleen. The above data indicate that HPCDE is immunosuppressive and that all three CDE isomers are considered to be moderately toxic in rats. The no-observable effects levels appear to be between 5-50 ppm in diet (0.36-3.0 mg/kg b.w.) for the three CDE's.

[Should the pharmaceutical industry play an active part in pharmacosurveillance? (author's transl)]. / L'industrie du médicament a-t-elle une vocation de pharmacovigilance?

The development of new drugs by pharmaceutical firms proceeds through different phases, i. e. pre-clinical studies and stage I, II and III clinical studies, which normally result in authorization to market. Once the drug is on the market, however, further research work is required to perfect its use and complete our knowledge of it. Stage IV clinical trials, which may be termed "pharmacosurveillance", fall as much as the previous ones within the responsibilities of the pharmaceutical industry, since reports on side-effects are collected and these may have practical applications. Thus, clinical research may be shifted towards possible new indications, or new pharmacological studies may be undertaken to elucidate the mechanism of some side-effects, develop them if they are beneficial, or find a way of preventing them if they are indesirable. With these considerations in mind, the authors have developed a protocol of pharmacosurveillance aimed at determining, through a preliminary in vitro study, the origin of some adverse reactions of anaesthetic drugs. Depending on the results of these studies, clinical applications are considered.