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Results for “Targeted dosing”

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PubMed2001

Comparison of twice- and three times daily tiagabine for the adjunctive treatment of partial seizures in refractory patients with epilepsy: an open label, randomised, parallel-group study.

UNLABELLED: A multicentre, open label, randomised, parallel group study compared the efficacy, tolerability and safety of two dosing regimens, t.i.d. and b.i.d., of tiagabine as an adjunctive therapy for the treatment of refractory patients with partial seizures. A total of 347 patients were randomised and treated (175 t.i.d. and 172 b.i.d.). Each group was administered the same daily dose of tiagabine incremented stepwise during a 12-week fixed-schedule titration period to a target dose of 40 mg/day. The patients were followed for a further 12-week flexible continuation phase. A significantly greater number of patients in the t.i.d. group completed the fixed schedule titration period (81.4% versus 73.1%; 95% CI of odds ratio = 0.331, 0.970; p = 0.038). The proportion of responders (patients showing at least a 50% decrease in all-seizure frequency from baseline) was similar for both groups (42.3% for b.i.d. and 47.1% for t.i.d.) during the last 8 weeks of the flexible phase and seven (4.0%) patients in the b.i.d. group were seizure-free compared to 14 (8.1%) patients in the t.i.d. group. Adverse events were of similar incidence in both groups, and mainly occurred during the fixed schedule titration period; they were mainly mild and CNS-related with somnolence being the most frequently reported. CONCLUSION: Tiagabine was effective as add-on treatment of refractory partial seizures. Although both regimens appear to offer a similar efficacy and safety profile, significantly more patients completed the study in the t.i.d. group compared to b.i.d., probably as a consequence of a lesser tolerability when high doses are given undivided. These results confirm that a slow titration and appropriate adjustment of dosing are essential conditions to ensure optimal use of tiagabine.

Adolescent↗

PubMed1992

Endometrial carcinoma in patients aged 75 years or older: outcome and complications after postoperative radiotherapy or radiotherapy alone.

A retrospective analysis is reported of 89 patients at least 75 years old (median age 79 years) treated with irradiation for endometrial carcinoma between 1972 and 1989, the median follow-up being 39 months. In 66 patients radiotherapy was given postoperatively and in one case preoperatively, 22 patients were treated with radiotherapy alone: intravaginal insertions exclusively in 22 patients (median dose 60 Gy to the mucosa) and combined with external radiotherapy in 53 patients (median external target dose 45 Gy; three or four fields, all treated daily, 1.8 to 2.0 Gy per fraction, five fractions per week; 30 Gy to the vaginal mucosa with low-dose rate). A few patients were treated with external radiotherapy or intrauterine insertions only. 65% of the patients treated with radiotherapy alone and 34% of the patients receiving postoperative radiotherapy had FIGO stage II or III disease. Five-year actuarial overall survival and disease-free survival for all patients with adenocarcinomas treated with curative intent was 47.5% and 57.2%, respectively. In 48 patients with surgical stages I and II, treated with postoperative adjuvant radiotherapy, overall actuarial survival is 58.2% and disease-free survived 65.5% at five years. After postoperative vaginal insertions only, no vaginal recurrence occurred. With combined external and intravaginal radiotherapy in surgical stage I and II, 4/36 patients (11%) showed a recurrence in the vagina only, the abdominal and pelvic recurrence rate being 8.3%. Grade 3 to 4 late toxicity was observed in 6/53 patients (11.3%) treated with external and intravaginal radiotherapy. However, in patients receiving external radiotherapy less than 45 Gy and intravaginal radiotherapy 30 to 40 Gy, as is standard postoperative adjuvant treatment today, only one grade 3 late toxicity was observed in 17 patients (5.9%). We conclude, that treatment of elderly patients with adenocarcinoma of the uterus should follow the same pattern as in younger patients, the acute side-effects and late toxicity of radiotherapy being similar.

Actuarial Analysis↗

PubMed1989

Three-dimensional photon dose distributions with and without lung corrections for tangential breast intact treatments.

The influence of lung volume and photon energy on the 3-dimensional dose distribution for patients treated by intact breast irradiation is not well established. To investigate this issue, we studied the 3-dimensional dose distributions calculated for an 'average' breast phantom for 60Co, 4 MV, 6 MV, and 8 MV photon beams. For the homogeneous breast, areas of high dose ('hot spots') lie along the periphery of the breast near the posterior plane and near the apex of the breast. The highest dose occurs at the inferior margin of the breast tissue, and this may exceed 125% of the target dose for lower photon energies. The magnitude of these 'hot spots' decreases for higher energy photons. When lung correction is included in the dose calculation, the doses to areas at the left and right margin of the lung volume increase. The magnitude of the increase depends on energy and the patient anatomy. For the 'average' breast phantom (lung density 0.31 g/cm3), the correction factors are between 1.03 to 1.06 depending on the energy used. Higher energy is associated with lower correction factors. Both the ratio-of-TMR and the Batho lung correction methods can predict these corrections within a few percent. The range of depths of the 100% isodose from the skin surface, measured along the perpendicular to the tangent of the skin surface, were also energy dependent. The range was 0.1-0.4 cm for 60Co and 0.5-1.4 cm for 8 MV. We conclude that the use of higher energy photons in the range used here provides lower value of the 'hot spots' compared to lower energy photons, but this needs to be balanced against a possible disadvantage in decreased dose delivered to the skin and superficial portion of the breast.

Breast Neoplasms↗

PubMed1996

Accelerated hyperfractionated radiotherapy for malignant gliomas.

PURPOSE: To evaluate accelerated hyperfractionated radiotherapy for the treatment of malignant gliomas. METHODS AND MATERIALS: Between April 1985 and June 1994, 70 adult patients with pathologically confirmed malignant glioma (75% glioblastoma multiforme, 25% anaplastic astrocytoma) suitable for high-dose therapy were selected for treatment with accelerated hyperfractionated radiotherapy, 1.5 Gy twice daily to a total target dose of 60 Gy. Two patients were excluded from analysis (one patient had a fatal pulmonary embolism after 18 Gy; one patient discontinued therapy after 28.5 Gy against medical advice and without sequelae or progression). The 68 patients in the study group had a median age of 52 years and a median Karnofsky performance status of 90. Stereotactic implant (125I) or stereotactic radiosurgery boosts were delivered to 16 patients (24%) in the study group. Minimum follow-up was 6 months. RESULTS: Median survival was 13.8 months and median progression-free survival was 7.4 months. The absolute Kaplan-Meier survival rate was 16% at 2 years and 4% at 5 years. Multivariate analysis for the prognostic impact of age, gender, histology, Karnofsky performance status, symptomatology, surgical resection vs. biopsy, and boost vs. nonboost therapy revealed that Karnofsky performance status > or = 90, boost therapy, and surgical excision predicted significantly improved outcome. No severe toxicity occurred in patients treated with accelerated hyperfractionated radiotherapy alone, although 5% required steroids temporarily for edema. Progression occurred during treatment in one patient (1.5%). CONCLUSION: This regimen of accelerated hyperfractionated radiotherapy is well tolerated and leads to results comparable with those of standard therapy. The rate of disease progression during treatment is significantly better (p = 0.001) than is reported for patients treated with standard fractionation, with or without chemotherapy. This regimen is a reasonable starting point for future trials and may have some advantages over standard fractionation.

Adolescent↗

PubMed1998

Dosimetric verification of the dynamic intensity-modulated radiation therapy of 92 patients.

PURPOSE: To verify that optimized dose distributions provided by an intensity-modulated radiation therapy (IMRT) system are delivered accurately to human patients. METHODS AND MATERIALS: Anthropomorphic phantoms are used to measure IMRT doses. Four types of verification are developed for: I) system commissioning with beams optimized to irradiate simulated targets in phantoms, II) plans with patient-optimized beams directed to phantoms simulating the patient, III) patient-phantom hybrid plans with patient-optimized beams calculated in phantom without further optimization, and IV) in vivo measurements. Phantoms containing dosimeters are irradiated with patient-optimized beams. Films are scanned and data were analyzed with software. Percent difference between verified and planned maximum target doses is defined as "dose discrepancy" (deltavp). The frequency distribution of type II deltavp from 204 verification films of 92 IMRT patients is fit to a Gaussian. Measurements made in vivo yield discrepancies specified as deltaivp, also fit to a Gaussian. RESULTS AND DISCUSSION: Verification methods revealed three systematic errors in plans that were corrected prior to treatment. Values of [deltavp] for verification type I are <2%. Type II verification discrepancies are characterized by a Gaussian fit with a peak 0.2% from the centroid, and 158 [deltavp] <5%. The 46 values of [deltavp] >5% arise from differences between phantom and patient geometry, and from simulation, calculation, and other errors. Values of [deltavp] for verification III are less than half of the values of [deltavp] for verification II. A Gaussian fit of deltaivp from verification IV shows more discrepancy than the fit of deltavp, attributed to dose gradients in detectors, and exacerbated by immobilization uncertainty. CONCLUSIONS: Dosimetric verification is a critical step in the quality assurance (QA) of IMRT. Hybrid Verification III is suggested as a preliminary quality standard for IMRT.

Brain Neoplasms↗

PubMed1998

Implications of hormesis on the bioassay and hazard assessment of chemical carcinogens.

Hormesis has been defined as a dose-response relationship which depicts improvement in some endpoint (increased metabolic rates, reduction in tumor incidence, etc.) at low doses of a toxic compound followed by a decline in the endpoint at higher doses. The existence of hormetic responses to carcinogenic agents has several implications for the bioassay and hazard assessment of carcinogens. To be capable of detecting and statistically testing for hormetic or other nonlinear dose-response functions, current study designs must be modified to include lower doses and sufficiently large numbers of animals. In addition, improved statistical methods for testing nonlinear dose-response relationships will have to be developed. Research integrating physiologically-based pharmacokinetic model descriptions of target dose with mechanistic data holds the greatest promise for improving the description of the dose-response curve at low doses. The 1996 Proposed Carcinogen Risk Assessment Guidelines encourage the use of mechanistic data to improve the descriptions of the dose-response curve at low doses, but do not distinguish between the types of nonlinear dose-response curves. Should this refined approach lead to substantial support for hormesis in carcinogenic processes, future guidelines will need to provide guidance on establishing safe doses and communicating the results to the public.

Animals↗

PubMedDate not supplied

[Determinants of tiagabine (TGB) efficacy and safety. A Polish multicenter study of 1307 patients with focal epilepsy].

Tiagabine (TGB) is a novel anti-epileptic drug providing new therapeutic possibilities to patients with focal seizures resistant to treatment. Since there is no clear algorithm for the best add-on therapy, the aim of our work was to establish factors that statistically significantly affect tiagabine efficacy and toxicity in patients with focal seizures. Data in the study were obtained from over 200 neurologists all over Poland. A group of 1307 patients aged from 3.5 to 80 years with drug-resistant focal epilepsy participated in the study. They were under observation for 16 weeks when receiving TGB as an add-on therapy. Prior to TGB treatment they had at least 1 seizure per month (mean 7.42 +/- 9.86) during the past 3 months. On the study completion 40.47% of the patients were seizure-free for at least a month. Two factors turned out to be significant for TGB efficacy: the number of drugs used since the onset of epilepsy (p = 0.005) and seizure type (p = 0.047). The best outcome was attained in patients with simple partial seizures. Co-medication with phenytoin was better than TGB + carbamazepine or TGB + valproic acid. The factor determining the presence of side effects was the rate of TGB dose increment during the first six weeks of treatment. Toxicity of TGB was not related to its target dose. Tiagabine is a safe and efficient anti-epileptic drug for children and adults with focal epilepsy. Efficacy of tiagabine treatment depends on the number of drugs administered since the epilepsy onset and on the type of seizures. A slow dose increment is crucial for safety of TGB treatment.

Adolescent↗

PubMed2005

The effect of catheter-directed CT angiography on yttrium-90 radioembolization treatment of hepatocellular carcinoma.

PURPOSE: Yttrium 90 radioembolization is a transcatheter therapy for unresectable hepatocellular carcinoma (HCC) that delivers internal radiation to tumors. In contrast to the usual method of lobar regional delivery, catheter-directed computed tomographic (CT) angiography was investigated as a potentially useful technique to evaluate the administration of segmental 90Y tumor radiation doses superselectively without significantly altering liver function or Child-Pugh classification. MATERIALS AND METHODS: Fourteen patients underwent 90Y therapy for unresectable HCC. After standard angiographic placement of a 3-F microcatheter in a segmental hepatic artery supplying the tumor, each patient underwent CT angiography with use of segmental hepatic artery injection of iodinated contrast agent to confirm segmental perfusion and delineate segmental liver volume. 90Y was later injected into the same segmental artery. Target dose was calculated according to infused 90Y activity and targeted hepatic volume with standard lobar volume (before CT angiography) versus segmental liver volume (after CT angiography). The Wilcoxon signed-rank test (alpha = 0.05) was used to compare the estimated 90Y dose before CT angiography with the actual 90Y dose after CT angiography, as well as changes in serum bilirubin level and Child-Pugh classification as a result of treatment. RESULTS: The mean estimated tumor dose before CT angiography (SD) was 100 Gy +/- 43 (range, 35-169 Gy). The mean actual tumor dose after CT angiography was 348 Gy +/- 204 (range, 105-857 Gy), which was significantly greater (P < .001). The mean bilirubin level before treatment was 1.0 mg/dL +/- 0.97 (range, 0.2-4.0 mg/dL), whereas the mean bilirubin level after treatment was 1.3 mg/dL +/- 0.85 (range, 0.5-3.8 mg/dL). This difference, although statistically significant (P = .03), was not clinically important. Thirteen of 14 patients had no change in Child-Pugh class. CONCLUSION: CT angiography can be used to delineate the blood supply and volume to a targeted hepatic segment, allowing superselective 90Y radioembolization. This approach significantly increases effective 90Y tumor radiation dose without clinically altering liver function or Child-Pugh class.

Adult↗

PubMed2002

Tools for the analysis of dose optimization: II. Sensitivity analysis.

Dose optimization requires that the treatment goals be specified in a meaningful manner, but also that alterations to the specification lead to predictable changes in the resulting dose distribution. Within the framework of constrained optimization, it is possible to devise a tool that quantifies the impact on the objective of target volume coverage of any change to a dosimetric constraint of normal tissue or target dose homogeneity. This sensitivity analysis relies on properties of the Lagrange function that is associated with the constrained optimization problem, but does not depend on the method used to solve this problem. It is useful particularly in cases with multiple target volumes and critical normal structures, where constraints and objectives can interact in a non-intuitive manner.

Algorithms↗

PubMed2004

A randomized long-term trial of tacrolimus and sirolimus versus tacrolimus and mycophenolate mofetil versus cyclosporine (NEORAL) and sirolimus in renal transplantation. I. Drug interactions and rejection at one year.

BACKGROUND: To reduce long-term nephrotoxic calcineurin inhibitor dosage, adjunctive sirolimus or mycophenolate mofetil (MMF) was used in a 150-patient, randomized, three-armed trial in cadaveric or human leukocyte antigen non-identical living-donor first renal transplant recipients (n=50/group). METHODS: Group A received tacrolimus and sirolimus. Target tacrolimus trough levels postoperatively were 10, 8, and 6 ng/mL at 1 month, 6 months, and 1 year, respectively. Group B received tacrolimus and MMF. Target tacrolimus trough levels were 10 and 8 ng/mL at 1 month and 1 year, with a targeted dose of MMF of 1 g twice daily. Group C received cyclosporine A (CsA) (Neoral, Novartis, Basel, Switzerland) and sirolimus with target CsA trough levels of 225 and 175 ng/mL at 1 month and 1 year. Maintenance sirolimus target trough levels were 8 ng/mL in groups A and C. Each group received daclizumab induction and methylprednisolone maintenance. This first of two companion 1-year reports details demographics, drug-dosing interactions, and rejection. RESULTS: There were no notable differences in group demographics, but a somewhat less favorable course occurred in group C, despite higher bioavailability of sirolimus in group C versus group A (P<0.001). Acute rejection rates were lower in groups A (4%) and B (4%) combined versus group C (14%) (P=0.03). Histopathologic findings were supported by comparing perioperative with 1-year postoperative protocol biopsies. CONCLUSIONS: This 1-year interim analysis indicates that a decreasing dosage of tacrolimus with either adjunctive sirolimus or MMF may optimize future graft survival versus a less favorable outcome using a similar algorithm with CsA and sirolimus.

Adult↗

PubMed1996

Mixed-model analysis of incomplete longitudinal data from a high-dose trial of tacrine (Cognex) in Alzheimer's patients.

Mixed-model techniques are applied to incomplete longitudinal data from a double-blind, placebo-controlled, parallel-group, high-dose study of tacrine in patients with Alzheimer's disease. The study consisted of a 30-week double-blind treatment period. Patients were randomized to one of four treatment groups. Dosing was initiated at 40 mg/day and increased in increments of 40 mg/day every 6 weeks until the target dose was achieved. If the study medication was not well tolerated or there were significant elevations in alanine aminotransferase, patients were withdrawn from the study. The use of SAS procedure PROC MIXED for the analysis of incomplete longitudinal data is discussed. This approach is used to evaluate disease progression over time and the effect of incremental dose increases of tacrine on changes on the Alzheimer's Disease Assessment Scale-Cognitive subscale.

Aged↗

PubMed2002

Disposition of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) in bile duct-cannulated rats: stereoselective metabolism and tissue distribution.

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) is a chiral compound, and the primary metabolite of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a major carcinogen in tobacco smoke. The goal of the present work was to study the pharmacokinetics and stereoselective metabolism and tissue retention of NNK and NNAL in the rat. Groups of rats were dosed with [5-(3)H]NNK (n = 3) or racemic [5-(3)H]NNAL (n = 3) at a target dose of 8.45 micromol/kg and were killed at selected time points for tissue collection. Separate groups of rats (n =5 per group) received the same dose of either NNK or NNAL and serial sampling of blood, bile and urine was carried out over 24 h. All samples were analyzed by C(18) reversed-phase HPLC with gradient elution and radioflow detection. A gas chromatograph-thermal energy analyzer (GC-TEA) was used to separate the (R)-/(S)-NNAL enantiomers. Racemic NNAL and NNK had large volumes of distribution (321 +/- 137 ml for NNK and 2772 +/- 1423 ml for NNAL) and similar total body clearances (12.8 +/- 2.0 ml/min for NNK and 8.6 +/- 2.6 ml/min for NNAL). The results indicated that the enantiomers of NNAL are stereoselectively metabolized and excreted. The glucuronide of (R)-NNAL, ((R)-NNAL-Gluc) was identified as the major metabolite in the bile after administration of either NNK or NNAL. (R)-NNAL was the major NNAL enantiomer in the bile or urine samples. At 24 h after racemic NNAL administration, NNAL comprised an average of 75.4% of total radioactivity in the lung with an (S)-/(R)-ratio of >20. The stereoselective localization of (S)-NNAL to lung tissue may contribute to the lung selectivity of NNK carcinogenesis. The present studies suggest a need to look beyond metabolic activation as the sole mechanism for lung carcinogenesis.

Animals↗

PubMed1999

Carbamazepine in comparative trials: pharmacokinetic characteristics too often forgotten.

OBJECTIVES: To compare the use of carbamazepine (CBZ) in comparative monotherapy trials with its use in practice. BACKGROUND: CBZ is often the drug of first choice for partial onset seizures and is frequently used as the reference drug in comparative trials with newly developed antiepileptic compounds. There are several issues related to CBZ that may have an impact on the final outcome of these trials. CBZ has nonlinear time-dependent kinetics due to autoinduction, and this may cause adverse reactions on starting treatment; somnolence and rash usually occur in the first weeks and may be related to the dose and titration schedule. Total daily dose or the serum levels of the drug do not correlate with therapeutic efficacy. METHODS: Review of the current literature on the pharmacokinetics properties of CBZ and of comparative trials of new antiepileptic drugs that used CBZ as the reference drug. CONCLUSIONS: The use of CBZ differed in comparative clinical trials and in clinical practice, with slower and lower titration rates used in the latter. This may be disadvantageous for CBZ because its pharmacokinetics peculiarities are ignored. If CBZ is to be used in these trials, titration rates and dosages should resemble those used in clinical practice because this is likely to improve efficacy and tolerability. Otherwise, the results of these trials may support regulatory applications but have little relevance to clinical practice. We suggest an initial CBZ dose of 100 mg/d and a slow titration schedule with dose incremental steps of 100 mg/d every week up to 600 mg/d. Blood levels should determine the initial target dose, but after this has been achieved titration should be based on seizure control and tolerability rather than by blood levels.

Carbamazepine↗

PubMed1985

[Biological monitoring of exposure to industrial toxic substances. Present-day situation and prospects for development].

Biological monitoring of exposure to an industrial chemical may be defined as the evaluation of the internal dose (internal exposure) by a biological method with the view of assessing the associated health risk. Depending on the biological parameter selected and on the time of sampling, internal dose may mean the amount of chemical recently absorbed, the amount stored in one or several compartments of the organism, or, under ideal conditions, the amount bound to the sites of action. The estimation of the internal dose has usually relied on two categories of tests: those based on the determination of the chemical and/or its metabolites in various biological media (eg, alveolar air, blood, urine) and those based on the quantification of a nonadverse biological effect, the intensity of which is related to the internal dose. Biological tests providing information on the amount of active chemical bound to the critical sites of action (target dose) and noninvasive analytical methods which measure the amount of cumulative toxins stored in certain body compartments (eg, bone, liver, kidney) are currently being developed. The main criteria to be considered in the selection of the most appropriate biological monitoring test of exposure are the specificity of the parameter and its sensitivity with respect to the exposure level, the analytical and biological applicability, the convenience for the workers, the possible risks associated with its application, and, of course, the accuracy of the exposure and/or health risk evaluation. Normally, the biological approach of exposure monitoring is reserved for chemicals which enter the organism and may exert systemic toxic effects. When a biological monitoring test of exposure is applicable, it offers several advantages over ambient air monitoring. A biological parameter reflecting the internal dose is necessarily more closely related to the systemic adverse effect(s) than any environmental measurement. Biological monitoring of exposure integrates the exposure by all routes (pulmonary, oral, and cutaneous) and sources. It may also take into account several factors which determine the uptake and the absorption of the chemical (individual variability, work load, hygiene habits, etc). However, contrary to ambient monitoring, biological monitoring is applicable only when sufficient information has been gathered on the metabolism of the chemical, its toxicity or that of its metabolites, and when some of the relationships between external exposure, internal dose and adverse effects have been assessed.(ABSTRACT TRUNCATED AT 400 WORDS)

Humans↗

PubMed2005

Aripiprazole: an overview of a novel antipsychotic.

Aripiprazole exhibits high affinity for dopamine D2 and D3, serotonin 5-HT1A and 5-HT2A receptors, moderate affinity for dopamine D4, serotonin 5-HT2C and 5-HT7, alpha1-adrenergic and histamine H1 receptors. The mean elimination half-lives are about 75 hours and 94 hours for aripiprazole and dehydroaripiprazole, respectively. Steady-state concentrations are attained within 14 days of dosing for both active moieties. At least 1 to 2 weeks, and sometimes up to 4 weeks, may pass before aripiprazole reaches its full effect. The efficacy of aripiprazole was investigated in the treatment of schizophrenia, in the treatment of acute manic episode associated with Bipolar I Disorder, and in the treatment of psychosis associated with Alzheimer's dementia. Aripiprazole has demonstrated superiority to placebo in clinical studies of the treatment of both schizophrenia and acute bipolar mania. Aripiprazole has been evaluated for safety in 5592 patients who participated in multiple dose, premarketing trials in schizophrenia, bipolar mania, and dementia of the Alzheimer's type. The recommended starting and target dose for aripiprazole is 10 or 15 mg/day administered on a once-a-day schedule without regard to meals. Aripiprazole has been systematically evaluated and shown to be effective in a dose range of 10 to 30 mg/day. Dosage increases should not be made before 2 weeks of continuous therapy, the time needed to achieve steady state. At least 1 to 2 weeks, and sometimes up to 4 weeks, may pass before aripiprazole reaches its full effect. In this presentation was given an overview of novel antipsychotic aripiprazole.

Alzheimer Disease↗

PubMed1998

[Allogenic blood stem cell transplants: characteristics of transplantation material and clinical transplantation course].

We have analysed the clinical course of the 14 consecutive allogeneic peripheral blood stem cell transplantations (PBSCT) and cellular composition of the grafts. Donors were HLA-identical siblings except for the one donor who was only HLA-phenotypically identical brother. Nine of them were sex-mismatched to their recipient. Donors received filgrastim (G-CSF) at a dose of 10 microkilograms/kg for 5 days (4-6). Leukaphereses were started at 5 day to obtain the target dose 4 x 10(6) CD34+ cells/kg recipient weight. Median 24 l of blood (24-36) was processed collecting: 10.3 x 10(8)/kg (6.69-18.8) WBC, 9.9 x 10(8)/kg (5.87-16.02) MNC, 9.72 x 10(6)/kg (0.74-18.98) CD34+ cells, 242.5 x 10(6)/kg (77.9-422) T lymphocytes (CD4+ to CD8+ ratio was 1.5), 76 x 10(6)/kg (24-113) B lymphocytes, 33 x 10(6)/kg (14-88) NK cells and 168.8 x 104/kg (23.1-271.4) CFU-GM with 131.7 x 10(4)/kg (8.4-297.6) BFU-E. Engraftment times to a neutrophil count (ANC) > 0.5 x 10(9)/l was achieved at a median of 15 days (range 10-23) in all patients whereas the platelet count > 20 x 10(9)/l at a median of 14 days (9-19) in all but one patient who received the smallest dose of CD34+ cells. Acute graft versus host disease (GvHD) developed in 8 patients who survived more than 30 days. Most of them (75%) were patients with chronic myeloid leukaemia (CML). In 4 of them GvHD was steroid resistant. Chronic GvHD developed in 3 of 6 evaluable patients. We confirm that allogeneic PBSCT result in rapid and longterm trilineage engraftment. However, the observation of the increasing incidence and severity of acute GvHD in patients with CML will require verification in the larger setting of patients after completion of ongoing clinical trials.

Adult↗

PubMed1989

Toxicity studies of amphetamine sulfate, ampicillin trihydrate, codeine, 8-methoxypsoralen, alpha-methyldopa, penicillin VK and propantheline bromide in rats and mice.

Thirteen-week toxicity studies in F344/N rats and B6C3F1 mice were conducted to determine general toxicity and target organ toxicity with amphetamine sulfate, ampicillin trihydrate, codeine, 8-methoxypsoralen, alpha-methyldopa sesquihydrate, penicillin VK, and propantheline bromide. This paper discusses the toxicity observed; use of the toxicity data to set dose levels for subsequent 2-year studies; and comparison of dose levels administered to rodents with doses used in the treatment of human disease. Drugs were administered orally in the feed or by gavage. The lowest doses in the 13-week studies were comparable to therapeutic doses in man on a mg/m2 (body surface area) basis or 5-10 times doses used in man on a mg/kg body weight basis. Little toxicity was seen at the low dose level with ampicillin, penicillin VK, 8-methoxypsoralen or propantheline bromide. At higher doses, target organ toxicity seen included the urinary bladder in male rats after propantheline bromide; the glandular stomach in rats and mice after penicillin VK; the liver and adrenals in rats after 8-methoxypsoralen; and the kidney in mice and rats after alpha-methyldopa. After amphetamine, codeine, or ampicillin administration, no target organ toxicity was seen in rats or mice, even at doses which caused body weight gain depression. The high doses chosen for subsequent 2-year studies were within 10 times human dose levels when compared on a mg/m2 body surface area.

Ampicillin↗

PubMed1996

Unexpected genetic toxicity to rodents of the N',N'-dimethyl analogues of MNU and ENU.

Lijinsky and his colleagues have reported that the N',N'-dimethyl analogues of ENU and MNU [N',N'-dimethyl-N-ethyl-N-nitrosourea (DMENU) and trimethylnitrosourea (TMNU), respectively] are carcinogenic to rats despite their extreme hydrolytic stability which would reduce or preclude generation of alkylating species analogous to those formed upon hydrolysis of ENU and MNU. Lijinsky and his colleagues were unable to rationalize those activities of DMENU and TMNU despite extensive experimentation. We therefore decided to study this problem further. Whichever mode is accepted for the generation of electrophilic/mutagenic/carcinogenic reactive species from ENU and MNU, blocking of the free-NH2 group with methyl groups (-NMe2) should ablate or abolish activity. Consistent with this DMENU and TMNU gave negative results in the NBP alkylation test while the parent compounds gave an instantaneous deep blue coloration. Studies of the rate of hydrolysis of these four compounds revealed ENU and MNU to have half-lives of 8 min, while the alkylated analogues (DMENU and TMNU) had half-lives of 25 and 41 days, respectively. Hydrolysis of ENU and MNU, to yield the alkylating species, proceeds either via proton abstraction from the -NH2 group or by attack by water on the carbon of the carbonyl group. Methylation will inhibit both of these pathways, the first absolutely (no -NH2 protons) and the second partially, via steric inhibition. The slow hydrolysis observed for DMENU and TMNU suggests that the latter route of hydrolysis is applicable. Studies with strain TA1535 of Salmonella typhimurium (without S9 mix) confirmed the potent mutagenic activity for ENU and MNU (approximately 300-fold increase in revertants at 2,000 micrograms/plate and approximately 180-fold increase in revertants at 150 micrograms/plate respectively). In contrast, the methylated analogues showed only weak mutagenic activity (approximately 3-fold) at approximately 100-fold higher dose-levels. Addition of S9 mix did not affect the mutagenicity of DMENU or TMNU. To this point, hypothesis and data coincide. ENU and MNU are potent micronucleus-inducing agents to the mouse bone marrow, and given the above data, it was expected that DMENU and TMNU would show weak or no activity in that assay. In fact, the methylated analogues were as effective as ENU and MNU as clastogens to the mouse bone marrow. Four possible reasons for this conflict of theory and data are explored. The speculative explanation we favour for these effects is that the net alkylation of bone marrow DNA is the same for all four chemicals. With ENU and MNU, most of the alkylating activity is dissipated by rapid hydrolysis. Thus, only a small fraction of the administered dose survives to alkylate the bone marrow. Due to the enhanced stability of the methyl analogues most of the delivered dose will reach the bone marrow. However, because of their lower intrinsic reactivity, only a small fraction of the target dose will alkylate the bone marrow DNA during the time window of the experiment. If these opposing influences happen to balance out, the essentially identical bone marrow genetic toxicity for the four chemicals could be explained.

Alkylating Agents↗