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Results for “Targeted dosing”

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At least 451 records · Page 25Linked to original sources

PubMed1999

Conformal radiation therapy treatment planning reduces the dose to the optic structures for patients with tumors of the paranasal sinuses.

PURPOSE: Compare dose distributions of traditional versus conformal beam orientations in paranasal sinus malignancies. MATERIALS AND METHODS: Maximum normal tissue doses, dose volume histograms (DVH), normal tissue complication probabilities (NTCP), and the percentage of each normal tissue receiving >80% of the average target dose (V80) were calculated. RESULTS/CONCLUSIONS: Conformal planning reduced the V80 to the optic nerves and chiasm as well as the normal tissue maximum doses to the ipsilateral and contralateral optic nerves and chiasm, and mean NTCPs.

Ethmoid Sinus↗

PubMed1999

Clinical experiences with topiramate in children with intractable epilepsy.

At a tertial referral epilepsy centre 39 children were consecutively enrolled in an open add-on study with topiramate (TPM). All children had intractable epilepsy; the mean seizure frequency was 36 per month, and 31 children were treated with polypharmacy. All but five children were mentally retarded. The initial dose of TPM was 0.5-1 mg/kg daily, slowly titrated with 1-3 mg/kg daily every second week with an estimated target dose of 10 mg/kg daily. At latest follow-up 19 children continued on TPM, three (8%) were seizure-free, eight (21%) had a seizure reduction of more than 50% and eight (21%) improved their general condition. Mean follow-up was 13 months (range 9-36 months). Seizure reduction was seen in focal as well as generalized epilepsies. Adverse effects were reported in 21 cases (54%), weight loss and sedation being most frequent. The mean steady state dose in the children continuing on TPM was at latest follow-up: 14 mg/kg daily (< 5 years), 10 mg/kg daily (5-7 years), 5.8 mg/kg daily (8-17 years). The corresponding plasma level varied from 3 to 45 mumol/litre, and a significant correlation between the daily dose in mg/kg and the plasma level was found. Two patients with progressive myoclonus epilepsy are described separately; one had a dramatic general improvement. It is concluded that TPM seems to be a promising new broad-spectrum anti-epileptic drug, which is efficacious even in epilepsy syndromes, intractable to other new anti-epileptic drugs such as vigabatrin and lamotrigine.

Adolescent↗

PubMed2003

Growth hormone resistance in chronic heart failure and its therapeutic implications.

BACKGROUND: In recent years the administration of recombinant human growth hormone (GH) has received great attention. This review compares the potential of this therapeutic intervention in heart failure with that in other diseases where wasting is commonly seen. The pathophysiologic importance of GH and insulin-like growth factor (IGF)-I in these conditions will be discussed. METHODS AND RESULTS: Abnormalities of the GH-IGF-I axis play an important role in the development of cachexia in chronic illnesses. GH resistance is a major determinant of the wasting process, acting through several different mechanisms: increased catabolism, impaired anabolism, and enhanced apoptosis in peripheral tissues. GH therapy has been evaluated in chronic heart failure (CHF); acquired GH resistance may explain the general lack of therapeutic success in the majority of studies. The assessment of plasma levels of GH, IGF-I, and, in particular, GH binding protein may help to guide dosing of GH for CHF patients. CONCLUSIONS: GH resistance might be overcome by use of intermittent or higher doses of GH, or alternatively by combining GH with IGF-I. Randomized studies of GH therapy in catabolic states, with targeted dosing and longer duration of treatment are required to fully assess the safety and efficacy of this treatment approach.

Heart Failure↗

PubMed1998

Phase-IV multicentre clinical study of risperidone in the treatment of outpatients with schizophrenia. The RIS-CAN-3 Study Group.

OBJECTIVE: Since most clinical trials of atypical antipsychotics have been conducted in hospitalized patients, a Phase-IV, multicentre, 8-week, open-label, flexible-dose study was performed to assess the efficacy and safety of risperidone in outpatients with schizophrenia. METHOD: Three hundred and thirty patients with a Diagnostic and Statistical Manual of Mental Disorders (DSM-III-R) diagnosis of schizophrenia were enrolled at 61 Canadian sites. Upon trial entry, the patients had their neuroleptic and antiparkinsonian drugs discontinued, and treatment with risperidone was initiated at a dose of 2 mg daily, then increased by 2 mg daily on each of the 2 following days until the initial target dose of 6 mg daily was reached on day 3. No further titration was allowed until day 14, after which the dose could be increased or decreased. RESULTS: During the stabilization phase (days 14-56), the dose was unchanged in 44% of the patients, increased in 24%, decreased in 23%, and titrated both up and down in 9% of the patients. In the efficacy-evaluable population (n = 292), treatment with risperidone produced substantial (-26.4) and significant (P = 0.0001) improvement in the total Positive and Negative Syndrome Scale (PANSS) score. At the end of the study (week 8), 85% of patients were classified as clinically improved according to an a priori definition (that is, 20% or more decrease from baseline in total PANSS score). On their last study visit, 75% of patients reported their experience with risperidone as better than their previous neuroleptic therapy. Risperidone was generally well tolerated. The adverse events reported by more than 5% of the patients were insomnia, nausea, headache, somnolence, dizziness, fatigue, anxiety, vomiting, and ejaculation disorder. Seventy-four percent of the reported treatment-related adverse events were recorded during the first 2 weeks of the trial, possibly because of the discontinuation of prior neuroleptic and antiparkinsonian drugs followed by immediate upward titration of risperidone. However, only 8.5% of adverse events were reported to have occurred during week 3, and only 0.8% of adverse events were reported for week 8. Risperidone treatment produced significant improvements over baseline in the incidence and severity of extrapyramidal symptoms (EPS). A slight but statistically significant increase in body weight was observed. CONCLUSIONS: The results of this open-label, Phase-IV trial in a large population of outpatients with schizophrenia found that risperidone was superior to the neuroleptics that patients had previously taken in terms of efficacy and severity of EPS. Our results suggest the use of risperidone at lower doses in outpatients with schizophrenia.

Adolescent↗

PubMed2003

Lamotrigine versus valproate monotherapy-associated weight change in adolescents with epilepsy: results from a post hoc analysis of a randomized, double-blind clinical trial.

Recent trends toward obesity and associated health risks in children highlight the significance of weight gain as a side effect with certain antiepilepsy drugs. No previous study has prospectively compared, in adolescents, weight effects for two commonly used antiepilepsy drugs. We report results from a post hoc subanalysis of adolescent data from a randomized, double-blind study comparing weight effects of lamotrigine and valproate. Patients were > or = 12 years of age with new-onset partial or generalized seizures who were randomized 1:1 to lamotrigine or valproate. Patients were escalated to a dose range of 100 to 500 mg/day for lamotrigine and 10 to 60 mg/kg/day for valproate based on clinical response, with target doses maintained for 24 weeks. Results are reported for adolescents aged 12 to 20 years. Weight changes during maintenance were higher (P < .05) in valproate (n = 20) patients than in lamotrigine (n = 18) patients, and change in body mass index was higher (P < .05) in valproate patients at the end of the study. At week 32, mean body mass index in the valproate group was above the 85th percentile representing "at risk for overweight." Whereas weight remained stable in adolescents treated with lamotrigine, weight increased in those treated with valproate by week 10 of this study and continued to increase at the end of the study.

Administration, Oral↗

PubMed2005

A cluster randomized trial to assess the impact of opinion leader endorsed evidence summaries on improving quality of prescribing for patients with chronic cardiovascular disease: rationale and design [ISRCTN26365328].

BACKGROUND: Although much has been written about the influence of local opinion leaders on clinical practice, there have been few controlled studies of their effect, and almost none have attempted to change prescribing in the community for chronic conditions such as heart failure (HF) or ischemic heart disease (IHD). These two conditions are common and there is very good evidence about how to best prevent morbidity and mortality - and good evidence that quality of care is, in general, suboptimal. Practice audits have demonstrated that about one-half of eligible HF patients are prescribed ACE inhibitors (with fewer still reaching appropriate target doses) and less than one-third of patients with established IHD are prescribed statins (with many fewer reaching recommended cholesterol targets). It is apparent that interventions to improve quality of prescribing are urgently needed. We hypothesized that an intervention that consisted of patient-specific one-page evidence summaries, generated and then endorsed by local opinion leaders, would be able to change prescribing practices of community-based primary care physicians. METHODS (STUDY DESIGN): A pragmatic single-centre cluster randomized controlled trial comparing an opinion leader-based intervention to usual care for patients with HF or IHD. Randomization will be clustered at the level of the primary care physician; as the design effect is anticipated to be negligible, the unit of analysis will be the patient. Patients with HF or IHD (not receiving ACE inhibitors or statins, respectively) will be recruited from community pharmacies and allocated to intervention or usual care based on the randomization status of their primary care physician. The primary outcome is improvement in prescription of proven efficacious therapies for HF (ACE inhibitors) or IHD (statins) within 6 months of the intervention. CONCLUSION: If the methods used in this intervention are found to improve prescribing practices, similar interventions could be designed for other chronic conditions dealt with in the outpatient setting.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2001

Atomoxetine in the treatment of children and adolescents with attention-deficit/hyperactivity disorder: a randomized, placebo-controlled, dose-response study.

OBJECTIVE: Atomoxetine is an investigational, nonstimulant pharmacotherapy being studied as potential treatment for attention-deficit/hyperactivity disorder (ADHD). It is thought to act via blockade of the presynaptic norepinephrine transporter in the brain. We assessed the efficacy of 3 doses of atomoxetine compared with placebo in children and adolescents with ADHD. METHODS: A total of 297 children and adolescents who were 8 to 18 years of age and had ADHD as defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, were randomized to placebo or atomoxetine dosed on a weight-adjusted basis at 0.5 mg/kg/day, 1.2 mg/kg/day, or 1.8 mg/kg/day for an 8-week period. ADHD symptoms, affective symptoms, and social and family functioning were assessed using parent and investigator rating scales. RESULTS: Approximately 71% of children enrolled were male, approximately 67% met criteria for mixed subtype (both inattentive and hyperactive/impulsive symptoms), and the only common psychiatric comorbidity was oppositional defiant disorder (approximately 38% of the sample). At baseline, symptom severity was rated as moderate to severe for most children. At endpoint, atomoxetine 1.2 mg/kg/day and 1.8 mg/kg/day were consistently associated with superior outcomes in ADHD symptoms compared with placebo and were not different from each other. The dose of 0.5 mg/kg/day was associated with intermediate efficacy between placebo and the 2 higher doses, suggesting a graded dose-response. Social and family functioning also were improved in the atomoxetine groups compared with placebo with statistically significant improvements in measures of children's ability to meet psychosocial role expectations and parental impact. Discontinuations as a result of adverse events were <5% for all groups. CONCLUSION: Among children and adolescents aged 8 to 18, atomoxetine was superior to placebo in reducing ADHD symptoms and in improving social and family functioning symptoms. Atomoxetine was associated with a graded dose-response, and 1.2 mg/kg/day seems to be as effective as 1.8 mg/kg/day and is likely to be the appropriate initial target dose for most patients. Treatment with atomoxetine was safe and well tolerated.

Adolescent↗

PubMed2000

Long-term effects of clinical outcome with low and high dose in the Captopril in Heart Insufficient Patients Study (CHIPS).

BACKGROUND: Although angiotensin-converting enzyme inhibitors are recommended as first line therapy in patients with chronic heart failure, the target doses proven to be effective in major morbidity and mortality trials (e.g. captopril 50 mg b.i.d), are generally not used in daily practice in Belgium. AIM: The objective of this study (CHIPS, Captopril in Heart Insufficient Patients Study) was to compare the long-term effects of a low dose (25 mg b.i.d.) and a high dose (50 mg b.i.d.) of captopril in mild to moderate heart failure. After a titration period of at least 10 days, patients who tolerated 50 mg b.i.d., were randomly assigned to receive either the low dose or the high dose of captopril and followed up to 2 years. RESULTS: 298 patients were included and were followed up for a mean of 12 months. Progression in heart failure seems to be favourably influenced by therapy with high dose in comparison to low dose; a relative difference of 29% in the rates of heart failure worsening was observed between the two doses, 31.5% and 22.4% for low and high dose (p = 0.088), respectively. Treatment with high dose showed also a trend to benefit as compared to low dose in reducing the number of hospitalizations for all causes from 22.4 to 14.5% (p = 0.1) and for congestive heart failure from 14.7 to 7.2% (p = 0.06); moreover, the incidence of fatal and nonfatal cardiac events showed a trend in favour of the high dose of 22% (p = 0.142). The total number of adverse events was comparable for both doses, but dizziness and hypotension were a little more frequently reported in the high-dose group. Serum creatinine values showed no significant changes either in the low-dose or in the high-dose group. CONCLUSION: In the CHIPS-study, in comparison to a low dose, therapy with a high dose of captopril tends to improve the long-term clinical outcome of patients with mild to moderate heart failure without significantly more toxicity.

Adolescent↗

PubMed2006

Levetiracetam for cerebellar tremor in multiple sclerosis: an open-label pilot tolerability and efficacy study.

PURPOSE: Disabling tremor is frequent in multiple sclerosis (MS) and its treatment remains challenging. We conducted an open-label trial to evaluate the effect of levetiracetam (LEV) to treat cerebellar tremor in MS patients. PATIENTS AND METHODS: Fourteen MS patients, aged 27 to 57 years, with cerebellar tremor. Tremor duration ranged from 3 to 14 years. The tremor clinical rating scale, the spiral drawings scale, and ataxia clinical scale were used to assess the severity of tremor. Data about the tremor-induced disability were obtained by using the specific Activities of Daily Living Questionnaire (ADL). LEV was orally administered at a starting dose of 500 mg twice daily for one week followed by increments of 500 mg twice daily each week up to the target dose of 50 mg/Kg/day. Patients were evaluated at baseline and two weeks after the end of titration phase. The Wilcoxon matched-pairs test was used for statistical analysis. RESULTS: Eleven patients completed the trial. LEV administration was associated with subjective and objective improvement of the tremor, with significant lowering of all tremor measurements' sum of scores as well as of ADL mean score between the baseline and follow-up. No correlation was found between the degree of improvement of the tremor and the disease duration or progression. LEV was well tolerated by subjects who completed the study. CONCLUSIONS: LEV could be useful for the management of cerebellar tremor in MS and the good tolerability makes it easy to test. LEV long-term efficacy should be confirmed in extended studies.

Activities of Daily Living↗

PubMedDate not supplied

Oral (drinking water) developmental toxicity study of ammonium perchlorate in New Zealand White rabbits.

This developmental toxicity study was conducted to evaluate the embryo-fetal toxicity and teratogenic potential of ammonium perchlorate in New Zealand White [Hra:(NZW)SPF] rabbits. Pregnant rabbits were given continual access to ammonium perchlorate in drinking water at target doses of 0, 0.1, 1.0, 10.0, 30.0, and 100.0 mg/kg-day on gestation days 6 through 28. The actual consumed doses in the study were 0, 0.1, 0.9, 10.4, 30.3, and 102.3 mg/kg-day. The rabbits were sacrificed on gestation day 29, and fetuses were examined for developmental alterations. In addition, blood was collected from does for determination of serum thyroid stimulating hormone (TSH), triiodothyronine (T3), and thyroxine (T4) levels and the thyroid was subjected to histopathologic examination. No maternal deaths were attributed to perchlorate exposure. Ammonium perchlorate as high as 100.0 mg/kg-day did not affect caesarean sectioning or litter parameters studied, and all values were found to be within the historical ranges of the laboratory. The litter averages for corpora lutea, implantations, litter sizes, live and dead fetuses, percent dead or resorbed conceptuses, and fetal body weights were comparable and also did not differ significantly in the six dose groups. All placentae appeared normal and no dam had a litter consisting of only resorbed conceptuses. The maternal thyroid was the target organ for ammonium perchlorate in this study. Increased incidence of thyroid follicular hypertrophy was observed in does treated with > or =10 mg/kg-day perchlorate and significantly decreased T4 was observed in does treated with > or =30 mg/kg-day. Based on these data, the maternal no-observable-adverse-effect level (NOAEL) for ammonium perchlorate was 1.0 mg/kg-day. The developmental NOAEL for ammonium perchlorate was found to be 100.0 mg/kg-day for rabbits.

Animals↗

PubMed2006

Dose of intravenous immunoglobulins in chronic inflammatory demyelinating polyneuropathy.

The usual initiating dose of intravenous immunoglobulins (IVIg) in the treatment of chronic inflammatory demyelinating polyneuropathy (CIDP) is 2 g/kg/course. Although not evidence based, subsequent reductions are advised to the lowest possible level for maintenance. In practice, the achievable levels of such reductions and their impact on treatment frequency have not been studied. Factors determining maximal dosage reduction are unknown. We retrospectively reviewed data concerning IVIg therapy for 15 patients with CIDP, from their medical records between 1997 and 2005. Lowest effective dose and treatment frequency were determined. The following correlations were ascertained: dose to frequency, dose to weight, dose to disease duration, amplitude of dose reduction to disease duration, and dose to pre-therapeutic disease severity. Dose reductions were possible in all (mean: 63.3%, range: 42.4-88%). The lowest effective dose of IVIg per course and treatment frequency were both very variable (18-108 g and 2-17 weeks, respectively). Lowest dose per course did not correlate to weight, frequency of administration, disease duration, or pre-therapeutic degree of disability. Amplitude of dose reduction achieved was independent of disease duration. Treatment frequency could not be lowered in any patient. Our findings show that IVIg target doses should be titrated individually but suggest that infusion frequencies are fixed in each case in relapsing CIDP. Importantly, lower dose treatment is not associated with shorter intervals between courses, and lowest effective dose is independent of weight and disease duration. Initial level of disability does not appear to influence dose required. These results suggest considerably lower, standardized, initiating, and maintenance doses might be effective and highlight the need for prospective dose comparative trials.

Age of Onset↗

PubMed2005

Towards biologically conformal radiation therapy (BCRT): selective IMRT dose escalation under the guidance of spatial biology distribution.

It is well known that the spatial biology distribution (e.g., clonogen density, radiosensitivity, tumor proliferation rate, functional importance) in most tumors and sensitive structures is heterogeneous. Recent progress in biological imaging is making the mapping of this distribution increasingly possible. The purpose of this work is to establish a theoretical framework to quantitatively incorporate the spatial biology data into intensity modulated radiation therapy (IMRT) inverse planning. In order to implement this, we first derive a general formula for determining the desired dose to each tumor voxel for a known biology distribution of the tumor based on a linear-quadratic model. The desired target dose distribution is then used as the prescription for inverse planning. An objective function with the voxel-dependent prescription is constructed with incorporation of the nonuniform dose prescription. The functional unit density distribution in a sensitive structure is also considered phenomenologically when constructing the objective function. Two cases with different hypothetical biology distributions are used to illustrate the new inverse planning formalism. For comparison, treatments with a few uniform dose prescriptions and a simultaneous integrated boost are also planned. The biological indices, tumor control probability (TCP) and normal tissue complication probability (NTCP), are calculated for both types of plans and the superiority of the proposed technique over the conventional dose escalation scheme is demonstrated. Our calculations revealed that it is technically feasible to produce deliberately nonuniform dose distributions with consideration of biological information. Compared with the conventional dose escalation schemes, the new technique is capable of generating biologically conformal IMRT plans that significantly improve the TCP while reducing or keeping the NTCPs at their current levels. Biologically conformal radiation therapy (BCRT) incorporates patient-specific biological information and provides an outstanding opportunity for us to truly individualize radiation treatment. The proposed formalism lays a technical foundation for BCRT and allows us to maximally exploit the technical capacity of IMRT to more intelligently escalate the radiation dose.

Dose-Response Relationship, Radiation↗

PubMed1994

RTOG #89-06: a phase I study to evaluate intraoperative radiation therapy and the hypoxic cell sensitizer etanidazole in locally advanced malignancies.

PURPOSE: To identify the maximum tolerated dose of the oxygen mimetic radiation sensitizer Etanidazole in the setting of surgery and intraoperative radiation therapy. 12 grams/meter2 was the maximum chosen target dose based on tolerance from other trials. METHODS AND MATERIALS: 42 patients were entered in an escalating dose scheme, 5.5, 7.5, 9, 10.5, and 12.0 grams/meter2. Etanidazole was given via intravenous infusion over 15 minutes, followed within 20 to 30 minutes by intraoperative radiation therapy. Multiple tissue samples from tumor, tumor bed, and/or normal tissue were obtained with simultaneous plasma samples. Etanidazole concentrations in tissue and serum were determined in 33 of the 42 patients. RESULTS: The median time to maximum serum concentration was 25 minutes. Median time to maximum tissue concentration was 40 minutes. Tissue concentrations began falling approximately one hour after infusion. Acute drug toxicities were minimal. Toxicities reported during follow-up related to surgery and/or radiation, not to drug. The concentration of sensitizer in tumor/tumor bed tissues was ten-fold greater than in previous trials. A sensitizer enhancement ratio for the hypoxic cells of 2 to 2.5 is projected. CONCLUSION: On the basis of tissue biopsy information, intraoperative radiation therapy will be given 40 minutes after the start of the 15 minute infusion allowing time for maximum intracellular uptake into tumor cells. In view of these findings, a Phase III trial testing etanidazole with intraoperative radiation therapy will be conducted. The tolerable single dose level of 12 grams/meter2 has potential with other high-dose radiation settings such as brachytherapy or stereotactic radiosurgery.

Adolescent↗

PubMed2003

Changes in treatment volume of hormonally treated and untreated cancerous prostate and its impact on rectal dose.

Late chronic side effects of the rectum constitute one of the principal limiting factors for curative radiation therapy in patients with prostate cancer. The purpose of the study was to determine the impact of immediate androgen deprivation (IAD) prior to conformal radiotherapy on rectal volume exposed to high doses, as compared with a deferred treatment strategy (DAD). Twenty-five patients (13 in the IAD group and 12 in the DAD group) with bulky tumours of the prostate, T3pN1-2M0 from the prospective EORTC trial 30846 were analysed. Three-dimensional conformal radiation treatment plans (3DCRT) using a 4-field box technique were generated based on the digitized computed tomographic or magnetic resonance findings acquired during the first 9 months after inclusion in the EORTC trial. Dose-volume histograms (DVHs) were calculated for the prostate and rectum. In the DAD group, there was no obvious alteration in the mean size of the prostate or other evaluated structures. In the IAD patients, a statistically significant reduction of approximately 40% of the gross tumour volume (GTV) was reached after a 6 months' course of hormonal treatment (p < 0.001). High-dose rectal volume was correlated with the volume changes of the GTV (p < 0.001). Mean rectal volume receiving 95% or more of the target dose was significantly reduced by 20%. Our study confirms the effect of downsizing of locally advanced prostate tumours following AD treatment and demonstrates the interdependence of the high-dose rectal volume with the volume changes of the GTV. However, the mean beneficial sparing of rectal volume was outweighed in some patients by considerable inter-patient variations.

Adenocarcinoma↗

PubMed2003

Bisoprolol dose-response relationship in patients with congestive heart failure: a subgroup analysis in the cardiac insufficiency bisoprolol study(CIBIS II).

AIMS: Whether all patients with congestive heart failure (CHF) need to reach the target dose of beta-blocker to obtain a benefit in terms of survival remains uncertain. METHODS AND RESULTS: We classified by tertile the 2647 patients enrolled in CIBIS II according to the last tolerated dose: low dose (LD: 1.25, 2.5 or 3.75mg/day, n=434), moderate dose (MD: 5 or 7.5mg/day, n=328) and high dose (HD: 10mg/day, n=565) of bisoprolol or placebo (LD=234, MD=278 and HD=808). In both groups, patients tolerating only low doses were significantly older with more severe New York Heart Association (NYHA) functional class and higher frequency of co-morbidities. Treatment withdrawal was associated with a significant increase of mortality in the bisoprolol group (relative hazard (RH)=2.13, 95% confidence interval (CI)=1.43-3.17, p=0.0002). After adjustment, all-cause mortality was significantly reduced in the bisoprolol group compared to placebo regardless of the dose level considered: LD (RH=0.66, 95% CI=0.48-0.92), MD (RH=0.33, 95% CI=0.21-0.51) or HD (RH=0.59, 95% CI=0.40-0.89). CONCLUSIONS: Bisoprolol reduces mortality in CHF patients at all tolerated dose levels and its withdrawal increases the risk of mortality. Efforts should be made to maintain bisoprolol therapy based on the individual patient's tolerability.

Adrenergic beta-Antagonists↗

PubMed1996

Dose-rate effects in targeted radiotherapy.

The physical dose delivered in radio-immunotherapy (RIT) may not, by itself, be a reliable indicator of the likely effectiveness of the treatment. Radiobiological considerations, in particular those relating to the dose-rate, are also very relevant. Dose-rate effects are important in conventional radiotherapy because of their ability to produce differential sparing effects between normal and malignant tissue. With targeted radiotherapy, in which dose-rates are likely to vary both spatially and temporally, the instantaneous dose-rate is additionally relevant since it determines whether or not any on-going clonogenic tumour re-population can be controlled. Therefore, for RIT in particular, there are two separate facets to the dose-rate effect, one concerned with the relative ability of different tissues to recover from radiation damage, the other concerned with the absolute ability to control concurrent tumour re-growth. In this article these two aspects are examined in terms of the linear-quadratic model and the implications assessed. Other radiobiological issues, such as re-oxygenation and cell cycle re-distribution are not discussed here.

Animals↗

PubMed1997

Collection of peripheral blood progenitor cells after the administration of cyclophosphamide, etoposide, and granulocyte-colony-stimulating factor: an analysis of 497 patients.

BACKGROUND: There is great interpatient variability in the number of peripheral blood stem cells collected, as measured by CD34+ cell content, after the administration of chemotherapy and a growth factor. The ability to predict patients who fail to yield adequate quantities of CD34+ cells would be of value. However, very few reports include large numbers of patients treated in an identical fashion. STUDY DESIGN AND METHODS: Between 1991 and 1995, 497 consecutive patients with a variety of malignant diseases received cyclophosphamide (4 g/m2), etoposide (600 mg/m2), and granulocyte-colony-stimulating factor (6 micrograms/kg/day) for mobilization and collection of a target dose > or = 2.5 x 10(8) CD34+ cells per kg. Multivariate analyses were performed to determine the factors associated with failure to achieve this target harvest. RESULTS: A median of 14.71 x 10(6) CD34+ cells per kg (range, 0.08-137.55) was harvested with a median of 2 (range, 1-11) apheresis procedures. Ninety-one percent of patients yielded > or = 2.5 x 10(5) CD34+ cells per kg. Patients with Stage II-III breast cancer, who had pretreatment platelet counts > or = 150 x 10(9) per L and patients who underwent < or = 1 prior chemotherapy regimen had improved CD34+ cell yields. However, most patients with adverse risk factors yielded > or = 2.5 x 10(6) CD34+ cells per kg. CONCLUSION: A regimen of cyclophosphamide, etoposide, and granulocyte-colony-stimulating factor led to the successful collection of adequate numbers of CD34+ cells in most patients without excessive toxicity. These observations confirm previous reports that intense prior therapy adversely affects the quantity of CD34+ cells harvested. Pretreatment and posttreatment variables did not predict with any certainty the small fraction of patients who fail to yield > or = 2.5 x 10(6) CD34+ cells per kg via multiple apheresis procedures.

Adolescent↗

PubMed1999

Circulatory effects and pharmacology of clevidipine, a novel ultra short acting and vascular selective calcium antagonist, in hypertensive humans.

The pharmacokinetics of clevidipine, a potent short-acting vascular-selective calcium antagonist, was investigated during steady state and the postinfusion period in patients with mild to moderate hypertension. Furthermore, the dose-effect and blood concentration-effect relations and the tolerability of the drug were studied. Twenty patients were randomized to clevidipine intravenously at target dose rates of 0.18, 0.91, 2.74, and 5.48 microg/kg/min, respectively, or placebo. Each patient received in random order three infusion rates of clevidipine or placebo during three separate study days. Dose-dependent reduction in blood pressure and a modest increase in heart rate were noted. The extremely high clearance value and the small volume of distribution resulted in short half-lives of clevidipine, 2.2 and 16.8 min, respectively. The blood concentration and dose rate producing half the maximal effect (i.e. EC50 and ED50) were approximately 25 nM and 1.5 microg/kg/min, respectively. There was a linear relation between blood concentration and dose rate in the range studied. Clevidipine was safe and generally well tolerated; one patient was excluded because of adverse events at 2.74 microg/kg/min. In conclusion, clevidipine is a high-clearance calcium antagonist that may become a valuable contribution to the drugs used in conditions in which precise and rapid control of blood pressure is needed.

Adolescent↗