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Results for “Targeted dosing”

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PubMed1988

Hydroxydesipramine in the elderly.

Elevation of the hydroxy metabolites of the tricyclic antidepressants in the elderly has been demonstrated for nortriptyline and suggested for desipramine by a study reporting elevated hydroxydesipramine (OH-DMI) plasma levels in four older patients. In the current study, patients treated with desipramine (DMI) were studied to determine whether OH-DMI was elevated in two larger samples of depressed elderly patients and to determine the magnitude of the increase, if present. In Sample I, which consisted of 68 patients of whom 23 were over 60 years of age, a fixed target dose of DMI was employed. Sample II, in which 20 of the 56 patients were over 60, received a dose adjusted to attain a fixed target DMI blood level. OH-DMI levels were higher in patients over 60 than in younger patients but the differences were not significant in either sample individually. In the two samples combined, average OH-DMI levels were 11 ng/ml higher in patients over 60 and the difference was significant (t = 2.30, p = 0.02). If variations in dose are accounted for, OH-DMI concentrations are positively correlated with age in both samples. OH-DMI/DMI ratios were not higher in the patients over 60 in these samples, but OH-DMI/DMI ratios may be higher in patients on lower doses with low DMI levels, as is common in the treatment of elderly patients. If comparable dosage is administered, nonlinear increases in DMI levels result in lower OH-DMI/DMI ratios similar to those in younger patients. Although our findings of elevated hydroxy levels in the elderly are consistent with prior reports, the clinical importance of an 11 ng/ml difference, particularly in relation to total drug levels averaging 220 ng/ml, is questioned.

Administration, Oral↗

PubMed1996

Carboplatin pharmacokinetics in young children with brain tumors.

PURPOSE: The pharmacokinetic parameters and maximal tolerated systemic exposure were determined for carboplatin in young children given in combination with cyclophosphamide and etoposide. PATIENTS AND METHODS: Carboplatin was administered as part of a multiagent chemotherapy regimen to 21 pediatric patients less than 5 years of age with newly diagnosed, malignant central nervous system tumors. Patients, received cyclophosphamide, 1.2 g/m2, on day 1 and carboplatin on day 2 followed by etoposide, 100 mg/m2, each day. Carboplatin doses were calculated to achieve a targeted area under the serum concentration versus time curve (TAUC) of 5, 6.5 or 8 mg/ml.min based on each patient's measured glomerular filtration rate (GFR). Carboplatin pharmacokinetic parameters were determined after course 1 and then after every third course of therapy. RESULTS: The median carboplatin clearance and GFR after course 1 were 118 and 98 ml/min per m2, respectively. Targeted doses based on measured GFR reliably achieved the TAUC for carboplatin. The median (range) carboplatin clearance for four children less than 1 year of age was 76 (66-84) ml/min per m2, significantly lower (P = 0.05) than the value of 131 (80-158) ml/min per m2 for children from 1 to 4 years of age. The mean carboplatin clearance declined by 23% in 12 patients studied from course 1 to course 4 of therapy. The decrease was greater than 20% (range 20-53%) in 7 of the 12 patients studied. CONCLUSION: Carboplatin clearance for children aged between 1 and 4 years at diagnosis is approximately 45% higher than previously reported for pediatric patients, but declines after four courses of therapy. For children less than 1 year of age, carboplatin clearance per square meter is approximately 40% lower than patients 1 to 4 years of age. There are corresponding differences in GFR that provide a plausible explanation for the age and therapy-related changes in carboplatin clearance. Toxicity was acceptable for patients treated at a TAUC of 6.5 mg/ml.min for carboplatin given with etoposide and cyclophosphamide. The average carboplatin dose required for this AUC was 767 mg/m2.

Adolescent↗

PubMed1995

The implications for risk assessment of measuring the relative contribution to exposure from occupation, environment and lifestyle: hemoglobin adducts from amino- and nitro-arenes.

Recent progress in biomonitoring allows measurement of internal exposure of individuals ranging from occupational and life style exposures to environmental levels. Ten specific hemoglobin adducts generated by polycyclic and monocyclic nitro-arenes were measured in coke oven workers and residents living on ground contaminated with explosive wastes, respectively. Consistently, adducts were found in most 'exposed' as well as control individuals, interindividual variation being great. Adduct levels in the majority of exposed individuals were within the range of reference values (95 percentile). Although hemoglobin adduct levels do not directly reflect genotoxic potential and potency of the parent compounds, they correlate with the biologically active dose. On the basis of such target doses, the contribution of specific exposures relative to 'background' and to related chemicals can be assessed. The impact of 'relative risk' on risk perception and risk management is to provide a rationale for the application of the ALARA principle (As Low As Reasonably Achievable).

Carcinogens, Environmental↗

PubMed1995

Neurohormonal modulation in heart failure: ACE inhibition and beyond.

Angiotensin converting enzyme (ACE) inhibition undoubtedly has become the cornerstone of heart failure treatment. Useful in each stage, it should possibly be considered first-line treatment in many patients with mild heart failure in whom fluid retention is not clearly present. Careful consideration of the optimal dose for the individual is important. Until further data are available concerning the efficacy and tolerability of high and low doses, the clinician should consider the target doses used in large controlled heart failure trials. Even under optimal dosing conditions, it is likely that ACE inhibition may not suffice in completely modulating the extensive neurohormonal stimulation extant in heart failure. In part this may result from a breakthrough of the ACE inhibitor effect as well as from activation of hormones and peptides that may not be affected by ACE inhibition. Also, a substantial proportion of patients may not tolerate sufficient ACE inhibition. Alternative or additional therapy aimed at modulating neurohormonal activation concerns interference with other parts of the renin angiotensin system, such as angiotensin II receptor and aldosterone receptor antagonism. Sympathetic activity and catecholamine levels may decrease with dopaminergic D2 agonists and, possibly, beta-blockade; in the latter, this may be confined to patients with pre-existing sympathetic over-activation. Increasing circulating levels of atrial natriuretic peptide via neutral endopeptidase inhibition may offer an alternative way to increase diuresis and natriuresis without neuroendocrine stimulation. Novel possibilities that have not yet been tested sufficiently in patients with heart failure include endothelin receptor antagonism, arginine vasopressin antagonism, and renin inhibition. Finally, digitalis glycosides may be considered neurohormonal modulators in addition to being positive inotropes. Heart failure is a complex condition that involves many organs and systems besides the heart. Polypharmacy tailored to the individual is mandatory. It is thus necessary to investigate approaches to the modulation of neurohormonal activation beyond ACE inhibition.

Angiotensin Receptor Antagonists↗

PubMed1994

Is ambient ethene a cancer risk factor?

Ethene is, on a molar basis, a major urban air pollutant. It has been shown beyond doubt that a fraction of inhaled ethene is metabolized in mammals (including humans) via ethylene oxide, an electrophilic reagent that has been shown to be mutagenic and carcinogenic. To the extent that the linearity hypothesis for dose-response relationships at low levels is accepted, exposure to ethene is therefore expected to lead to a risk increment. In order to judge whether ethene as a single compound should be considered a risk factor, it has to be evaluated whether this risk increment is negligibly small or of concern to individuals or societies. The magnitude of the cancer risk from ethene cannot be inferred from animal experiments. Because of saturation of the metabolism of ethene, sufficient statistical power cannot be attained in long-term animal tests with about 100 animals per dose. By application of the radiation-dose equivalent of the unit of target dose of ethylene oxide and using the best (although still uncertain) value for the conversion factor (about 5%), exposure to 10 ppb ethene--a level occurring in urban areas--is expected to lead to a lifetime risk of cancer death amounting to approximately 70 per 100,000. According to a recent estimate the average exposure in Sweden to ethene is some six times lower. These figures are uncertain by a factor of at least three. They indicate ethene to be a risk factor of concern.

Air Pollutants↗

PubMed1986

Analysis of dose intensity for chemotherapy in early (stage II) and advanced breast cancer.

In chemotherapy of advanced breast cancer, the dose intensities of regimens containing cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) and cyclophosphamide, doxorubicin, and 5-fluorouracil (CAF) correlate with remission rate. The correlation is even better if dose intensity is calculated from doses actually given instead of from targeted doses. Also, in adjuvant chemotherapy of stage II breast cancer, the dose intensities of CMF-containing regimens correlate with relapse-free survival. The adjuvant trials analyzed included studies containing only 1 or 2 of C, M, or F or with L-phenylalanine mustard (melphalan) instead of C. Three-year relapse-free survival was clearly related to dose intensity whether the analysis was of trials containing all 4 prognostic groups [women less than 50 yr with 1-3 and greater than 3 positive nodes; and those greater than or equal to 50 yr with 1-3 and greater than 3 positive nodes (P less than .00001)] or of trials in which each of these 4 groups were analyzed separately (P less than .005). In multivariate analysis, dose intensity correlated with relapse-free survival (P less than .00001), independent of the number of positive nodes or menopausal status. Randomized trials will be required before we can determine if prospective increases of dose intensity will improve outcome of chemotherapy in breast cancer.

Adult↗

PubMed1990

Radiation target sizes of the Na,K-ATPase and p-aminohippurate transport system in the basolateral membrane of renal proximal tubule.

Basolateral membrane vesicles made from rabbit kidney proximal tubules were frozen and irradiated with a high energy electron beam and the effects of irradiation on Na,K-ATPase activity, p-aminohippurate (PAH) transport, the membrane diffusion barrier and vesicle volume were measured. The vesicle volume and diffusion barrier were not significantly changed by radiation exposure. Na,K-ATPase activity was inactivated as a simple exponential function of radiation dose. Target size analysis of the data yielded a molecular size of 267 +/- 17 kDa, consistent with its existence as a (alpha beta)2 dimer. The carrier-mediated PAH uptake by basolateral membrane vesicles was also inactivated as a function of radiation dose. A target molecular size of 74 +/- 16 kDa was calculated for the PAH transport system. This study is the first measurement of the functional size of the organic acid transport system based directly on flux measurements.

Aminohippuric Acids↗

PubMed1996

Current controversies with ACE inhibitor treatment in heart failure.

Although the beneficial effects of angiotensin-converting enzyme (ACE) inhibitors on symptoms, morbidity and mortality have been proven beyond any doubt, some controversies remain. First, surveys have shown that a minority of patients in whom ACE inhibition is indicated, actually receive ACE inhibitors. Moreover, the majority of patients on ACE inhibitors use doses that are far lower than the target dose used in the large trials. These lower doses may be less effective. There is limited evidence to show that low-dose ACE inhibition is as effective as high-dose ACE inhibition. However, two ongoing trials--ATLAS and NETWORK--will determine the relative efficacy of high- and low-dose ACE inhibition. Second, the large ACE inhibitor trials have shown major variations in mortality, suggesting that differences between the efficacy of ACE inhibitors exist. However, the major differences in mortality are related mainly to the variations in inclusion criteria, suggesting a class effect of ACE inhibition. A study, assessing the relative efficacy of various ACE inhibitors seems unrealistic at this time. Third, mortality data on asymptomatic left ventricular dysfunction are conflicting, suggesting that initial treatment can wait until symptoms of heart failure appear. However, studies are consistent in showing reduction of events. Thus, early treatment in asymptomatic dysfunction may be warranted. Finally, it has been demonstrated that ACE inhibitors act favorably on volume and pressure overload, electrolytes and autonomic function. Nevertheless, the ACE inhibitor trials have failed to demonstrate that reduction of mortality is related to reduction of malignant ventricular arrhythmias/sudden death. This issue needs further study as specific antiarrhythmic strategies may be appropriate for arrhythmias.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1996

Methylphenidate dosing: twice daily versus three times daily.

OBJECTIVE: To evaluate the short-term efficacy and side effects associated with two methylphenidate hydrochloride (MPH) dosing patterns. METHODS: Twenty-five boys with attention deficit hyperactivity disorder (ADHD) participated in a 5-week, triple-blind, placebo-controlled, crossover evaluation of MPH administered twice (b.i.d.) versus thrice (t.i.d.) per day (mean dose = 8.8 +/- 5 mg, .30 +/- .1 mg/kg/dose). Four dosing conditions (placebo, titration [gradual increase to target dose], b.i.d., and t.i.d.) were used. Dependent measures obtained on a weekly basis included: parent and teacher ratings of child behavior, parent-child conflicts, parent report of stimulant side effects, child self-report of mood symptoms, a sleep log, laboratory measures of attention, and actigraphic recording of sleep activity. RESULTS: All dosing conditions resulted in significant effects on ADHD symptoms when compared with baseline. Relative to placebo, t.i.d. dosing was characterized by improvement on the greatest number of behavioral measures, and both b.i.d. and t.i.d. were generally more effective than titration. Direct comparisons of b.i.d. and t.i.d. dosing revealed that t.i.d. was associated with greater improvement on the Conners Parent Rating Scale Impulsivity/Hyperactivity factor, with a similar marginally significant effect for the ADD-H Teacher Rating Scale Hyperactivity factor. The analysis of clinically significant change favored a three-times-a-day dosing schedule over placebo on both parent and teacher ratings of impulsivity/hyperactivity and attention. Compared with placebo, appetite suppression was rated, on average, as more severe in the t.i.d. and titration conditions, but not in the b.i.d. condition. However, the number of subjects who exhibited any or severe appetite suppression did not differ significantly between the b.i.d. and t.i.d. schedules. Although there was no difference in sleep duration for children on b.i.d. and t.i.d. schedules, total sleep time appeared to decrease slightly on t.i.d. relative to placebo according to both parent ratings and actigraphic assessment. There were no significant differences between b.i.d. and t.i.d. on any other side effects or sleep variables. CONCLUSIONS: For many children with ADHD, t.i.d. dosing may be optimal. There are few differences in acute side effects between b.i.d. and t.i.d. MPH dosing. The dosing schedule should be selected according to the severity and time course of ADHD symptoms rather than in anticipation of dosing schedule-related side effects.

Attention Deficit Disorder with Hyperactivity↗

PubMed1990

The carcinogenic activity of commercial grade toluene diisocyanate in rats and mice in relation to the metabolism of the 2,4- and 2,6-TDI isomers.

Groups of 50 F344/N rats of each sex and 50 B6C3F1 mice of each sex were gavaged with corn oil or a mixture of toluene diisocyanate (TDI) in corn oil for 5 days per week for 105 or 106 weeks. Female rats and mice were given doses of 60 or 120 mg/kg body weight, while male rats received 30 or 60 mg/kg, and male mice received 120 or 240 mg/kg. The TDI reacted with the moisture in the corn oil vehicle resulting in doses that were 10% to 23% below the target dose concentrations. The chemical product used was commercial grade TDI, which was an 80%-20% mixture of the 2,4- and 2,6-isomers. Chemical disposition and metabolism studies were conducted with each of the radiolabelled TDI isomers in male rats. Absorption of both of the TDI isomers occurred, with the highest concentrations found in the stomach, cecum, large intestine, and bladder. Excretion occurred via the feces and urine. The major metabolic products from the metabolism of 2,4-TDI were shown to be identical with those from the metabolism of the carcinogen, 2,4-diaminotoluene, whereas the metabolism of the 2,6-TDI isomer yielded one major product, identified as 2,6-bis(acetylamino)toluene. Greater than 10% depression in body weight gain occurred in all dosed groups of rats throughout most of the study. The major non-neoplastic lesions that were observed in both sexes of the TDI-exposed rats were dose-related increases in acute broncho-pneumonia, characterized as chemical pneumonitis, with incidences as high as 50%. In mice mean body weight gain was depressed in dosed male and in high dose females. The principle non-neoplastic lesion in mice that was attributed to chemical treatment was cytomegaly of the kidney tubular epithelium in males. Survival in all groups of dosed rats was significantly lower than in controls. A dose-dependent pattern of mortality did not commence until 70 weeks of exposure, demonstrating that toluene diisocyanate elicited a cumulative toxic response. There was also significantly lower survival in high dose male, but not female mice, by comparison to controls. Despite the reduction of power and sensitivity in the rat studies caused by early mortality, statistically significant increases in tumor incidences were observed in many different target organs. TDI was carcinogenic in F344/N rats, causing subcutaneous fibromas and fibrosarcomas in males and females, pancreatic acinar cell adenomas in males, and pancreatic islet cell adenomas, neoplastic nodules of the liver, and mammary gland tumors in females.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1995

Carboplatin (CBDCA)-hexamethylmelamine (HMM)-oral etoposide (VP-16) first-line treatment of ovarian cancer patients with bulky disease: a phase II study.

Hexamethylmelamine (HMM) and oral etoposide (VP-16) have shown to be active against platinum-resistant epithelial ovarian cancer. On this basis a three-drug regimen including carboplatin (CBDCA) plus HMM and oral VP-16 was tested in previously untreated ovarian cancer patients with tumor size > 2 cm. Since October 1991, 29 chemotherapy-naive ovarian cancer patients with tumor larger than 2 cm (20 stage III and 9 stage IV) have been treated for a total of 153 courses. CBDCA was administered i.v. on Day 1. The dose was individualized using the Calvert formula (the target dose was AUC = 5). VP-16 was administered orally at the dose of 50 mg/m2 Days 1-14, HMM at the dose of 150 mg/m2 po Days 14-28. Therapy was repeated every 28 days for a total of 6 courses. In order to avoid severe leukopenia and delays in the treatment administration, G-CSF 5 micrograms/kg/day sc Days 8-14 (or until postnadir recovery of neutrophil count > 10,000/mm3) and Days 22-28 was administered. All patients were evaluable for toxicity. No treatment-related deaths occurred. Myelotoxicity was the main side effect. It was grade 3-4 in a total of 13/29(45%) patients. One patient discontinued treatment after the first course due to HMM-related gastrointestinal toxicity. The actual delivered dose intensity was 89% of the planned dose. At the time of this analysis (April 1994) 26 patients are evaluable for response. Fifteen patients achieved a clinical complete remission and 9 a partial response for a 92% overall response rate. Fourteen patients accepted second-look laparotomy. We observed 11 pathological complete regressions (42%; 95% CI, 21-63). At a median follow-up of 16 months 3 deaths have occurred. Only 2 patients with NED at second-look laparotomy have relapsed. We stopped the accrual since the 95% confidence interval of the pCR-rate observed exceeded 20%. This new first-line regimen seems to be highly effective in patients with poor-prognosis advanced ovarian cancer, although the data are not yet sufficiently mature for a final analysis of time to progression and overall survival.

Administration, Oral↗

PubMed2026

Efficacy and Safety of the Kidney Function-Based Finerenone Dosing Strategy Used in FINEARTS-HF.

BACKGROUND: Given that mineralocorticoid receptor antagonists have the potential to impair renal function and induce hyperkalemia, close monitoring of estimated glomerular filtration rate (eGFR) and serum potassium levels is essential to ensure the safe administration of this therapy. OBJECTIVES: In this prespecified analysis, the authors evaluated the efficacy and safety of the kidney function-based finerenone dosing strategy used in the FINEARTS-HF trial. METHODS: In FINEARTS-HF, patients with an eGFR of 25 to 60 mL/min/1.73 m2 at baseline were stratified at randomization to the low-dose group and started on 10 mg of finerenone once daily (titrated to a maximum 20 mg/d) or matching placebo, whereas those with an eGFR >60 mL/min/1.73 m2 at baseline were stratified to the high-dose group and started on 20 mg of finerenone once daily (titrated to a maximum 40 mg/d) or matching placebo. The primary outcome was the composite of total (first and recurrent) heart failure events and cardiovascular death. RESULTS: Among 5,986 (99.8%) analyzable patients, 3,159 were assigned to the higher eGFR/high-dose stratum and 2,827 to the lower eGFR/low-dose stratum group. The mean ± SD achieved dose was 32.3 ± 9.1 mg (finerenone) and 34.4 ± 7.8 mg (placebo) in the higher eGFR/high-dose stratum, and 15.6 ± 4.3 mg (finerenone) and 16.7 ± 4.0 mg (placebo) in the lower eGFR/low-dose stratum. The effect of finerenone on the primary outcome was consistent across the 2 dosing strata (higher eGFR/high-dose stratum: rate ratio: 0.77 [95% CI: 0.63-0.94] vs lower eGFR/low-dose stratum: rate ratio: 0.87 [95% CI: 0.74-1.03]; P for interaction = 0.34). Consistent benefits were observed for the components of the primary outcome and all-cause death. Safety was also consistent between dosing strata, except for hypokalemia, where the reduction in the odds of hypokalemia with finerenone compared to placebo was greater in the higher eGFR/high-dose stratum (P-interaction < 0.01). CONCLUSIONS: In FINEARTS-HF, an eGFR-based dosing strategy allowed effective and safe use of finerenone in patients with heart failure with mildly reduced ejection fraction/ heart failure with preserved ejection fraction with a baseline eGFR as low as 25 mL/min/1.73 m2. We recommend that clinicians implement the trial-validated dosing strategy and incorporate appropriate uptitration to the target dose to ensure optimal therapeutic outcomes. (FINEARTS-HF [Study to Evaluate the Efficacy (Effect on Disease) and Safety of Finerenone in Participants With Heart Failure and Left Ventricular Ejection Fraction (Proportion of Blood Expelled Per Heart Stroke) Greater or Equal to 40%; NCT04435626).

Aged↗

PubMed1996

Combined alpha-beta blockade (doxazosin plus metoprolol) compared with beta blockade alone in chronic congestive heart failure.

There has been growing evidence for the benefits of beta blockers, but alpha blockers have not shown sustained benefits in chronic congestive heart failure (CHF). Thirty patients with moderate to severe CHF (New York Heart Association class II to IV) were sequentially assigned to receive metoprolol 6.25 mg with the alpha-1 antagonist doxazosin 4 mg/day or metoprolol alone. The dose of metoprolol was gradually increased to a target dose of 50 mg orally twice daily. Hemodynamic measurements were obtained before drug therapy, 2 hours after the first dose of combined alpha-beta therapy or metoprolol alone, and after 3 months of continuous treatment. Nuclear ejection fraction, plasma norepinephrine, and submaximal and maximal exercise capacity were also measured before and after chronic therapy. With initial combined drug administration, mean arterial pressure, left ventricular filling pressure, and systemic vascular resistance decreased significantly compared with results after metoprolol alone. However, after 3 months of continuous therapy, both treatment groups showed similar and significant reductions in systemic vascular resistance and heart rate, with significant increases in cardiac index, stroke volume index, stroke work index, ejection fraction, and exercise capacity. Furthermore, the next dose of chronic combined medication no longer showed vasodilating effects. Chronic therapy with fixed-dose doxazosin and increasing doses of metoprolol produced identical effects as those seen in patients receiving metoprolol alone.

Adrenergic alpha-Antagonists↗

PubMed1995

The estimation of lung dose from mid-perineum ionization chamber measurements in total body irradiations: a quality control check on dose delivery.

A series of patients (eleven males and eight females) receiving total body irradiation prior to bone marrow transplantation was monitored during treatment by recording the dose from an ionization chamber placed between the thighs in the mid-perineal region. The treatment was delivered by opposed lateral 6 MV photon beams. The patient was encompassed by the radiation field with the maximum collimator opening at a distance of 3.49 m from the X-ray focus to the patient mid-line. An analysis was made of the measured dose and the calculated percentage average lung dose for each patient in the series to seek a correlation between measured doses and patients' anatomical data so that estimates of delivered lung doses could be made. Whilst a global factor can be applied to measured dose to predict lung dose, it is concluded that perineal dose measurements distal to the region where dose is prescribed (mean lung dose) are sub-optimal for checks on target dose delivery. Entrance and exit dose measurements at the level of dose prescription (in the thorax) are preferable for more accurate predictions and quality control checks.

Female↗

PubMed1986

Post-treatment fertility in patients with testicular cancer. III. Influence of radiotherapy in seminoma patients.

Sperm analysis and serum hormone measurements (LH, FSH, testosterone) were performed in 29 patients after orchiectomy for seminoma before and after irradiation. Before radiotherapy 14 of 20 orchiectomized patients were azoospermic or had impaired spermatogenesis. A minimum sperm count was found 1 year after radiotherapy with gradual improvement up to 2 years. The recovery of sperm cell production was impaired most in patients with pre-treatment sperm counts less than 3 million/ml. Serum testosterone remained at low normal levels throughout the observation period. The mean serum FSH was increased 1 year after radiotherapy but returned to normal in 50% of patients within 3 years after treatment. This post-treatment increase in FSH was significantly correlated with increased pre-treatment FSH but not with the gonadal dose, which was 1 to 3% of the target dose. Severe disturbances in spermatogenesis, observed 2 to 3 years after radiotherapy for early seminoma, are likely to be the expression of a highly impaired pre-treatment sperm cell production and only to a lesser degree dependent on the irradiation of the remaining testicle.

Adult↗

PubMed1996

The effects of prostaglandin E1 on hepatic allograft vascular inflow: a prospective randomized double-blind study.

Improved hepatic microcirculation is one of the postulated mechanisms by which prostaglandin E1 (PGE(1)) could improve liver function in the setting of fulminant hepatic failure or poor allograft function immediately post-transplant. The purpose of this study was to determine whether PGE(1) improves hepatic allograft arterial and portal vein inflow. Fifty patients receiving a primary liver transplant were entered into a prospective randomized double-blind study. Measurements of hepatic arterial and portal venous flow were taken immediately after revascularization and after steady state drug infusion. PGE(1) (or placebo) was infused peripherally at an increasing dose and titrated for blood pressure to a target dose of 1 microgram/kg/hr (80 microgram/hr maximum). Changes in hepatic arterial and portal vein flow, and time to reach maximum dose were compared using the student's t test. Of the 50 patients entered, 15 were excluded from analysis (10 because of inability to obtain flow measurements, 4 because they were pediatric recipients <2 yrs of age, and 1 patient who was placed on open PGE(1)). Thirty-five patients were available for final analysis (control, N = 14; PGE(1),N = 21). There were no statistical differences in the change in hepatic artery of portal vein flow between PGE(1)-treated and -untreated grafts. The time to reach maximum dose of PGE(1) was longer in the PGE(1) treatment group. Maximum dose was reached in 85.7 per cent of patients in both groups. There was an effect on blood pressure in the study group as demonstrated by a longer time to reach maximum dose. There was no effect on hepatic vascular in flow.

Adult↗

PubMed1991

Improved dose homogeneity in the breast using tissue compensators.

The improvements achievable by introducing individual tissue compensators in photon therapy of the breast were assessed. In 37 patients the dose ranged from +15% to -10% of the mid target dose using combinations of wedge filters and beam weights alone. With a tissue compensator the dose ranged from +4% to -11% provided that allowance was made for lung attenuation. A megavoltage imaging system is a potential source of the X-ray transmission data which can provide a basis for the calculation of thickness of the compensator.

Breast Neoplasms↗

PubMed1987

The value of the NSD formula in equation of acute and late radiation complications in normal tissue following 2 and 5 fractions per week in breast cancer patients treated with postmastectomy irradiation.

In 1978-1980, inclusive, all breast cancer patients referred for postmastectomy irradiation were treated by 2 fractions per week (73 patients) but due to a high incidence of late complications this fractionation schedule was changed from early 1981 to 5 fractions per week (66 patients) with dose adjustment according to the nominal standard dose (NSD) concept. The dose aim in both regimens was 1345 ret minimum target dose. This allowed a comparison of acute and late complications in the two patient groups treated to the same NSD value, but with different fractionation. The patients have been analysed with respect to acute and late reaction in the skin, subcutaneous tissue, lung and bone, as well as related complications, such as arm oedema and impairment of shoulder movement. Except for the acute skin reactions, all other endpoints could not be adequately predicted by the NSD formula. Thus, telangiectasia greater than or equal to grade 1 and skin fibrosis greater than or equal to grade 2 were found to be 75% and 67% in patients treated with the 2-fraction scheme versus 39% and 5% in patients treated with the 5-fraction scheme. In the 2-fraction regimen, a higher frequency of impairment of shoulder movement and arm oedema was found compared to the 5-fraction regimen, 38% versus 11% and 44% versus 33%, respectively. The acute lung reaction as well as late lung reaction were significantly more pronounced in the 2-fraction regimen than in the 5-fraction regimen (pneumonitis greater than or equal to grade 2, 43% versus 23%, and lung fibrosis greater than or equal to grade 2, 32% versus 17%, in the photon fields, respectively). Further, radiation-induced osteonecrosis in the ribs was significantly more frequent in patients treated with large dose per fraction (19% versus 2%). The data clearly demonstrates the danger by using the NSD formula in equation of two different fractionation schedules. This formula as well as other mathematical models can only be used with caution within the limitations defined by the underlying clinical and experimental data on which they have been derived.

Breast Neoplasms↗