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PubMedDate not supplied

Optimization of brachytherapy dose distributions by simulated annealing.

An algorithm based on the method of simulated annealing is presented for optimizing brachy-therapy dose distributions. The algorithm accommodates either static configurations of multiple sources or single stepping sources, hence in principle can be used to optimize both low- and high-dose rate treatments delivered with remote afterloading equipment. Required inputs include the specification of target dose rates and dose rate limits, expressed in absolute or relative terms, at operator selected points near the treatment site. The influence of the dose rate limits can be adjusted continuously through the use of one or more penalty factors. The algorithm generates a set of integer weights, one for each available source position, which are interpreted in terms of configuration occupancy numbers for static source arrangements and relative dwell times for stepping sources. Application is made to several variations of a hypothetical low-dose rate vaginal vault planning problem involving one rectal and six applicator calculation points. The algorithm's performance for different source strengths, annealing schedules, target dose rates, dose rate limits, and values of a single penalty factor lambda was examined. With a simple annealing schedule and value of lambda = 25, the algorithm found solutions of high quality for all problem variants. The CPU time required for optimization on a Vax 11/750 computer ranged from 2 min for a single configuration to 25 min for a solution consisting of four configurations. These results support the use of simulated annealing for clinical planning of low dose rate vaginal treatments, and encourage investigation of other applications in brachytherapy.

Algorithms↗

PubMed2000

Safety and tolerability of a rapidly escalating dose-loading regimen for risperidone.

BACKGROUND: Risperidone is an "atypical" antipsychotic with strong binding affinity for dopamine-2 and serotonin-2 receptors. Risperidone is often used to treat hospitalized patients who have acute psychotic decompensation, and the therapeutic target dose commonly used is 2 to 6 mg/day. The most common clinical practice is to titrate the dose of risperidone to the target therapeutic dose over several days. This study investigated the safety and tolerability of a rapid oral-loading regimen for risperidone developed to achieve therapeutic doses of this antipsychotic within 24 hours. METHOD: Rapid-loaded risperidone was initiated with 1 mg. Subsequent doses were increased by 1 mg every 6 to 8 hours up to 3 mg. Dose increases were contingent on tolerance of last administered dose. RESULTS: Of a sample of 11 consecutive inpatients admitted to an acute psychiatric facility who were treated with this protocol, 7 tolerated the most rapid titration, achieving a standing dose of 3 mg b.i.d. in 16 hours. Three required a slightly slower titration and achieved this target dose in 24 hours. One patient could not tolerate the 3-mg dose but tolerated a standing regimen of 2 mg t.i.d. No patient experienced serious extrapyramidal side effects, sedation, or any other adverse event during the rapid titration, and in no case did risperidone have to be discontinued. CONCLUSION: These results suggest that aggressive dosing of risperidone is well tolerated in most psychiatric inpatients.

Administration, Oral↗

PubMed1998

Side effects resulting from the use of growth hormone and insulin-like growth factor-I as combined therapy to frail elderly patients.

BACKGROUND: The objective of this study was to examine the relationship between serum IGF-I concentration and the incidence of side effects of therapy with recombinant human growth hormone (rhGH) and recombinant human insulin-like growth factor-I (rhIGF-I). METHODS: Thirteen high-risk, undernourished elderly males were started on a 15-day course of rhGH and rhIGF-I by subcutaneous injection. The dose of rhGH was held constant at .0125 mg/kg/day, whereas the dose of rhIGF-I was increased in a stepwise fashion from 10 micrograms/kg to the targeted dose of 40 micrograms/kg twice a day. RESULTS: Nine subjects completed the protocol and reached the full target dose of both hormones. Fluid retention, gynecomastia, and orthostatic hypotension were the most common complications. The hormone injections increased the serum concentration of IGF-I (from 72.7 +/- 40.9 to 483.7 +/- 251.4 eta g/ml, p = .001) and IGFBP-3 (from 1.82 +/- 0.66 to 2.72 +/- 1.18 mg/L, p = .012), and decreased serum albumin (from 34.3 +/- 5.5 to 31.4 +/- 4.6 g/L, p = .009). The magnitude of the initial increase in the serum IGF-I concentration was a powerful risk factor for severe orthostatic hypotension, diffuse myalgias, and drug-induced hepatitis. There was no association between the serum IGF-I concentration and fluid retention or gynecomastia. CONCLUSIONS: Treatment of the undernourished frail elderly with the anabolic agents rhGH and rhIGF-I at the specified dosages may produce undesirable side effects including fluid retention, gynecomastia, and orthostatic hypotension. Although these agents hold therapeutic promise, they must be used with caution in this high-risk population.

Aged↗

PubMed2004

An algorithm for systematic selection of beam directions for IMRT.

Selection of the number of beams and their directions can be an important problem in radiation therapy, especially when a tumor surrounds a critical organ or is surrounded by multiple critical organs. Beam directions, in this sense, are chosen to not only avoid critical organs, but also to achieve better target dose uniformity. In intensity-modulated radiation therapy (IMRT), optimization of beam directions is further complicated due to the dependence of one beam direction on its corresponding beamlet intensities and the beamlet intensities of all other beam directions. The result is an excessively enlarged search space, even when the number of beams is small (two to three). Until now, only a handful of publications exist regarding beam direction optimization in IMRT. Here, we report a new systematic approach that determines a suitable number of "more optimal" beam directions without optimizing a complicated objective function or resorting to brute force. We start by assuming that beam directions chosen for an N-beam plan are candidates for beam directions in the search for an (N + 1)-beam plan. Knowing that beam directions in an N-beam plan are not always the best choices for the (N + 1)-beam plan, we introduce into the beam direction selection process an analysis of the beamlet weights of every beam direction set sampled. If the relative weights of any particular beam compared to other beams are insignificant and hence have no significant effect on the quality of the treatment plan, then we eliminate this beam from the plan. The algorithm terminates basically when the relative weights of the last beam compared to other beams are insignificant or the replacement of an eliminated beam does not improve the plan. This concept was applied to three two-dimensional phantoms and each plan was compared to a standard equally spaced IMRT plan in terms of dose distributions, dose-volume histograms, and objective function values. The results show improvements in both target dose uniformity and critical organ sparing often with a fewer number of beams than standard equally spaced beam plans.

Algorithms↗

PubMed2005

Effect of a community heart failure clinic on uptake of beta blockers by patients with obstructive airways disease and heart failure.

OBJECTIVE: To determine the pattern of beta blocker prescribing over one year in a heart failure clinic with a structured approach towards initiation and dose titration and to give a real life perspective on beta blocker use, compliance, and target dose achievement. METHODS: Data were retrospectively analysed on 513 consecutive patients regularly attending a community heart failure clinic over a year. Systolic dysfunction was determined from two dimensional echocardiography (left ventricular ejection fraction < or = 40%) and lung function was assessed by spirometry. All patients were considered for beta blocker initiation and dose up titration. RESULTS: Within one year 157 patients died. 143 patients started beta blockers resulting in 315 (88%) patients taking beta blockers at one year; 38% were taking the target dose. 124 had evidence of airways obstruction at baseline, 100 (81%) of whom were taking beta blockers at one year. Forced expiratory volume in one second (1.1 v 1.5 l, p < 0.01) and forced vital capacity (2.3 v 2.5 l/min, p = 0.2) were not reduced in patients with airways obstruction who received beta blockers. Daily doses of beta blockers at one year did not differ statistically between patients with obstructive and patients with non-obstructive spirometry results. 12 patients discontinued beta blockers and 14 required dose reduction due to side effects. CONCLUSION: The majority of patients with heart failure and obstructive airways disease can safely tolerate low dose initiation and gradual up titration of beta blockers.

Adrenergic beta-Antagonists↗

PubMed2000

Irradiation to ensure quarantine security for Cryptophlebia spp. (Lepidoptera: Tortricidae) in sapindaceous fruits from Hawaii.

Studies were undertaken to determine whether irradiation treatment at 250 Gy, an accepted treatment for disinfestation of fruit flies in spindaceous fruits from Hawaii, would also disinfest fruit of two species of Cryptophlebia. Cryptophlebia illepida (Butler) was determined to be more tolerant of irradiation than Cryptophlebia ombrodelta (Lower); therefore, C. illepida was the focus for detailed tests. Using the criterion of success in developing to the adult stage, the pattern of tolerance to irradiation in C. illepida was generally eggs < early instars < late instars < pupae. The most tolerant stage potentially occurring in harvested fruits was late (fourth and fifth) instars. Development to adult was reduced slightly in late instars receiving an irradiation dose of 62.5 Gy, whereas development to adult was dramatically reduced in late instars receiving irradiation doses > or = 125 Gy. No C. illepida larvae receiving an irradiation dose > or = 125 Gy emerged as adults and produced viable eggs, indicating sterility can be achieved at doses well below 250 Gy. In large scale tests, when 11,256 late instars were irradiated with a target dose of 250 Gy, 951 pupated (8.4%) and none eclosed as adults. Within the pupal stage, tolerance increased with age; 7- to 8-d-old pupae (the oldest pupae tested) treated with an irradiation dose of 125 Gy produced viable offspring, whereas those treated with a dose of 250 Gy produced no viable offspring. Irradiation of adults with a target dose of 250 Gy before pairing and mating resulted in no viable eggs. Irradiation of actively ovipositing adult females resulted in no subsequent viable eggs. Therefore, the irradiation quarantine treatment of a minimum absorbed dose of 250 Gy approved for Hawaii's fruits will effectively disinfest fruits of any Cryptophlebia in addition to fruit flies.

Animals↗

PubMed2003

Intensity modulation in radiotherapy: photons versus protons in the paranasal sinus.

PURPOSE: The purpose of this study is to investigate whether successive tightening of normal tissue constraints on an intensity modulated X-ray therapy plan might be able to improve it to the point of clinical comparability with the corresponding intensity modulated proton therapy plan. MATERIALS AND METHODS: Photon and proton intensity modulated plans were calculated for a paranasal sinus case using nominal dose constraints. Additional photon plans were then calculated in an effort to match the dose-volume histograms of the critical structures to those of the proton plan. RESULTS: On reducing the low dose contribution to both orbits in the photon plan by tightening the constraints on these structures, an increased dose heterogeneity across the target resulted. When all critical structures were more strictly constrained, target dose homogeneity and conformity was further compromised. An increased integral dose to the non-critical normal tissues was observed for the photon plans as dose was progressively removed from the critical structures. CONCLUSIONS: Both modalities were found to provide comparable target volume conformation and sparing of critical structures, when the nominal dose constraints were applied. However, the use of intensity modulated protons provided the only method by which critical structures could be spared at all dose levels, whilst simultaneously providing acceptable dose homogeneity within the target volume.

Algorithms↗

PubMed2000

The effects of chronic, sustained-release moxonidine therapy on clinical and neurohumoral status in patients with heart failure.

AIMS: Congestive heart failure (CHF) is characterized by elevated plasma norepinephrine (PNE) associated with a poor prognosis. Moxonidine selectively stimulates medullary imidazoline receptors which centrally inhibit sympathetic outflow and potently suppress levels of circulating PNE. This study was designed to evaluate the effects of central sympathetic inhibition on clinical and neurohumoral status in patients with CHF. METHODS AND RESULTS: This study evaluated 25 patients (age=69+/-7 years, 20 males) with symptomatic CHF (NYHA II-III), stabilized on standard therapy. The mean ejection fraction was 28+/-7% at baseline. Patients were titrated in a double-blind fashion to 11 weeks of oral therapy with placebo (n=9) or sustained-release (SR) moxonidine 0.9 mg bid (n=16). Clinical and neurohumoral status were evaluated at baseline, on chronic therapy at the target dose, and during cessation of therapy. All patients completed the trial and reached the target dose. Dry mouth, symptomatic hypotension, and asthenia were more frequent in the moxonidine SR-treated group. PNE was substantially reduced after 6 weeks at the maximum dose (0.9 mg bid) by 50% vs. placebo (P<0. 0005). A reduction in 24-h mean heart rate (P<0.01) was correlated to the reduction in PNE (r=0.70, P<0.05). A 36% increase in the standard deviation of normal-to-normal intervals (SDNN) was observed in the moxonidine SR group vs. a 2% decrease for placebo (P=0.06); for the root mean square of successive differences (rMSSD), there was a 21% increase for moxonidine SR vs. a 19% decrease for placebo (P<0.05). Abrupt cessation of chronic therapy resulted in substantial increases in PNE, blood pressure, and heart rate. CONCLUSIONS: Chronic therapy with a sustained-release formulation of moxonidine in patients with CHF was well tolerated, with substantial and sustained reductions in PNE. The tachyarrhythmias were attenuated, with evidence of improved autonomic tone. Due to the observed effects following moxonidine discontinuation, tapering of therapy is recommended.

Blood Pressure↗

PubMed2000

Intravenous morphine in postoperative infants: intermittent bolus dosing versus targeted continuous infusions.

Eighty-three infants received i.v. morphine following surgery as a continuous infusion to a targeted morphine concentration of 20 ng ml(-1) (n = 56) or as intermittent bolus doses as needed (n = 27). Ventilation was compared in the two groups by continuous pulse oximetry, by venous blood gases on postoperative day 1 (POD 1) and by CO2 response curves. Infant pain scores were done to assess analgesia every 4 h. Both groups achieved pain scores consistent with analgesia but the bolus group showed a higher percentage of pain scores indicating distress (32 vs. 13%, P < 0.001). Room air saturations of < 90% were seen for 2.3% of POD1 in infusion-treated infants and for 2.5% of POD1 in bolus-treated infants. Mean venous PCO2S were normal in the two groups. Four infants showed ventilatory effects in the infusion group (4/ 56 = 7%); venous hypercarbia in two (2 days, 36 days), oximetry desaturation in one (240 days), both effects in one (6 days). Ventilatory effects were not statistically different between the intermittent bolus-treated and infusion-treated infants but may be clinically important. Monitoring with continuous oximetry is necessary. Morphine clearance increased with age. Infants with detectable morphine also had measurable morphine-6-glucuronide in both groups. Oral intake began at 16 h in both groups and other side effects were infrequent.

Analgesics, Opioid↗

PubMed1997

Effects of RheothRx on mortality, morbidity, left ventricular function, and infarct size in patients with acute myocardial infarction. Collaborative Organization for RheothRx Evaluation (CORE).

BACKGROUND: Previous studies suggested that RheothRx (poloxamer 188) reduces infarct size and improves left ventricular (LV) function in acute myocardial infarction (AMI). We therefore evaluated the effects of various doses of RheothRx in 2948 patients presenting with AMI. METHODS AND RESULTS: Patients were randomized to a control group (n = 963) or to receive RheothRx. Patients receiving RheothRx were allocated to receive a 1-hour bolus only (regimen A, n = 844), an additional 11-hour infusion at a low dose (target serum concentration of 0.5 mg/mL) (regimen Y, n = 490), or an additional 23-hour infusion at a low dose (regimen B, n = 483). Three higher doses (1-hour bolus+low-dose infusion for 47 hours, 1-hour bolus+high dose, target serum concentration of 1.0 mg/ml for 24 hours, or 1-hour bolus+high dose for 48 hours) were discontinued because of high rates of renal dysfunction (8.8%). Renal dysfunction was also observed at lower doses (regimen A, 3.1%; Y, 2.7%; and B, 4.1%) compared with the control patients (1.0%). There was no significant difference in the composite outcome of death, cardiogenic shock, or reinfarction at 35 days (all RheothRx, 13.6%; control, 12.7%). There was a higher incidence of sinus tachycardia (24.7% versus 21.6%, P = .02), atrial flutter (3.0% versus 1.3%, P = .019), atrial fibrillation (10.2% versus 7.3%, P = .082), pericarditis (6.6% versus 4.7%, P = .055), and clinical (21.9% versus 17.9%, P = .005) and radiological (15.3% versus 12.3%, P = .12) evidence of heart failure. This was associated with a lower LV ejection fraction (n = 1053) in treated patients (by = -0.02, P = .026), but there was little difference (P = .34) in infarct size (n = 1088). CONCLUSIONS: In this study of nearly 3000 patients, RheothRx had no effect on mortality, reinfarction, or cardiogenic shock and an adverse effect on renal function, LV ejection fraction, and various clinical manifestations of LV dysfunction or heart failure.

Acute Kidney Injury↗

PubMed1999

Topiramate in medically intractable partial epilepsies: double-blind placebo-controlled randomized parallel group trial. Korean Topiramate Study Group.

PURPOSE: To evaluate the efficacy and safety of topiramate (TPM) as add-on therapy in medically intractable partial epilepsies. METHODS: We used a multicenter double-blind placebo-controlled randomized parallel-group trial consisting of 12 weeks of baseline phase, 10 weeks of titration phase, and 8 weeks of stabilization phase. The primary efficacy variable was the median seizure frequency reduction rate (MSFRR), and the other efficacy variables included responder rate, seizure-free rate, and global evaluations by the patient and the physician. The patient should have partial epilepsies refractory to the maximally tolerable doses of one to two antiepileptic drugs (AEDs) and should have two or more episodes of clinical seizures every 4 weeks during the baseline phase. The target dose of study drugs was 600 mg/day. The study drugs were started at the initial dose of 50 mg/day and gradually increased to the target dose over a 10-week period. RESULTS: A total of 177 patients was randomized into the TPM group (n = 91) and the placebo (PLC) group (n = 86). Baseline median seizure frequencies were 5.6 episodes/4 weeks in the TPM and the PLC groups. Among those who were randomized, 174 patients (TPM, 89 patients; PLC, 85 patients) were available for the efficacy measurement by intention-to-treat analysis. The MSFRR was 51.3% for TPM and 9.1% for PLC, which was highly in favor of TPM (p = 0.0001). The responder rate was 50.6% for TPM and 12.9% for PLC (p = 0.001). Seven (7.9%) of 89 patients taking TPM became seizure free compared with one (1.2%) of 85 patients taking PLC (p = 0.004). The global evaluation greatly favored TPM (p = 0.001). The incidence of adverse events (AEs) was higher in the TPM (81.3%) than in the PLC (48.9%) group, with central nervous system (CNS)-related AEs being the most frequent. Among individual AEs, anorexia (20.9%) and abdominal pain or discomfort (20.9%) were the most common AEs in the TPM group. AEs precipitated early drop-out in seven (7.6%) patients taking TPM and three (3.5%) patients taking PLC. No serious systemic AEs were observed. CONCLUSIONS: TPM was highly effective and safe as add-on therapy in medically intractable partial epilepsies. Slower titration of TPM might be responsible for the lesser drop-out rate than previous trials, but the incidence of AEs was still high. The AE profile of TPM in Koreans was different from that in whites.

Abdominal Pain↗

PubMed1985

Physical optimization of afterloading techniques.

Physical optimization in brachytherapy refers to the process of determining the radioactive-source configuration which yields a desired dose distribution. In manually afterloaded intracavitary therapy for cervix cancer, discrete source strengths are selected iteratively to minimize the sum of squares of differences between trial and target doses. For remote afterloading with a stepping-source device, optimized (continuously variable) dwell times are obtained, either iteratively or analytically, to give least squares approximations to dose at an arbitrary number of points; in vaginal irradiation for endometrial cancer, the objective has included dose uniformity at applicator surface points in addition to a tapered contour of target dose at depth. For template-guided interstitial implants, seed placement at rectangular-grid mesh points may be least squares optimized within target volumes defined by computerized tomography; effective optimization is possible only for (uniform) seed strength high enough that the desired average peripheral dose is achieved with a significant fraction of empty seed locations.

Brachytherapy↗

PubMed2005

Automatic selection of non-coplanar beam directions for three-dimensional conformal radiotherapy.

An algorithm is described, based on ray-tracing and the beam's-eye-view, that exhaustively searches all permitted beam directions. The evaluation of the search is based on a general cost function that can be adapted to the clinical objectives by means of parameters and weighting factors. The approach takes into account the constraints of the linear accelerator by discarding beam directions that are not permitted. A sensitivity analysis was carried out to determine appropriate parameters for different sized organs, and a prostate case was used to benchmark the approach. The algorithm was also applied to two clinical cases (brain and sinus) to test the benefits of the approach compared with manual angle selection. The time to perform a beam direction search was approximately 2 min for the coplanar and 12 min for the non-coplanar beam space. The angles obtained for the prostate case compared well with reports in the literature. For the brain case, the mean dose to the right and left optic nerves was reduced by 12% and 50%, respectively, whilst the target dose uniformity was improved. For the sinus case, the mean doses to the right and left parotid glands were reduced by 54% and 46%, respectively, to the right and left optic nerves by 37% and 62%, respectively, and to the optic chiasm by 39%, whilst the target dose uniformity was also improved. For the clinical cases the plans based on optimized beam directions were simpler and resulted in better sparing of critical structures compared with plans based on manual angle selection. The approach provides a practical alternative to elaborate and time consuming beam angle optimization schemes and is suitable for routine clinical usage.

Adenocarcinoma↗

PubMed2004

Ionizing irradiation quarantine treatment against oriental fruit moth (Lepidoptera: Tortricidae) in ambient and hypoxic atmospheres.

Oriental fruit moth, Grapholita molesta (Busck), is a pest of many rosaceous temperate fruits, including pomes, Malus spp., and stone fruits, Prunus spp., in much of the world. However, some areas are free of the pest, and shipments of fruit hosts from infested to noninfested areas may be regulated. Current quarantine treatments for oriental fruit moth include methyl bromide fumigation and cold storage for several weeks. Methyl bromide use is being restricted because it is a stratospheric ozone-depleting substance, and alternatives are sought. Cold is not tolerated by many hosts of oriental fruit moth. The objective of this research was to develop irradiation quarantine treatments against the pest under ambient and hypoxic storage conditions because some hosts of oriental fruit moth are stored in hypoxic atmospheres, and hypoxia is known to lessen the effects of irradiation. In ambient atmospheres, no adults emerged from 58,779 fifth instars (the most radiotolerant stage present in fruit) irradiated with a target dose of 200 Gy (195-232 Gy measured). In atmospheres flushed with nitrogen, 5.3% of adults emerged from 44,050 fifth instars irradiated with a target dose of 200 Gy (194-230 Gy measured), but they died at a faster rate than control adults and without laying eggs. A dose of 232 Gy (the maximum recorded when 200 Gy was targeted) is recommended to disinfest any fruit of oriental fruit moth under ambient and hypoxic atmospheres.

Animals↗

PubMed2002

Comparison of perindopril versus captopril for treatment of acute myocardial infarction.

Angiotensin-converting enzyme (ACE) inhibitors reduce mortality in patients with acute myocardial infarction (AMI), but these benefits might be limited by acute hemodynamic changes and difficulties in titrating to recommended doses. The objective of this study was to compare the hemodynamic changes and tolerability of perindopril with captopril after AMI. We randomized 212 patients to receive either captopril (n = 102) or perindopril (n = 110) within 72 hours of AMI. Captopril was given as an initial dose of 6.25 mg, and then 50 mg/day on day 1 and 100 mg/day thereafter. The corresponding doses of perindopril were 2, 4, and 8 mg/day. Acute hemodynamic changes, the percentage of patients who reached target doses, and in-hospital and 6-month cardiovascular events were monitored. Baseline clinical characteristics of the 2 groups were identical, but patients randomized to perindopril were in a higher Killip class (1.4 +/- 0.6 vs 1.2 +/- 0.5, p = 0.05). During the first 6 hours, treatment with perindopril resulted in higher minimal systolic (97 +/- 15 vs 91 +/- 14 mm Hg, p <0.01) and diastolic blood pressure (BP) (57 +/- 11 vs 54 +/- 10 mm Hg, p <0.02), later occurrence of minimal BP (3.6 +/- 0.2 vs 2.7 +/- 0.1 hour, p <0.001), and a lower incidence of persistent hypotension with systolic BP < 90 mm Hg for > or =1 hour (5% vs 16%; p < 0.01) compared with captopril. At initial administration, target doses of perindopril and captopril were attained in 97% and 82% of the patients, respectively (p < 0.01). After 6 months, there were no differences between patients treated with perindopril and captopril in mortality rates (6% vs 13%, p = 0.16) and need for revascularization (20% vs 21%, p = 0.9). Thus, in patients during AMI, perindopril treatment showed better short-term tolerance than treatment with captopril, with significantly less acute hemodynamic changes and fewer withdrawals.

Aged↗

PubMed2000

What does ATLAS really tell us about "high" dose angiotensin-converting enzyme inhibition in heart failure?

The Assessment of Treatment with Lisinopril and Survival (ATLAS) results have been widely quoted by proponents advocating the use of "high" doses of angiotensin-converting enzyme (ACE) inhibitors for the treatment of heart failure. In ATLAS, however, the relative benefits of "high" versus "low" dose ACE inhibition were small. Intermediate doses of ACE inhibitors proven effective in previous placebo-controlled trials provide benefit that appears likely to equal or exceed the benefit from "high" dose ACE inhibition. Therefore, we recommend that physicians continue to prescribe ACE inhibitors for patients with heart failure based on the target doses used in the placebo-controlled trials and not on the "high" dose target used in ATLAS.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1998

Phase I trial of subcutaneous recombinant human interleukin-12 in patients with advanced renal cell carcinoma.

Patients with advanced renal cell carcinoma were treated in a Phase I trial with escalating doses of recombinant human interleukin-12 (rHuIL-12) given on days 1, 8, and 15 of each 28-day cycle. Treatment in the initial dose scheme consisted of a fixed dose with dose levels of 0.1, 0.5, and 1.0 microg/kg given to cohorts composed of three or six patients. On the basis of the toxicity profile, a second scheme (up-titration) was undertaken wherein rHuIL-12 was escalated for each patient from week 1 to week 2, to a target dose given week 3 and thereafter; cohort target dose levels were 0.5, 0.75, 1.0, 1.25, and 1.5 microg/kg. Fifty-one patients were treated: 32 (63%) had prior cytokine therapy and 19 (37%) had received no prior systemic therapy. The maximum tolerated dose for the fixed dose scheme was 1.0 microg/kg. Dose-limiting toxicities included increase in transaminase concentration, pulmonary toxicity, and leukopenia. The most severe toxicities occurred with the first injection and were milder upon further treatment. With the up-titration dose scheme, the maximum tolerated dose was reached at 1.5 microg/kg, and dose-limiting toxicity consisted of an increase in serum transaminase levels. At the maximum tolerated dose of 1.5 microg/kg, serum IL-12 levels increased to a mean peak level of 706 pg/ml. Serum levels of IFN-gamma increased to a mean peak level of about 200 pg/ml at 24 h after the first maintenance dose of 1.5 microg/kg. The best responses were as follows: one patient had complete response, 34 patients were stable, 14 patients showed progression, and 1 patient was inevaluable. In conclusion, rHuIL-12 was relatively well tolerated when administered by s.c. injection. The recommended dose according to the up-titration schedule of rHuIL-12 (microg/kg) for Phase II trials was as follows: cycle 1, 0.1 (day 1), 0.5 (day 8), 1.25 (day 15); cycle 2 onwards, 1.25. Phase II trials of rHuIL-12 were initiated in previously untreated patients with renal cell carcinoma and in patients with melanoma.

Adolescent↗

PubMed1990

Anaplastic thyroid carcinoma. Doxorubicin, hyperfractionated radiotherapy and surgery.

Sixteen consecutive patients with anaplastic carcinoma of the thyroid were prospectively treated according to a combined regimen consisting of hyperfractionated radiotherapy, doxorubicin and debulking surgery. The radiotherapy was preoperatively administered to a target dose of 30 Gy in 3 weeks, and postoperatively to an additional dose of 16 Gy in 1.5 weeks. Radiotherapy was administered twice daily, 5 days a week, with a target dose of 1 Gy per fraction and with a minimum interval of 6 hours. A dose of 20 mg doxorubicin was administered intravenously 1 to 2 hours before the first radiotherapy session every week. Debulking surgery was feasible in 9 patients. Local complete remission was achieved in 5 patients and 3 of these are still alive disease-free at 10, 30, and 30 months respectively after diagnosis. Only 6 patients succumbed to a local failure. This combination regimen was well tolerated despite the patients' high age and advanced disease.

Aged↗