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PubMed2004

Influence of intra-fractional breathing movement in step-and-shoot IMRT.

Efforts have been made to extend the application of intensity-modulated radiotherapy to a variety of organs. One of the unanswered questions is whether breathing-induced organ motion may lead to a relevant over- or underdosage, e.g., in treatment plans for the irradiation of lung cancer. Theoretical considerations have been made concerning the different kinds of IMRT but there is still a lack of experimental data. We examined 18 points in a fraction of a clinical treatment plan of a NSCLC delivered in static IMRT with a new phantom and nine ionization chambers. Measurements were performed at a speed of 12 and 16 breathing cycles per minute. The dose differences between static points and moving target points ranged between -2.4% and +5.5% (mean: +0.2%, median: -0.1%) when moving with 12 cycles min(-1) and between -3.6% and +5.0% (mean: -0.4%, median: -0.6%) when moving with 16 cycles min(-1). All differences of measurements with and without movements were below 5%, with one exception. In conclusion, our results underline that at least in static IMRT breathing effects (concerning target dose coverage) due to interplay effects between collimator leaf movement and target movement are of secondary importance and will not reduce the clinical value of IMRT in the step-and-shoot technique for irradiation of thoracic targets.

Body Burden↗

PubMed2006

Application of the isolated perfused rat kidney model to assess gender effects on drug excretion.

PURPOSE: To study the effect of gender on the renal disposition of two organic anions, p-aminohippuric acid (PAH) and furosemide (FSM) in the isolated perfused rat kidney (IPK). METHODS: IPK experiments (3-4 per treatment group) were conducted using kidneys from male and female Sprague Dawley rats. PAH was administered as a continuous infusion (with loading dose, targeted steady-state concentration 10 ug/mL). FSM was added as a bolus dose (2.65 mg, targeted concentration 33 ug/mL). Urine was collected in 10-min. intervals and perfusate was sampled at the midpoint of each collection period. Control (drug naïve) perfusions were performed for both genders. PAH and FSM were measured by HPLC. Kidney viability (GFR [estimated using inulin clearance], sodium reabsorption, glucose reabsorption) was monitored continuously during each perfusion experiment (2-h duration). RESULTS: Good kidney function was maintained across all study groups, and lower GFR estimates in female kidneys were due to differences in kidney weight. For PAH, kidney weight corrected renal clearance (0.88 +/- 0.37 mL/min/g vs. 0.59 +/- 0.19 mL/min/g) and excretion ratio (3.8 +/- 1.7 vs. 2.2 +/- 0.72) were significantly higher in male kidneys. For FSM, renal clearance was significantly lower in female (0.10 +/- 0.05 mL/min/g) compared to male kidneys (0.15 +/- 0.07 mL/min/g). Mass balance analysis showed that FSM cumulative urinary excretion was significantly higher and kidney accumulation was significantly lower in experiments with male kidneys. CONCLUSIONS: The study demonstrates that the IPK is a useful model to assess gender effects on renal drug disposition. The renal excretion of organic anions is reduced in female rats, possibly due to gender differences in expression and/or activity of membrane transporters (both basolateral and luminal) in the kidney.

Animals↗

PubMed2004

Prospective feasibility trial of radiotherapy target definition for head and neck cancer using 3-dimensional PET and CT imaging.

UNLABELLED: The aim of this investigation was to evaluate the influence and accuracy of (18)F-FDG PET in target volume definition as a complementary modality to CT for patients with head and neck cancer (HNC) using dedicated PET and CT scanners. METHODS: Six HNC patients were custom fitted with head and neck and upper body immobilization devices, and conventional radiotherapy CT simulation was performed together with (18)F-FDG PET imaging. Gross target volume (GTV) and pathologic nodal volumes were first defined in the conventional manner based on CT. A segmentation and surface-rendering registration technique was then used to coregister the (18)F-FDG PET and CT planning image datasets. (18)F-FDG PET GTVs were determined and displayed simultaneously with the CT contours. CT GTVs were then modified based on the PET data to form final PET/CT treatment volumes. Five-field intensity-modulated radiation therapy (IMRT) was then used to demonstrate dose targeting to the CT GTV or the PET/CT GTV. RESULTS: One patient was PET-negative after induction chemotherapy. The CT GTV was modified in all remaining patients based on (18)F-FDG PET data. The resulting PET/CT GTV was larger than the original CT volume by an average of 15%. In 5 cases, (18)F-FDG PET identified active lymph nodes that corresponded to lymph nodes contoured on CT. The pathologically enlarged CT lymph nodes were modified to create final lymph node volumes in 3 of 5 cases. In 1 of 6 patients, (18)F-FDG-avid lymph nodes were not identified as pathologic on CT. In 2 of 6 patients, registration of the independently acquired PET and CT data using segmentation and surface rendering resulted in a suboptimal alignment and, therefore, had to be repeated. Radiotherapy planning using IMRT demonstrated the capability of this technique to target anatomic or anatomic/physiologic target volumes. In this manner, metabolically active sites can be intensified to greater daily doses. CONCLUSION: Inclusion of (18)F-FDG PET data resulted in modified target volumes in radiotherapy planning for HNC. PET and CT data acquired on separate, dedicated scanners may be coregistered for therapy planning; however, dual-acquisition PET/CT systems may be considered to reduce the need for reregistrations. It is possible to use IMRT to target dose to metabolically active sites based on coregistered PET/CT data.

Adult↗

PubMed2000

A quantitative treatment planning study evaluating the potential of dose escalation in conformal radiotherapy of the oesophagus.

BACKGROUND AND PURPOSE: This study aims to evaluate the reduction in radiation dose to normal thoracic structures through the use of conformal radiotherapy techniques in the treatment of oesophageal cancer, and to quantify the resultant potential for dose escalation. MATERIALS AND METHODS: Three different CT-derived treatment plans were created and compared for each of ten patients. A two-phase treatment with conventional straight-edged fields and standard blocks (CV2), a two-phase conformal plan (CF2), and a three-phase conformal plan where the third phase was delivered to the gross tumour only (CF3), were considered for each patient. Escalated dose levels were determined for techniques CF2 and CF3, which by virtue of the conformal field shaping, did not increase the mean lung dose. The resulting increase in tumour control probability (TCP) was estimated. RESULTS: A two-phase conformal technique (CF2) reduced the volume of lung irradiated to 18 Gy from 19.7+/-11.8 (1 SD) to 17.1+/-12.3% (P=0.004), and reduced the normal tissue complication probability (NTCP) from 2.4+/-4.0 to 0.7+/-1.6% (P=0.02) for a standard prescribed dose of 55 Gy. Consequently, technique CF2 permitted a target dose of 59.1+/-3.2 Gy without increasing the mean lung dose. Technique CF3 facilitated a prescribed dose of 60.7+/-4.3 Gy to the target, the additional 5 Gy increasing the TCP from 53. 1+/-5.5 to 68.9+/-4.1%. When the spinal cord tolerance was raised from 45 to 48 Gy, technique CF3 allowed 63.6+/-4.l Gy to be delivered to the target, thereby increasing the TCP to 78.1+/-3.2%. CONCLUSIONS: Conformal radiotherapy techniques offer the potential for a 5-10 Gy escalation in dose delivered to the oesophagus, without increasing the mean lung dose. This is expected to increase local tumour control by 15-25%.

Adult↗

PubMed2006

Erythropoietin dose requirements when converting from subcutaneous to intravenous administration among patients on hemodialysis.

BACKGROUND: The optimal route for administration of exogenous erythropoietin remains controversial, particularly after the increased incidence in pure red cell aplasia. In Canada, the majority of hemodialysis units have converted to the intravenous route for administration of erythropoietin to potentially decrease the risk of pure red cell aplasia. OBJECTIVE: To compare the difference in the weight-adjusted, weekly erythropoietin dose (units/kg/wk) administered by the subcutaneous compared with the intravenous route in a chronic hemodialysis population followed for 12 months. METHODS: This prospective cohort study recruited patients receiving subcutaneous erythropoietin for at least 3 months while undergoing dialysis in a tertiary care hemodialysis program. Participants were switched to intravenous erythropoietin, and the average weekly dose was recorded at 1, 2, 3, 6, and 12 months. Anemia management and hemoglobin, iron, and delivered dialysis dose targets remained constant throughout the study. RESULTS: The erythropoietin dose increased by 24.5 units/kg/wk (95% CI 12.7 to 36.3; p < 0.001), representing a 20.2% increase (95% CI 10.5% to 29.9%; p < 0.001) 12 months after conversion from the subcutaneous to intravenous route of administration. Both patients with and without residual renal function at baseline required a significant increase in the intravenous dose. CONCLUSIONS: A 20.2% increase in erythropoietin dose was required to maintain hemoglobin targets between 11 and 12 g/dL after conversion from a subcutaneous to intravenous formulation. Healthcare funding agencies need to reexamine the cost benefit of using intravenous erythropoietin in the hemodialysis population with a low incidence of pure red cell aplasia.

Aged↗

PubMed1998

Cost- and time-sparing simplified conformal therapy for prostate cancer: is it feasible?

PURPOSE: It was hypothesized that using a simplified technique of volumes profiles determination (STVPD) based on CT data sets (correlate and projection) would increase the target dose without increasing the bladder and rectal dose obtained by conventional simulation techniques. To test this hypothesis, patients referred for radical radiation treatment for prostate carcinoma were prospectively evaluated by performing treatment planning using standard simulation, with (SSB) and without corner blocks (SSWB), STVPD, and 3D beam's eye view. METHODS AND MATERIALS: Twenty-one patients with prostate carcinoma (stage B: 7; stage C: 14) underwent four treatment planning procedures where the field arrangement was defined by standard simulation (SSB and SSWB), STVPD, and 3D beam's eye view (BEV) with a four field (10 MV photons) box technique. Dose-volume histograms (DVHs) for the planning target volume (PTV), bladder, and rectum (relatives to the four techniques) were generated for all patients and compared; average percentage dose to the bladder and rectum were also calculated. RESULTS: STVPD and 3D BEV treated an increased percentage of PTV at 95% isodose level, in comparison to standard simulation (with and without blocks). No statistically significant differences were found between the two techniques. A significant reduction of irradiated bladder volume was found between 3D BEV and STVPD versus simulation with and without blocks (mean percentage dose: 77.3%, 81.8%, 93.5%, and 92.6% respectively). No marked differences were recorded in rectal irradiation (mean percentage dose: 53.1%, 53.7%, 51.9%, and 50.2% respectively). Time required for treatment planning (excluding CT scan and definitive simulation) was less than 15 minutes for STVPD and more than 120 minutes for 3D BEV. CONCLUSION: Our results confirm the inadequacy of standard simulation. It is possible, with conformal therapy, to increase the dose to the PTV, decreasing the irradiated volume of the bladder. The absence of sparing effect in the rectum is discussed. Using a box technique, STVPD can be used routinely to define the PTV in patients with prostate cancer, reducing the time required for treatment planning, with dosimetric results similar to those of 3D BEV.

Aged↗

PubMed2004

Clinical implementation of intensity-modulated tangential beam irradiation for breast cancer.

A Monte Carlo based intensity-modulated radiation therapy (IMRT) treatment planning system has been developed and used for breast treatment. An iterative method was used for optimization to generate IMRT plans and a step-and-shoot technique was used for beam delivery. The patient setup and incident beam directions were the same as those for conventional tangential photon treatment. The weights for the opposed beamlets in the two tangential beams were determined first by the doses at the depths of the maximum dose at both sides to minimize hot spots. The intensity of an individual beamlet pair was then optimized based on the dose at the midplane. Fine tuning was made to achieve optimal target dose uniformity and to reduce the dose to the heart when necessary. The final dose calculations were performed using the Monte Carlo method and the plans were verified by phantom measurements. The dose distributions and dose-volume-histograms of IMRT plans were compared with those of conventional plans that were generated using a commercial treatment planning system and recalculated using an in-house Monte Carlo system for the first 25 patients. The dose comparisons showed that the percentage volume receiving more than 95% of the prescription dose (V95) and the percentage volume receiving more than 100% of the prescription dose (V100) for the clinical target volume (CTV) of IMRT plans were about the same as those of conventional plans. The percentage volume receiving more than 105% of the prescription dose (V105) for the CTV was reduced from 23.1% to 7.9% on average. The percentage volume of the lung receiving more than 20 Gy dose (V20 Gy) during the entire treatment was reduced by about 10%. The percentage volume of the heart receiving more than 30 Gy dose (V30 Gy) is reduced from 3.3% to 0.3%. Further studies revealed that a less than 5 degrees change in couch angle and collimator angle at patient setup had no significant effect on the dose coverage of CTV but had significant effect on the dose to the lung and heart. The study on the effect of beam spoiler showed that it increased the dose at the buildup region by 0- 13% that varies with location. The machine output linearity and stability for small monitor unit delivery of Siemens accelerators used for this study was checked and found to be suitable for breast IMRT. The total effect of variations was calculated to be less than 1% for typical breast treatments. The beam delivery time was increased by about 2 min compared with conventional tangential treatments. The whole treatment including patient setup and beam delivery can be completed in a 15 min slot. The IMRT technique has been proven practical for breast treatment clinically. The results showed that tangential IMRT improved the dose homogeneity in the breast and reduced the dose to the lung and heart.

Algorithms↗

PubMed2006

Topiramate in essential tremor: a double-blind, placebo-controlled trial.

BACKGROUND: Essential tremor is most prevalent and most disabling in older patients. Additional therapies are required for patients with an inadequate response or intolerable side effects. In small trials, topiramate appeared to be beneficial in essential tremor. METHODS: In this multicenter, double-blind, placebo-controlled, parallel-design trial, patients with moderate to severe essential tremor of the upper limbs were randomized to 24 weeks of treatment with placebo or topiramate (target dose, 400 mg/day) as monotherapy or as an adjunct to one antitremor medication. The primary efficacy variable was the final visit tremor score based on the Fahn-Tolosa-Marin Tremor Rating Scale (TRS). RESULTS: The intent-to-treat population was 208 patients (topiramate, 108; placebo, 100). The final visit score (last observation carried forward) was lower in the topiramate group than with placebo (p < 0.001). Mean percentage improvement in overall TRS scores was 29% with topiramate at a mean final dose of 292 mg/day and 16% with placebo (p < 0.001). Topiramate was associated with greater improvement in function and disability (p = 0.001). A between-group difference (p < 0.001) was observed at the first on-treatment visit at 4 weeks when the target topiramate dose was 100 mg/day (mean achieved dose, 62 +/- 9 mg/day). The most common treatment-limiting adverse events in topiramate-treated patients were paresthesia (5%), nausea (3%), concentration/attention difficulty (3%), and somnolence (3%). Adverse events were treatment limiting in 31.9% of topiramate patients and 9.5% of placebo patients. CONCLUSIONS: Topiramate was effective in the treatment of moderate to severe essential tremor. Tremor reduction was accompanied by functional improvements, such as in motor tasks, writing, and speaking.

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↗

PubMedDate not supplied

[Selection of the optimal radiotherapy technique for locally advanced maxillary carcinoma using a three-dimensional treatment planning system].

AIM: To compare the isodose distribution of three radiotherapy techniques for locally advanced maxillary sinus carcinoma and analyze the potential of three-dimensional (3D) conformal radiotherapy planning in order to determine the optimal technique for target dose delivery, and spare uninvolved healthy tissue structures. METHODS: Computed tomography (CT) scans of fourteen patients with T3-T4, N0, M0 maxillary sinus carcinoma were acquired and transferred to 3D treatment planning system (3D-TPS). The target volume and uninvolved dose limiting structures were contoured on axial CT slices throughout the volume of interest combining three variants of treatment plans (techniques) for each patient: 1. A conventional two-dimensional (2D) treatment plan with classically shaped one anterior + two lateral opposite fields and two types of 3D conformal radiotherapy plans were compared for each patient. 2. Three-dimensional standard (3D-S) plan: one anterior + two lateral opposite coplanar fields, which outlines were shaped with multileaf collimator (MLC) according to geometric information based on 3D reconstruction of target volume and organs at risk as seen in the beam eye's view (BEV) projection. 3. Three-dimensional non-standard (3D-NS) plan: one anterior + two lateral noncoplanar fields, which outlines were shaped in the same manner as in 3D-S plans. The planning parameters for target volumes and the degree of neurooptic structures and parotid glands protection were evaluated for all three techniques. Comparison of plans and treatment techniques was assessed by isodose distribution, dose statistics, and dose-volume histograms. RESULTS: The most enhanced conformity of the dose delivered to the target volume was achieved with 3D-NS technique, and significant differences were found comparing 3D-NS vs. 2D (Dmax: p<0.05; Daver: p<0.01; Dmin: p<0.05; V90: p<0.05, and V95: p<0.01), as well as 3D-NS vs. 3D-S technique (Dmin: p<0.05; V90: p<0.05, and V95: p<0.01), while there were no differences between 2D vs. 3D-S technique. 3D-S conformal plans were significantly superior to 2D plans regarding the protection of parotid glands, and the additional improvement of dose conformity was achieved with 3D-NS technique. 3D-NS technique resulted in the decrease of Dmax for ipsilateral retina compared with 3D-S technique, while the level of Dmax for optic nerve was increased (within an acceptable range) with 3D-NS technique. CONCLUSION: In this study, 3D planning of radiotherapy for locally advanced maxillary sinus carcinoma with noncoplanar fields, which number did not exceed the number of fields for conventional arrangement enabled conformal delivering of the adequate dose to the target volume with the improved sparing of adjacent uninvolved healthy tissue structures.

Carcinoma↗

PubMed2004

Beta-blockers in heart failure: is more better?

Therapies that modulate the sympathetic nervous system and renin-angiotensin-aldosterone system reduce morbidity and mortality in patients with heart failure. However, they are grossly underused in clinical practice; when used, the doses prescribed are substantially smaller than the target doses used in the large-scale studies that established their utility. Whether these suboptimal doses are as effective in reducing morbidity and mortality is largely unknown. This review focuses on the relationship between the dose of b-blockers and their effect on clinical outcomes. Because direct dose comparisons of b-blockers are limited, we draw upon a broader spectrum of clinical trials across the cardiovascular continuum that involved neurohormonal modulators to address the question, "Is more better?"

Adrenergic beta-Antagonists↗

PubMed2001

Safety, tolerability, and pharmacokinetics of remacemide in children.

Eleven patients (nine males, two females), 9-14 years of age, received adjunctive therapy with remacemide in an open ascending-dose study at two residential centers in the United Kingdom. Children taking enzyme-inducing drugs were given remacemide twice daily, starting at approximately 4 mg/kg per day and doubling the dose at two weekly intervals to a target dose of approximately 16 mg/kg per day. Children not taking enzyme-inducing drugs (n = 5) received half of these doses. After the dose-escalation phase, remacemide was slowly withdrawn over 2 weeks except in two children who, because of apparent benefit, entered a continuation phase. Remacemide generally was well tolerated in doses up to 13.5 mg/kg per day. Adverse events were similar to those reported in adults, with central nervous system and gastrointestinal events being the most common. One patient died after a suspected seizure, which was unlikely to have been related to remacemide treatment. No adverse effects on neuropsychologic functioning were observed; effects on vital signs and laboratory variables were not clinically significant. The pharmacokinetic profile for remacemide and its desglycinyl metabolite in children is similar to that seen in adult patients. Plasma concentrations of remacemide and the desglycinyl metabolite are reduced in the presence of concomitant antiepileptic drugs with hepatic enzyme-inducing activity.

Acetamides↗

PubMed1999

Quality of care for Medicare patients hospitalized with heart failure in rural Georgia.

BACKGROUND: It is not known whether quality of care for congestive heart failure (CHF) at rural hospitals is similar to that in larger, urban hospitals. METHODS: We reviewed hospital charts for 310 Medicare patients hospitalized with CHF at six hospitals in rural Georgia. RESULTS: Of the 310 patients, 101 (33%) had left ventricular systolic dysfunction, and 60 (19%) had preserved systolic function. Information on left ventricular function was not available for 48% (range, 29% to 87% across the six hospitals). Among patients with systolic dysfunction, 77% were prescribed an angiotensin converting enzyme (ACE) inhibitor at discharge, and 73% were prescribed digoxin. However, the mean daily ACE inhibitor dose was only 48% of the recommended target dose. Only 30% of all patients with atrial fibrillation were prescribed warfarin. CONCLUSIONS: Overall quality of care for CHF at rural hospitals appears similar to that in other settings, though many patients may not receive evaluation of ventricular function.

Aged↗

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↗

PubMed2004

Clinical, cognitive, and neurophysiologic correlates of short-term treatment with carbamazepine, oxcarbazepine, and levetiracetam in healthy volunteers.

BACKGROUND: The adverse effects of the antiepileptic drugs (AEDs) originally developed are well known, while those of the newer AEDs remain unclear. OBJECTIVE: To investigate clinical, cognitive, and neurophysiologic effects of carbamazepine, oxcarbazepine, and levetiracetam in healthy volunteers. METHODS: A double-blind crossover study was conducted in 10 volunteers. Eight-day treatment with carbamazepine, oxcarbazepine, levetiracetam, or placebo was administered in random order. Drug doses were titrated gradually to the daily target doses on day 7: carbamazepine 800 mg, oxcarbazepine 1200 mg, and levetiracetam 1500 mg. At baseline and at the end of each treatment period, participants underwent cognitive and neurophysiologic assessment. A washout period of 14 days between treatment periods was conducted. RESULTS: More adverse events were self-reported with carbamazepine (63%) than the other treatments (oxcarbazepine 12%, levetiracetam 20%, placebo 5%; p < 0.001 between the 4 groups). Carbamazepine induced the greatest motor slowing (p = 0.002), followed by oxcarbazepine (p = 0.01). Levetiracetam left baseline motor speed unchanged. All AEDs increased attention span from baseline values as shown on the Stroop test. Quantitative electroencephalogram (EEG) analysis showed that carbamazepine significantly increased the delta-theta power and reduced the frequency of alpha rhythm; oxcarbazepine induced smaller changes than carbamazepine. Levetiracetam did not change any EEG measurements. On color visually evoked potential (VEP) tests, carbamazepine induced a constant slowing of P1 latency, while oxcarbazepine induced changes only after the blue-black pattern. All color VEP measures for volunteers receiving levetiracetam were almost unchanged. CONCLUSIONS: After short-term treatment in healthy volunteers, carbamazepine induced major clinical and neurophysiologic changes. Oxcarbazepine was better tolerated than carbamazepine. Levetiracetam interfered least with clinical and neurophysiologic test results.

Adult↗

PubMed2003

Nortriptyline for treatment-resistant depression.

BACKGROUND: Up to 30% of patients with major depression fail to respond to an antidepressant trial, with most taking a selective serotonin reuptake inhibitor (SSRI) as initial treatment. While the tricyclic antidepressants might be effective for SSRI nonresponders, they have been relegated to third- and fourth-line treatment. This study assesses the efficacy of nortriptyline for patients with treatment-resistant major depression. METHOD: 92 patients with treatment-resistant DSM-III-R major depression, with resistance defined by at least 1, but no more than 5, well-documented adequate trials of antidepressants during the current episode, were treated openly with nortriptyline for 6 weeks. Patients were titrated up to full target doses of nortriptyline within 1 week, with target blood levels of 100 ng/mL. Response was defined as a 50% or greater decrease of baseline 17-item Hamilton Rating Scale for Depression score. We performed an intent-to-treat analysis with the last observation carried forward. RESULTS: Approximately 40% of patients were responders (N = 39) and 12% were remitters (N = 11) after 6 weeks of nortriptyline. Over a third of patients were unable to complete the trial. CONCLUSION: Nortriptyline was effective for over a third of patients with treatment-resistant depression, and nortriptyline should be considered as potential treatment if patients fail to respond to other antidepressants.

Adolescent↗

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↗

PubMed2004

A comparison of conventional, conformal and intensity-modulated coplanar radiotherapy plans for posterior fossa treatment.

Radiotherapy of the posterior fossa for medulloblastoma treatment can induce ototoxicity, especially when combined with cisplatin chemotherapy. Sensorineural hearing loss can be severe enough to cause permanent disability, which may compromise cognitive development in paediatric patients. This study evaluates the sparing of the cochlea in conventional radiotherapy, three-dimensional conformal radiotherapy (3D-CRT), and intensity-modulated radiotherapy (IMRT). CT scans of three patients were used to plan posterior fossa radiotherapy using coplanar beam arrangements. The posterior fossa and the cochlea were contoured as well as other organs-at-risk (non-posterior fossa brain, lenses, optic nerves, pituitary and cervical spinal cord). Three treatment plans were compared: conventional two-dimensional treatment (parallel-opposed lateral pair); 3D-CRT (two wedged posterior oblique fields); and a four-field coplanar IMRT plan. 3D-CRT and IMRT reduced cochlear doses to less than 70% of the mean target dose. These plans also reduced dose to the non-posterior fossa brain and cervical spinal cord. IMRT showed no advantage over 3D-CRT in sparing the optic nerves and lenses, compared with 3D-CRT. Normal tissue doses were higher in both conformal techniques than in the IMRT plans. Conformal techniques reduced the dose to the cochlea, non-posterior fossa brain and cervical spinal cord. The small size and proximity to the planning target volume (PTV) of the cochlea limited the effectiveness of the IMRT plan. Coplanar 3D-CRT was judged superior to coplanar IMRT, particularly in children, because it achieved adequate sparing of the cochlea and anterior cranial structures, such as the lenses and optic nerves, without compromising the dose to the posterior fossa.

Cerebellar Neoplasms↗