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Results for “Targeted dosing”

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At least 379 records · Page 21Linked to original sources

PubMed1992

Successful intervention in a group A meningococcal outbreak in Auckland, New Zealand.

During two consecutive winter seasons (1985 and 1986) Auckland, New Zealand, experienced epidemic rates of Group A meningococcal disease, a pattern not previously recognized in New Zealand. The overall rate was 8.3/100,000/year. The highest annual rate (64.7) occurred in children 0 to 23 months of age. A city-wide vaccine campaign commencing in May, 1987, was conducted over 6 weeks among children 3 months to 13 years of age with special emphasis on reaching populations at highest risk (Maori and Pacific Island Polynesian children in certain geographic regions of Auckland). Children from 2 to 13 years of age received a single dose of monovalent Group A meningococcal vaccine. Children ages 3 to 23 months received two doses at least 1 month apart. Overall approximately 130,000 doses were delivered; coverage was approximately 90% in the single dose target group. Among the younger children approximately 89% received the primary dose. Only approximately 26% received the recommended "booster" dose. After 2 1/2 years of active surveillance (1987 to 1989) there were no cases of invasive Group A meningococcal disease in children appropriately vaccinated for age. In contrast to this 100% efficacy the efficacy of a single dose of monovalent Group A meningococcal vaccine to prevent illness in the youngest children during the 1987 epidemic period was 52% (95% confidence interval (-330%, 95%)) falling to 16% (95% confidence interval, (-538%, 90%)) after 1 year. Four cases that occurred in infants 3 to 7 weeks before the scheduled "booster" campaign supports limited true efficacy. However, the prescribed 1 to 3-month interval between the two doses in infants may be too long.(ABSTRACT TRUNCATED AT 250 WORDS)

Bacterial Vaccines↗

PubMed1994

[Intravenous or oral 131I treatment of hyperthyroidism and thyroid cancer?].

The purpose of this study was to determine differences in 131I biokinetics after oral or intravenous treatment of hyperthyroidism (0.81 GBq) or differentiated thyroid cancer (1.85 GBq) following thyroidectomy. 20 patients with differentiated carcinoma and 20 patients with hyperthyroidism were studied. In each group 10 patients were treated perorally and 10 patients intravenously. The integrated whole-body activities during therapy were significantly lower, by an average 23% (cancer) and 45% (hyperthyroidism) than after oral application. It is most likely that these differences between oral and intravenous application are due to the higher serum activity after intravenous therapy. It is concluded that a higher activity dose of 131I must be given orally to achieve the same target dose as after intravenous application.

Administration, Oral↗

PubMed1999

Dose escalation and pharmacokinetic study of a humanized anti-HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer.

We conducted a phase I pharmacokinetic dose escalation study of a recombinant humanized anti-p185HER2 monoclonal antibody (MKC-454) in 18 patients with metastatic breast cancer refractory to chemotherapy. Three or six patients at each dose level received 1, 2, 4 and 8 mg kg(-1) of MKC-454 as 90-min intravenous infusions. The first dose was followed in 3 weeks by nine weekly doses. Target trough serum concentration has been set at 10 microg ml(-1) based on in vitro observations. The mean value of minimum trough serum concentrations at each dose level were 3.58 +/- 0.63, 6.53 +/- 5.26, 40.2 +/- 7.12 and 87.9 +/- 23.5 microg ml(-1) respectively. At 2 mg kg(-1), although minimum trough serum concentrations were lower than the target trough concentration with a wide range of variation, trough concentrations increased and exceeded the target concentration, as administrations were repeated weekly. Finally 2 mg kg(-1) was considered to be sufficient to achieve the target trough concentration by the weekly dosing regimen. One patient receiving 1 mg kg(-1) had grade 3 fever, one at the 1 mg kg(-1) level had severe fatigue defined as grade 3, and one at 8 mg kg(-1) had severe bone pain of grade 3. No antibodies against MKC-454 were detected in any patients. Objective tumour responses were observed in two patients; one receiving 4 mg kg(-1) had a partial response in lung metastases and the other receiving 8 mg kg(-1) had a complete response in soft tissue metastases. These results indicate that MKC-454 is well tolerated and effective in patients with refractory metastatic breast cancers overexpressing the HER2 proto-oncogene. Further evaluation of this agent with 2-4 mg kg(-1) weekly intravenous infusion is warranted.

Antibodies, Monoclonal↗

PubMed2003

A pooled analysis of adjunctive topiramate in refractory partial epilepsy.

OBJECTIVES: To evaluate the impact of different dosages of topiramate (TPM) add-on to stable antiepileptic therapy for refractory partial epilepsy in adults. MATERIAL AND METHODS: Pooled intention-to-treat analysis of six similarly designed double-blind, placebo-controlled trials, including 481 patients treated with doses of TPM 200, 400, 600 and 800 mg/day, and 265 patients receiving placebo. RESULTS: Seizures were reduced by >/=50% from baseline in 41% of TPM-treated patients and 15% of placebo-treated patients (P < 0.001); 5 and 0.8%, respectively, were seizure-free (P < 0.003). TPM was significantly better than placebo regardless of gender, age, baseline seizure rate as well as number and type of concomitant antiepileptic drugs. Efficacy was statistically significant in favour of TPM at all dose levels: at least 50% seizure reduction was achieved in 40% of patients with 200 mg, 41% with 400 mg, 44% with 600 mg and 41% with 800 mg TPM when compared with 15% with placebo (P </= 0.001 for each dosage arm vs placebo). The median reduction in monthly seizure frequency was 38%, 42%, 45% and 38% vs 8%, respectively (P </= 0.001). Moreover, response to TPM was significantly superior to placebo at each of the dose levels tested for most of the baseline variables. The total percentage of withdrawals increased with the dosage, and the withdrawals caused by adverse events increased from 3% with placebo to 7% with 200 mg TPM (not significant vs placebo), 15% with 400 mg TPM (P = 0.08), 16% with 600 mg TPM (P = 0.002) and 15% with 800 mg TPM (P = 0.003). CONCLUSION: The efficacy of TPM add-on in partial epilepsy is consistent across efficacy endpoints and independent of study population characteristics. The response at 200 mg TPM is similar to the response at higher doses, but as drop-outs caused by adverse events are more frequent above the 200 mg dose, this pooled analysis supports that 200 mg daily is a good target dose for add-on therapy in most patients with partial epilepsy, showing an excellent balance between efficacy and tolerability.

Adolescent↗

PubMedDate not supplied

Moving from external exposure concentration to internal dose: duration extrapolation based on physiologically based pharmacokinetic derived estimates of internal dose.

The potential human health risk(s) from chemical exposure must frequently be assessed under conditions for which adequate human or animal data are not available. The default method for exposure-duration adjustment, based on Haber's rule, C (external exposure concentration) or C(n) (the ten Berge modification) x t (exposure duration) = K (a constant toxic effect), has been criticized for prediction errors. A promising alternative approach to duration adjustment is based on equivalence of internal dose, that is, target-tissue dose levels, across different exposure durations. A proposed methodology for dose-duration adjustments for acute exposure guideline levels (AEGLs) based on physiologically based pharmacokinetic (PBPK) estimates of dose is illustrated with trichloroethylene (TCE). Steps in this methodology include: (1) selection and evaluation, or development and evaluation, of an appropriate PBPK model; (2) determination of an appropriate measure of internal dose; (3) estimation with the PBPK model of the tissue dose (the target tissue dose) resulting from the external exposure conditions (concentration, duration) of the critical effect; (4) estimation of the external exposure concentrations required to achieve tissue doses equivalent to the target tissue dose at exposure durations of interest; and (5) evaluation of sources of variability and uncertainty. For TCE, this PBPK modeling approach has allowed determination of dose metrics predictive of the acute neurotoxic effects of TCE and dose-duration adjustments based on estimates of internal dose.

Computer Simulation↗

PubMed2002

Effect of fluoxetine and imipramine on the pharmacokinetics and tolerability of the antipsychotic quetiapine.

The effects of fluoxetine and imipramine on the pharmacokinetics and nonpsychiatric side effect profile of quetiapine fumarate were investigated in 26 patients with schizophrenia, schizoaffective disorder, or bipolar disorder in a multicenter, two-period, multiple-dose, open-label, randomized trial. Over a 1- to 2-week period, patients were titrated to a 300-mg twice-daily dose of quetiapine. Patients treated for at least 7 days at the target dose entered a combination therapy period, receiving fluoxetine (60 mg daily) or imipramine (75 mg twice daily) for 8 days. Key assessments included pharmacokinetic analysis of quetiapine, the Udvalg for kliniske undersøgelser (UKU) Side Effect Rating Scale, and safety evaluations (e.g., adverse events, electrocardiograms, laboratory tests, and vital signs). Fluoxetine increased the quetiapine area under the plasma concentration time curve during a 12-hour interval (+12%), maximum plasma concentration during the dosing interval (C(ss)(max); +26%), and minimum plasma concentration at the end of the dosing interval (+8%), although it decreased oral clearance (-11%). The change in C(ss)(max) was statistically although not clinically significant. Imipramine did not affect the pharmacokinetics of quetiapine. Overall, scores on the UKU Side Effect Rating Scale improved during combination therapy with either agent, and no statistically significant deterioration was observed for any item. For safety assessments, the only clinically remarkable event was an imipramine-associated complete left bundle branch block in one patient. No unexpected side effects were reported. In conclusion, combination therapy with quetiapine and fluoxetine or imipramine had a minimal effect on quetiapine pharmacokinetics and was well tolerated.

Adolescent↗

PubMed1995

Radioiodine therapy of Graves' hyperthyroidism: standard vs. calculated 131iodine activity. Results from a prospective, randomized, multicentre study.

The present prospective, randomized, multicentre study was performed to directly compare for the first time the effectiveness of a standard activity of 555 MBq 131iodine vs. an activity calculated to deliver 100 Gy for treatment of Graves' thyrotoxicosis. Therapeutic success was defined as the elimination of hyperthyroidism 6 months after radioiodine application (range 4.5-8 months). A success rate of more than 90% in eliminating hyperthyroidism was reported for both approaches, but only in retrospective investigations. Investigated prospectively, hyperthyroidism was eliminated in only 71% of the patients receiving standard activity (70/98) and 58% of those randomized for calculated activity (62/107). In the patients with standard activity, therapeutic success was inversely related to thyroid size. The rate was 100% for thyroid volumes < or = 15 mL, 95% for 16-30 mL, 68% for 31-45 mL, 44% for 46-50 mL, 20% for 61-75 mL and 25% for > or = 75 mL. In those patients with an activity calculated to deliver 100 Gy (except in those with a volume < or = 15 mL) this size/outcome dependency was almost compensated. The rates were 86%, 65%, 45%, 61%, 41% and 45%, respectively. Furthermore, detailed statistical analysis revealed a strong correlation between the success of therapy and the radiation dose actually absorbed by the thyroid. The rate was 11% for a target dose of 50 Gy, 50% for 100 Gy, 67% for 150 Gy, 80% for 200 Gy, 84% for 250 Gy, 88% for 300 Gy, 90% for 350 Gy and 93% for 400 Gy.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed2004

Pharmacokinetics of treprostinil sodium administered by 28-day chronic continuous subcutaneous infusion.

The objective of this study was to assess the pharmacokinetics and safety of treprostinil sodium administered as a 28-day continuous subcutaneous infusion at escalating infusion rates of 2.5 to 15 ng/kg/min in normal subjects. Fourteen healthy adult volunteers received a 28-day continuous sub-cutaneous infusion of treprostinil at escalating infusion rates of 2.5, 5, 10, and 15 ng/kg/min. Doses were escalated every 7 days with no washouts between escalations. Serial plasma samples were collected predosing, during dosing, and postdosing. Samples were also collected every 3 hours on Day 7 of each dosing period to evaluate diurnal variation over a 24-hour steady-state interval. Plasma treprostinil concentration was measured by a validated liquid chromatography atmospheric pressure ionization tandem mass spectrometry (LC/MS/MS) method with a lower limit of quantitation (LLOQ) of 25 pg/mL. Distinct steady states were achieved for each of the four treprostinil doses. Linear regression analysis of mean steady-state treprostinil concentration versus targeted dose yielded a fitted line with an r(2) of 0.92. Variation in apparent plasma clearance for the four doses was small (i.e., 9.77-10.4 mL/kg/min). Consistent diurnal cycles of two peak and two trough treprostinil concentrations were observed over a 24-hour steady-state interval for each dose with peak levels 20% to 30% higher than trough levels. The terminal half-life of treprostinil was 2.93 hours. Intersubject variability for mean pharmacokinetic parameters was small (coefficients of variation ranging from 13.6%-25.5%). At clinically relevant doses, the pharmacokinetics of treprostinil were linear and dose independent with modest, consistent diurnal cycles consisting of two daily peaks and two daily troughs observed for all four doses. In addition, the elimination half-life was about 3 hours.

Adolescent↗

PubMed2006

Compliance by referring physicians with recommendations on heart failure therapy from a tertiary center.

BACKGROUND: We tested the assumption that general practitioners do not use medication as recommended and do not follow recommendations made by heart failure specialists. METHODS: The study included 193 stable patients referred to and subsequently seen at our heart failure clinic between 1995 and 2001 with an ejection fraction of 40% or less. They had 1906 visits (1661 with structured follow-up). Recommendations by heart failure specialists regarding medication influencing prognosis and adherence of referring physicians to them were recorded. RESULTS: Ninety-six percent of patients were taking angiotensin-converting enzyme (ACE) inhibitor/angiotensin-II receptor blocker (ARB) when referred. The prescription rate of beta-blockers and spironolactone increased after publication of large trials (more than 80% in 2001). Doses were inappropriate for both ACE-inhibitors/ARBs (55% +/- 30% of target dose) and beta-blockers (29% +/- 24%). Recommendations were followed closely for dose reduction/discontinuation of all drugs (82%) and start/uptitration of spironolactone (78%). Adherence was less (P < .01) for start/uptitration of ACE inhibitors/ARBs (62%) and beta-blockers (48%). Recommendations regarding single-step start/uptitration were more successful (ACE-inhibitors/ARBs, 70%; beta-blockers, 63%; single-step of both, 67%) than multiple-step uptitration (ACE inhibitors/ARBs, 48%; beta-blocker, 38%; P < .001). This was particularly true if recommendations concerned multiple-step uptitration of both drugs (25%, P < .001). There was no difference between general practitioners and cardiologists. CONCLUSIONS: Although penetration of drugs beneficial in heart failure was high upon referral, doses were lower than recommended, and recommendations regarding changes were insufficiently adhered to by the referring physicians. Simple, one-step recommendations were better implemented and may be combined with direct prescriptions during control visits to guarantee adequate medical therapy.

Attitude of Health Personnel↗

PubMed2000

Pilot and safety trial of carboplatin, paclitaxel, and thalidomide in advanced non small-cell lung cancer.

We performed a pilot study to assess the safety of thalidomide in combination with standard chemo-therapy in patients with advanced non small-cell lung cancer. Patients with unresectable stage IIIA, IIIB, or IV disease were enrolled starting in July 1999. Patients received paclitaxel 225 mg/m2 over 3 hours and carboplatin area under the curve = 6.0 with thalidomide at a starting daily dose of 200 mg. The thalidomide dose was escalated, if tolerated, by 200 mg per week to a target dose of 1000 mg per day and could continue for up to 6 months. Patients with stages IIIA and IIIB disease without effusion received radiotherapy with concurrent thalidomide after 2 cycles of chemotherapy. Nine patients were enrolled: one with IIIA disease, three with IIIB disease, and five with stage IV disease. Five of nine patients had previously been treated with chemotherapy and/or radiotherapy. The most frequent side effects noted were fatigue, myalgia, constipation, neuropathy, and myelosuppression. Sixteen of the 17 (94%) episodes of grade 3 or 4 hematologic toxicity occurred in the five patients who had previously received chemotherapy, although no patients developed neutropenic fever. The median tolerated daily thalidomide dose was 600 mg. One patient with IIIA disease had a partial response after 2 cycles of chemotherapy and went on to receive radiotherapy with thalidomide. One patient with stage IV disease continues on this study with stable disease at 187 days. The median time to progression was 118 days. This preliminary data supports the further investigation of this combination in chemotherapy-naive patients with advanced non small-cell lung cancer.

Journal Article↗

PubMed1999

Low dose interferon-alpha2b combined with PUVA is an effective treatment of early stage mycosis fungoides: results of a multicenter study. Cutaneous-T Cell Lymphoma Multicenter Study Group.

BACKGROUND AND OBJECTIVE: The early stages of mycosis fungoides (MF) can be treated but not cured by photochemotherapy (PUVA) alone; some recent studies of the effect of a combination of human interferon-alpha (IFN(alpha)) and PUVA reported a high degree of response. The aim of our study was to evaluate the activity of a low dose of IFN-alpha2b combined with PUVA. DESIGN AND METHODS: Twenty-five patients were included: 16 men and 9 women aged between 23-80 years; 19 patients ahd stage I and 6 stage II disease. In the induction phase, the dose of IFNalpha was gradually raised over 6-8 weeks to the target dose of 18 MU/week; in the maintenance phase, the combination with PUVA allowed IFNalpha to be reduced to a maximum dose of 6 MU/week; in this way the cumulative administration of IFNalpha and PUVA was considerably lower than in similar combination protocols. Treatment success was analyzed in terms of freedom from treatment failure (FFTF). RESULTS: After the induction phase 9/25 patients (36%) achieved complete remission (CR) and 15/25 (56%) achieved partial remission (PR). One to five months from the beginning of the maintenance phase, a CR was recorded in 19/25 patients (76%) and a PR in 5/25 patients (20%) accounting for an overall response rate of 96%. The median of FFTF was not reached; probability of FFTF was 82% at 12 months and 62% at 24 months. Disease free survival projected to 48 months was 75%. INTERPRETATION AND CONCLUSIONS: Even with low doses of IFNalpha plus PUVA it is possible to achieve excellent clinical responses,many of which are long-lasting, in patients with early MF.

Adult↗

PubMed2006

[Long-term outcome and tolerability of carvedilol therapy in Japanese patients with chronic heart failure].

OBJECTIVES: Randomized controlled clinical studies in western countries have shown that the beta-blockers improve the survival of patients with chronic heart failure and are highly tolerable. The tolerability of beta-blocker therapy and the long-term prognosis for patients with chronic heart failure receiving beta-blockers remain unclear in Japan. In the present study, carvedilol was employed for the treatment of mild to severe chronic heart failure and the long-term prognosis of the patients was monitored to evaluate the tolerability and chronic efficacy of beta-blocker therapy in Japanese patients. METHODS: Three hundred and twenty-seven patients with chronic heart failure [Classes II to IV according to the New York Heart Association (NYHA) classification] were studied. Carvedilol was started at a dose of 1.25 to 5 mg/day and then increased to the final target dose of 20 mg/day, depending on its tolerability in each patient. The patients were monitored with respect to their NYHA classification, daily mean heart rate (evaluated by Holter electrocardiography), changes of the plasma brain natriuretic peptide level, and prognosis. They were followed up for a mean period of 4.4 +/- 1.8 years. RESULTS: Carvedilol was not tolerated by 21 of the 327 patients (6.4%), and was discontinued during the follow-up period in 38 patients (11.6%). The mean maintenance dose for the remaining 268 patients (82.0%), in whom treatment could be continued over the long term, was 14.1 +/- 7.5 mg. The NYHA classification and plasma brain natriuretic peptide level were significantly improved, and the daily mean heart rate was also significantly reduced in the 268 patients. Significant improvement was also observed in patients with severe heart failure (classes III or IV of the NYHA classification). The five-year survival rate of patients continuously treated with carvedilol was 83%, and their outcome was significantly better than that of those who could not tolerate the drug (49%; p < 0.001) or those who discontinued treatment prematurely (68%; p < 0.001). The treated group also had a significantly lower cardiac death rate than the intolerant group or discontinued group. CONCLUSIONS: Carvedilol was well tolerated by Japanese patients with chronic heart failure. Treatment with low-dose carvedilol may improve the symptoms and prognosis of patients with mild to severe chronic heart failure over the long term.

Adrenergic beta-Antagonists↗

PubMed1998

Efficacy of pyridoxine to ameliorate the cutaneous toxicity associated with doxorubicin containing pegylated (Stealth) liposomes: a randomized, double-blind clinical trial using a canine model.

A cutaneous reaction termed palmar-plantar erythrodysesthesia (PPES) or hand-foot syndrome can be dose limiting for Doxil, a doxorubicin containing pegylated (Stealth) liposome. The objective of this study was to determine the ability of concomitant pyridoxine therapy to prevent the development of PPES during Doxil therapy. Forty-one dogs with non-Hodgkin's lymphoma were randomized in a double-blind fashion to receive either oral pyridoxine or placebo daily during Doxil chemotherapy (1.0 mg/kg, i.v., every 3 weeks for a total of five treatments). Cutaneous toxicity was determined by clinical and histological scoring. No difference was observed in remission rates (71.4 versus 75%) achieved between groups. The likelihood of developing serious PPES and having to decrease or discontinue Doxil therapy was 4.2 times (relative risk) greater in placebo group dogs than in pyridoxine group dogs (P = 0.032). Pyridoxine did not completely abrogate PPES; however, it occurred later and less dramatically than in placebo-treated dogs and resulted in fewer treatment delays or discontinuations, allowing a higher cumulative dose of Doxil to be received. Compared to the 5.0 mg/kg cumulative target dose, pyridoxine-treated dogs received a median cumulative dose of 4.7 mg/kg (mean, 4.1 mg/kg), and the placebo-treated dogs received a median of 2.75 mg/kg (mean, 2.9 mg/kg; P < 0.028). A trend (P = 0.084) toward prolongation of remission length was observed in dogs receiving pyridoxine, which was likely attributable to their ability to receive more Doxil without delay or discontinuation. We conclude that pyridoxine is effective in delaying the onset and severity of PPES in this canine model.

Animals↗

PubMed1981

In vivo kinetics of magnetically targeted low-dose doxorubicin.

The in vivo kinetics of low-dose doxorubicin (0.05 mg/kg), entrapped in a carrier and magnetically targeted, were characterized in a rat tail model. Tissue concentrations of doxorubicin at a preselected target site and in various organs were followed over time. As late as 60 min postinjection, 3.7 microgram/g of drug was found at the target site with no detectable drug levels found in any organ. In comparison, a 100-fold higher dose (5.0 mg/kg iv) of free doxorubicin yielded drug concentrations of 1.8 microgram/g at the target site and 15.0 microgram/kg in the pooled organs. Therefore, 1% of the free intravenous dose targeted magnetically yielded approximately twice the local doxorubicin concentration at a preselected target site with no detectable systemic distribution. Magnetic targeting of particulate drug carriers to localized disease sites is suggested as an efficient method of obtaining high local drug concentrations and may reduce many unwanted side effects from unrestricted systemic circulation.

Animals↗

PubMed1997

Irradiation of localized prostatic carcinoma with a combination of high dose rate iridium-192 brachytherapy and external beam radiotherapy with three target definitions and dose levels inside the prostate gland.

PURPOSE: Localized prostate cancer was treated with combined external beam radiotherapy and high dose rate Ir-192 brachytherapy with the purpose of a high dose. The technical aspects of a modified treatment are described. METHODS: The brachytherapy was given in two sessions preceded and succeeded by external beam radiation. The radioactive source was temporarily implanted by a remote afterloading device through six to 15 needles inserted transperineally guided by transrectal ultrasound. The entire prostate gland was included in the clinical target volume. The urethra and the tumour volume could be defined and irradiated to different dose levels in more than 90% of the patients. RESULTS: Fifty-four patients were treated. The total dose to the prostate was approximately 70 Gy and to the tumour volume 80 Gy. By calculating the corresponding dose given by 2.0 Gy fractions, considering the radiobiology by using the LQ formula and assuming an alpha/beta value for prostate tissue of 10, the dose to the prostate was approximately 84 Gy and to the tumour volume 112 Gy. For the late effects to the urethra an alpha/beta value of 3 was used, which corresponds to 85 Gy. The brachytherapy could be given with accuracy except when the dorsal border of the prostate was concave. The dose distribution then tended to be less satisfactory. Post-treatment calculations showed that the maximum dose to the rectum was 67 Gy (radiobiologically corrected to 88 Gy), given in a small volume. The early side effects from the brachytherapy were minimal. The treatment could not be performed as intended in four patients; three patients had a narrow pelvis and in one patient the prostate was unusually resilient, preventing the needles from being positioned properly. CONCLUSIONS: This modification of a previously reported brachytherapy technique for prostate carcinoma permits a high radiation dose to the tumour and to the prostate gland, which ultimately may improve local control.

Dose-Response Relationship, Radiation↗

PubMed1996

An evaluation of the accuracy of magnetic-resonance-guided Gamma Knife surgery.

An evaluation of the systematic accuracy of magnetic resonance (MR)-guided Gamma Knife surgery was performed. In two experiments, a cylinder phantom filled with dosimeter gel containing ferrous sulfate was fixed to a stereotactic frame. The gel phantom was irradiated with the Gamma Knife with a single shot using 4-mm collimators. The target point was set at the frame center of the stereotactic system giving coordinate values of X = 100, Y = 100, Z = 100. The maximum target dose was 15 Gy. MR imaging was undertaken immediately after the irradiation, using a superconductive 1.5-T MR scanner. Spin echo T1-weighted images, with transaxial, coronal, and sagittal views, were obtained. On the images, points with the highest signals were defined as the target point which received the maximum dose. Within the dose range of the experiment, this definition is based on a linear relationship between the dose to the gel and the T1 relaxation shortening after irradiation. The distances between the frame center and the target point defined on the MR images in the experiments were 0.12 mm (0.2375 pixels) and 0.43 mm (0.8515 pixels), respectively. Both are within the mechanical accuracy of the Gamma Knife. The imaging study confirms the accuracy of the Gamma Knife surgery used in the institution.

Evaluation Studies as Topic↗

PubMed2005

A group sequential adaptive treatment assignment design for proof of concept and dose selection in headache trials.

The trial objective was to test whether a new mechanism of action would effectively treat migraine headaches and to select a dose range for further investigation. The motivation for a group sequential, adaptive, placebo-controlled trial design was (1) limited information about where across the range of seven doses to focus attention, (2) a need to limit sample size for a complicated inpatient treatment and (3) a desire to reduce exposure of patients to ineffective treatment. A design based on group sequential and up and down designs was developed and operational characteristics were explored by trial simulation. The primary outcome was headache response at 2 h after treatment. Groups of four treated and two placebo patients were assigned to one dose. Adaptive dose selection was based on response rates of 60% seen with other migraine treatments. If more than 60% of treated patients responded, then the next dose was the next lower dose; otherwise, the dose was increased. A stopping rule of at least five groups at the target dose and at least four groups at that dose with more than 60% response was developed to ensure that a selected dose would be statistically significantly (p=0.05) superior to placebo. Simulations indicated good characteristics in terms of control of type 1 error, sufficient power, modest expected sample size and modest bias in estimation. The trial design is attractive for phase 2 clinical trials when response is acute and simple, ideally binary, placebo comparator is required, and patient accrual is relatively slow allowing for the collection and processing of results as a basis for the adaptive assignment of patients to dose groups. The acute migraine trial based on this design was successful in both proof of concept and dose range selection.

Clinical Trials, Phase II as Topic↗

PubMed2006

A phase II study of weekly paclitaxel combined with carboplatin for elderly patients with advanced non-small cell lung cancer.

We conducted this phase II study to explore the efficacy and safety of weekly paclitaxel combined with carboplatin in elderly patients with advanced non-small cell lung cancer (NSCLC). Elderly patients (> or = 70 years old) of stage IIIB, IV, or recurrent NSCLC with PS 0 or 1 were enrolled. Patients received paclitaxel at a dose of 70 mg/m2 on Days 1, 8, 15, and carboplatin at the target dose of the area under the curve (AUC) of six on Day 1 every 28 days for at least two cycles. Forty-two patients were enrolled and 40 patients were treated with a median of three cycles (range, 1-5). The overall response rate (ORR) was 45% (95% confidence interval, 30-60%). The median survival time (MST) was 14 months and the 1-year survival rate was 62%. Twenty-eight patients (70%) had grade 3/4 neutropenia and two patients (5%) experienced grade 3 febrile neutropenia. Non-hematological toxicities were generally mild to moderate and grade 3 peripheral neuropathy was seen in one patient (3%). There was one treatment-related death by infection due to neutropenia. Weekly paclitaxel and carboplatin combination chemotherapy was an effective and safe regimen in elderly patients with advanced NSCLC. A randomized trial comparing this treatment with the conventional tri-weekly regimen of paclitaxel and carboplatin is warranted.

Aged↗