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Results for “Targeted dosing”

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At least 487 records · Page 27Linked to original sources

PubMed2000

Phase II studies of the glycine antagonist GV150526 in acute stroke : the North American experience. The North American Glycine Antagonist in Neuroprotection (GAIN) Investigators.

BACKGROUND AND PURPOSE: GV150526, a selective glycine site antagonist, reduces infarct volume in rats with focal cerebral ischemia. Safety and efficacy in humans with acute stroke are being investigated. We sought to further explore the safety, pharmacokinetics, and preliminary outcome of GV150526 treatment in patients with a clinical diagnosis of acute stroke. METHODS: Two trials were conducted in North America. The North American Glycine Antagonist in Neuroprotection trial (GAIN 1) (GLYA2001; United States only) was designed as a sequential dose escalation study. GAIN 2 (GLYA2005; United States and Canada) was designed to further assess the safety of the highest dose tolerated in GAIN 1. Both trials were randomized (2:1), double-blind, and placebo controlled. Treatment was started within 12 hours of symptom onset; patients with both ischemic stroke and primary intracerebral hemorrhage were included in both trials. RESULTS: The dose escalation study (GAIN 1) completed 3 dosing tiers. Enrollment was suspended before escalation to the fourth tier because of laboratory reports of transiently elevated bilirubin levels in a concurrent European study that employed the dose targeted for this tier. After review by an independent safety committee of the worldwide safety data, the second study (GAIN 2) commenced. One hundred nine patients were randomized and dosed with study drug, either an 800-mg loading dose followed by 200 mg every 12 hours for 3 days of GV150526 or placebo. The incidence of serious adverse events was similar in the drug and placebo groups. Mild irritation at the infusion site and symptoms suggestive of mild and reversible altered mentation were reported more frequently in the GV150526 group than in the placebo group. Hyperbilirubinemia was reported in 6% of GV150526-treated patients compared with 3% of placebo-treated patients. Outcome at 4 weeks after stroke was better in GV150526-treated patients, but the studies were not powered to show statistical significance, and the baseline neurological deficits in the GV150526-treated patients were less severe. CONCLUSIONS: These preliminary studies suggest that GV150526 is well tolerated by patients with suspected acute stroke. Further pivotal studies testing the efficacy and safety of GV150526 in acute stroke are ongoing.

Aged↗

PubMed2004

The efficiency of transfusing high doses of platelets in hematologic patients with thrombocytopenia: results of a prospective, randomized, open, blinded end point (PROBE) study.

We performed a prospective, randomized, open, blinded end point (PROBE) study to assess the efficiency of transfusing high doses of platelets in patients with thrombocytopenia, either acute leukemia (AL) or those undergoing autologous hematopoietic stem cell transplantation (AT). Patients were randomly assigned to receive transfusions with a target dose of 0.5 x 10(11)/10 kg (arm A) or 1 x 10(11)/10 kg (arm B). A total of 101 patients were included, of whom 96 were given at least one transfusion. The median time between the first transfusion and when the platelet count reached at least 20 x 10(9)/L increased from 63 hours to 95 hours in the arm B group (P = .001), and the median number of transfusions was lower in this group (2; P = .037). The total number of transfused platelets did not differ between groups (14.9 x 10(11) for arm A versus 18.5 x 10(11) for arm B; P = .156). In such patients, a prophylactic strategy of high doses of platelets could improve platelet transfusion efficiency.

Adult↗

PubMed2004

Transition from argatroban to oral anticoagulation with phenprocoumon or acenocoumarol: effects on prothrombin time, activated partial thromboplastin time, and Ecarin Clotting Time.

Treatment with the direct thrombin inhibitor argatroban (ARG) is often followed by vitamin K-antagonist treatment (VKA). Phenprocoumon (PC) and acenocoumarol (AC) are frequently used in Europe. The standard monitoring test for VKA, pro-thrombin time (PT), is prolonged by direct thrombin inhibitors. Therefore the International Normalized Ratio (INR) obtained during combined treatment does not reflect the true effect of the VKA. A similar interference of the VKA on the activated partial thromboplastin time (aPTT), a monitoring assay for direct thrombin inhibitors, can occur. In 39 healthy volunteers the effect of ARG alone or combined with PC or AC on PT, INR, aPTT, and Ecarin Clotting Time (ECT) was investigated. 6 groups each of 6-8 volunteers received a 5-hour infusion of either 1.0, 2.0 or 3.0 microg/kg/min ARG (days 1, 3, 4 and 5) before initiation of either PC or AC (day 1) and during continued VKA dosing (target INR 2-3). A linear relationship (INR(ARG+VKA) = intercept + slope * INR (VKA alone)) was observed between the INR measured "on" and "off" ARG. The slope depended on the argatroban dose and on the International Sensitivity Index (ISI) of the PT reagent, the steepest slope (i.e., the largest difference between INR (ARG+VKA) and INR (VKA alone)) was seen with the highest ARG dose and the PT reagent with an ISI of 2.13. There was a close correlation between plasma levels of ARG and aPTT or ECT. Under VKA the ARG-aPTT relationship indicated an increased sensitivity of the aPTT to ARG, VKA treatment had no effect on the prolongation of the ECT induced by argatroban. In conclusion, ARG at doses up to 2 microg/kg/min can be discontinued at an INR of 4.0 on combined therapy with VKA, as this would correspond to an INR between 2.2 and 3.7 for the VKA. If it is necessary to monitor ARG in the critical transition period, the ECT which is not influenced by VKA can be used as an alternative to the aPTT.

Acenocoumarol↗

PubMedDate not supplied

Dose- (and time-) dependent blockade of pregnancy in Sprague-Dawley rats administered ammonium dinitramide in drinking water.

Ammonium dinitramide (ADN) is a class 1.1 explosive oxidizer that can be used in solid rocket propellant mixtures and explosives. A 90-day general toxicity/ reproductive screen performed on this compound at doses of 162, 103, 29, and 0.0 mg ADN/kg/day resulted in a treatment-related adverse effect on litter production. Incidences of animals producing litters (1/11, 3/12, 12/12, and 11/12, respectively) and mean numbers of pups per litter (7, 7, 16, and 15, respectively) both were statistically significantly less than controls. In a follow-up study, mated dams treated with ADN at the same doses and examined at gestation days (GDs) 10 and 20 showed an effect in fetus loss similar to that seen in the reproductive screen. A pre- versus postimplantation dosing regimen indicated that implantation is vulnerable to ADN effects during the preimplantation period (GDs 1-3). No implantation sites were found in the rats treated with 2000 mg ADN/L drinking water (target dose of 160 mg ADN/kg/day) during GDs 1-3. Numbers of implantation sites found in the rats treated during GDs 4-8 were similar to those found in the control group. The pituitary was not identified specifically in this study as the site of primary action, but serum progesterone was reduced by 27%, which may have resulted in reduced fertility.

Administration, Oral↗

PubMed2000

A phase I/II trial of iodine-131-tositumomab (anti-CD20), etoposide, cyclophosphamide, and autologous stem cell transplantation for relapsed B-cell lymphomas.

Relapsed B-cell lymphomas are incurable with conventional chemotherapy and radiation therapy, although a fraction of patients can be cured with high-dose chemoradiotherapy and autologous stem-cell transplantation (ASCT). We conducted a phase I/II trial to estimate the maximum tolerated dose (MTD) of iodine 131 ((131)I)-tositumomab (anti-CD20 antibody) that could be combined with etoposide and cyclophosphamide followed by ASCT in patients with relapsed B-cell lymphomas. Fifty-two patients received a trace-labeled infusion of 1.7 mg/kg (131)I-tositumomab (185-370 MBq) followed by serial quantitative gamma-camera imaging and estimation of absorbed doses of radiation to tumor sites and normal organs. Ten days later, patients received a therapeutic infusion of 1.7 mg/kg tositumomab labeled with an amount of (131)I calculated to deliver the target dose of radiation (20-27 Gy) to critical normal organs (liver, kidneys, and lungs). Patients were maintained in radiation isolation until their total-body radioactivity was less than 0.07 mSv/h at 1 m. They were then given etoposide and cyclophosphamide followed by ASCT. The MTD of (131)I-tositumomab that could be safely combined with 60 mg/kg etoposide and 100 mg/kg cyclophosphamide delivered 25 Gy to critical normal organs. The estimated overall survival (OS) and progression-free survival (PFS) of all treated patients at 2 years was 83% and 68%, respectively. These findings compare favorably with those in a nonrandomized control group of patients who underwent transplantation, external-beam total-body irradiation, and etoposide and cyclophosphamide therapy during the same period (OS of 53% and PFS of 36% at 2 years), even after adjustment for confounding variables in a multivariable analysis.

Adult↗

PubMed2003

INR self-management permits lower anticoagulation levels after mechanical heart valve replacement.

BACKGROUND: The Early Self Controlled Anticoagulation Trial (ESCAT I) showed that anticoagulation self-management after mechanical heart valve replacement decreased complication rates by maintaining INR levels closer to the target range than International Normalized Ratio (INR) home doctor management. The therapeutic range for the INR in that study was between 2.5 and 4.5 for all positions of prosthetic valves. ESCAT II should find out whether lowering the target range for INR self-management would further reduce complication rates. METHODS: ESCAT II is a prospective controlled randomized (valves: St. Jude Medical Standard or Medtronic Hall, treatment: conventional/low-dose) multicenter study with 3,300 patients. We present interim results of 1,818 patients. 908 were categorized as having a low-dose target range, which was INR 1.8 to 2.8 for prostheses in aortic position and 2.5 to 3.5 for prostheses in mitral position or in combined valve replacement. The control group (conventional group) with 910 patients aimed at an INR of 2.5 to 4.5 for all valve positions. RESULTS: In the conventional group, 74% of INR values measured were within the therapeutic range. In the low-dose group, 72% of the values were within that range. The linearized thromboembolism rate (% per patient year) was 0.21% for both groups. The bleeding complication rate was 0.56% in the low-dose regimen group versus 0.91% in the conventional group. CONCLUSIONS: Early onset INR self-management under oral anticoagulation after mechanical heart valve replacement enables patients to keep within a lower and smaller INR target range. The reduced anticoagulation level resulted in fewer grade III bleeding complications without increasing thromboembolic event rates.

Anticoagulants↗

PubMed2005

The HOPE TIPS: the HOPE study translated into practices.

The HOPE TIPS study assessed the practicality and tolerability of ramipril titration to a target dose of 10 mg (as achieved in definitive efficacy studies) in a clinical practice setting. 3881 patients at high cardiovascular risk (HOPE study criteria) were recruited in primary and specialist care settings in 9 countries by 439 investigators. Dose titration of ramipril from 2.5 mg to 10 mg daily took place over 9-12 weeks. The mean age of the patients was 64 years, 60% were male and 79% Asian. The target dosage of 10 mg daily was reached in 73% of patients with 96% of patients achieving 5 mg or 10 mg daily. During the study period uncontrolled hypertension (> 160/90) was recorded in 15% of patients, myocardial infarction or unstable angina 1.6%, heart failure 0.4%, new diabetes 0.6%. Only 9.8% of patients discontinued treatment with 5.9% attributed to treatment side-effects and 4% related to cough. The large majority of patients in a wide range of clinical practice settings with high cardiovascular risk can be treated with ramipril titrated to 10 mg daily with good tolerability.

Aged↗

PubMed1996

A nonbenzodiazepine partial agonist, S-(+)-DN-2327, has minimal physical dependence-producing liability, but shows cross-dependence on barbital in rats.

1. Physical dependence and cross-physical dependence on barbital of the benzodiazepine receptor partial agonist S-(+)-DN-2327 and the benzodiazepine receptor full agonist diazepam were compared in male Fischer 344 rats. 2. In the physical dependence study, rats were treated with S-(+)-DN-2327 (30, 100, 300 and 1000 mg/kg/day) or diazepam (30, 100 and 300 mg/kg/day) for 4 weeks by the drug admixed with food method. After stopping the treatment, the body weight and food consumption in the diazepam 100 and 300 mg/kg groups tended to decrease or decreased to values lower than those in the control group, whereas these parameters in the S-(+)-DN-2327 30, 100 and 300 mg/kg groups were comparable to the control group values. 3. In the cross-dependence study, rats were treated with increasing doses of barbital by admixing the drug with food for 4 weeks, after which the diet admixed with barbital was replaced by basal diet alone or admixed with S-(+)-DN-2327 or diazepam (target doses: 100 and 300 mg/kg/day for each compound). During the substitution period, the decreases in body weight and food consumption in both S-(+)-DN-2327 and both diazepam groups were suppressed compared with those in the basal diet group. 4. These results suggest that S-(+)-DN-2327 possesses minimal physical dependence-producing liability, but shows cross-dependence on barbital, as do benzodiazepine receptor full agonists.

Animals↗

PubMed2001

Dose-finding based on feasibility and toxicity in T-cell infusion trials.

A new modality for treatment of cancer involves the ex vivo growth of cancer-specific T-cells for subsequent infusion into the patient. The therapeutic aim is selective destruction of cancer cells by the activated infused cells. An important problem in the early phase of developing such a treatment is to determine a maximal tolerated dose (MTD) for use in a subsequent phase II clinical trial. Dose may be quantified by the number of cells infused per unit body weight, and determination of an MTD may be based on the probability of infusional toxicity as a function of dose. As in a phase I trial of a new chemotherapeutic agent, this may be done by treating successive cohorts of patients at different dose levels, with each new level chosen adaptively based on the toxicity data of the patients previously treated. Such a dose-finding strategy is inadequate in T-cell infusion trials because the number of cells grown ex vivo for a given patient may be insufficient for infusing the patient at the current targeted dose. To address this problem, we propose an algorithm for trial conduct that determines a feasible MTD based on the probabilities of both infusibility and toxicity as functions of dose. The method is illustrated by application to a dendritic cell activated lymphocyte infusion trial in the treatment of acute leukemia. A simulation study indicates that the proposed methodology is both safe and reliable.

Algorithms↗

PubMed2005

Dose heterogeneity in the target volume and intensity-modulated radiotherapy to escalate the dose in the treatment of non-small-cell lung cancer.

PURPOSE: To quantify the dose escalation achievable in the treatment of non-small-cell lung cancer (NSCLC) by allowing dose heterogeneity in the target volume or using intensity-modulated radiotherapy (IMRT), or both. METHODS AND MATERIALS: Computed tomography data and contours of 10 NSCLC patients with limited movements of the tumor and representing a broad spectrum of clinical cases were selected for this study. Four irradiation techniques were compared: two conformal (CRT) and two IMRT techniques, either prescribing a homogeneous dose in the planning target volume (PTV) (CRT(hom) and IMRT(hom)) or allowing dose heterogeneity (CRT(inhom) and IMRT(inhom)). The dose heterogeneity was allowed only toward high doses, i.e., the minimum dose in the target for CRT(inhom) and IMRT(inhom) could not be lower than for the corresponding homogeneous plan. The dose in the PTV was escalated (fraction size of 2.25 Gy) until either an organ at risk reached the maximum allowed dose or the mean PTV dose reached a maximum level set at 101.25 Gy. RESULTS: When small and convex tumors were irradiated, CRT(hom) could achieve the maximum dose of 101.25 Gy, whereas for bigger and/or concave PTVs the dose level achievable with CRT(hom) was significantly lower, in 1 case even below 60 Gy. The CRT(inhom) allowed on average a 6% dose escalation with respect to CRT(hom). The IMRT(hom) achieved in all except 1 case a mean PTV dose of at least 75 Gy. The gain in mean PTV dose of IMRT(hom) with respect to CRT(hom) ranged from 7.7 to 14.8 Gy and the IMRT(hom) plans were always more conformal than the corresponding CRT(hom) plans. The IMRT(inhom) provided an additional advantage over IMRT(hom) of at least 5 Gy. For all CRT plans the achievable dose was determined by the lung dose threshold, whereas for more than half of the IMRT plans the esophagus was the dose-limiting organ. The IMRT plans were deliverable with 10-12 segments per beam and did not produce an increase of lung volume irradiated at low doses (<20 Gy). CONCLUSIONS: The dose in NSCLC treatments can be escalated by loosening the constraints on maximum dose in the target volume or using IMRT, or both. For large and concave tumors, an average dose escalation of 6% and 17% was possible when dose heterogeneity and IMRT were applied alone. When they were combined, the average dose increase was as high as 35%. Intensity-modulated RT delivered in a static mode can produce homogeneous dose distributions in the target and does not lead to an increase of lung volume receiving (very) low doses, even down to 5 Gy.

Carcinoma, Non-Small-Cell Lung↗

PubMed2003

Fine-tuning risperidone dosage for acutely exacerbated schizophrenia: clinical determinants.

RATIONALE: Risperidone doses for acute schizophrenia were rather high in most recent studies. OBJECTIVES: We tested a hypothesis that fine-tuning risperidone dosage to relieve side effects still yields efficacy. Clinical factors influencing the dosing were also determined. METHODS: One hundred and forty-six schizophrenia inpatients with acute exacerbation entered a prospective, 6-week, repeated measures study. Risperidone doses were titrated to 6 mg/day (if tolerable) within 7 days, but were lowered thereafter if adverse reactions appeared. Efficacy and safety were measured biweekly. RESULTS: Forty-eight patients tolerated the 6-mg/day target dose well, while the other 98 received lower final doses (mean+/-SD=3.4+/-0.9 mg/day) to curtail adverse effects. At endpoint, 64.3% of the low-dose patients and 43.8% of the high-dose subjects responded to treatment [>/=20% reduction in the Positive and Negative Syndrome Scale (PANSS) total score] ( P=0.018). In detail, the low-dose individuals were significantly superior in percentage changes in the PANSS total and general-subscale scores at endpoint. The low-dose group also tended to improve more (albeit statistically insignificantly) in the PANSS positive and negative subscales and other efficacy measures. Compared to the patients with undifferentiated subtype, those with disorganized subtype received higher dosage by 0.90 mg/day, after controlling for other variables ( P=0.008). Paranoid subtype was similar to undifferentiated subtype in drug doses. Patients with longer illness duration also showed a trend to use higher dosage ( P=0.078). CONCLUSIONS: These findings suggest that dosage adjustment to diminish side effects does not compromise risperidone response and that disorganized patients and perhaps patients with longer illness duration are prone to receive larger doses.

Adult↗

PubMed2004

Consistency of the beneficial effect of metoprolol succinate extended release across a wide range dose of angiotensin-converting enzyme inhibitors and digitalis.

BACKGROUND: The effects of beta-blockade with different extent of angiotensin-converting enzyme inhibitors (ACEI) and digitalization are unknown. To assess the effect of metoprolol succinate controlled release/extended release (CR/XL) combined with high versus low doses of ACEI and digitalis, we analyzed data from The Metoprolol CR/XL Randomized Intervention Trial in Chronic Heart Failure (MERIT-HF) in which patients with heart failure and left ventricular ejection fraction < or =40% were randomized to metoprolol CR/XL versus placebo. METHODS AND RESULTS: Outcome was analyzed separately for those on a low dose (< or =median) of the ACEI or digitalis versus high dose (> median). The mean dose of ACEI in the high-dose group (n = 1457) was 3 times higher than that in the low-dose group (n = 2094). Mortality was reduced to a similar extent in the high- and low-dose ACEI subgroups (RR = .69 versus .64, respectively). Corresponding figures for combined mortality/all hospitalization and for mortality/hospitalization for heart failure were .85 versus .83, and .70 versus .68, respectively. Likewise, reduction in total mortality with metoprolol CR/XL was similar in patients receiving no digitalis (n = 1447; RR = .56), low dose (n = 1122; RR = .71), or high dose (n = 1421; RR = .71). CONCLUSION: This analysis of MERIT-HF demonstrates consistent and similar improvement in outcome of patients receiving metoprolol CR/XL when combined with either a high or low dose of an ACEI or digitalis, or no digitalis at all. Thus regardless of ACEI and digitalis dose and whether patients are treated with digitalis or not, it is very important to add a beta-blocker to the existing heart failure therapy. beta-blockers should not be withheld until target doses of ACEI have been achieved.

Adrenergic beta-Antagonists↗

PubMed2006

Continuous intensity map optimization (CIMO): a novel approach to leaf sequencing in step and shoot IMRT.

A new leaf-sequencing approach has been developed that is designed to reduce the number of required beam segments for step-and-shoot intensity modulated radiation therapy (IMRT). This approach to leaf sequencing is called continuous-intensity-map-optimization (CIMO). Using a simulated annealing algorithm, CIMO seeks to minimize differences between the optimized and sequenced intensity maps. Two distinguishing features of the CIMO algorithm are (1) CIMO does not require that each optimized intensity map be clustered into discrete levels and (2) CIMO is not rule-based but rather simultaneously optimizes both the aperture shapes and weights. To test the CIMO algorithm, ten IMRT patient cases were selected (four head-and-neck, two pancreas, two prostate, one brain, and one pelvis). For each case, the optimized intensity maps were extracted from the Pinnacle3 treatment planning system. The CIMO algorithm was applied, and the optimized aperture shapes and weights were loaded back into Pinnacle. A final dose calculation was performed using Pinnacle's convolution/superposition based dose calculation. On average, the CIMO algorithm provided a 54% reduction in the number of beam segments as compared with Pinnacle's leaf sequencer. The plans sequenced using the CIMO algorithm also provided improved target dose uniformity and a reduced discrepancy between the optimized and sequenced intensity maps. For ten clinical intensity maps, comparisons were performed between the CIMO algorithm and the power-of-two reduction algorithm of Xia and Verhey [Med. Phys. 25(8), 1424-1434 (1998)]. When the constraints of a Varian Millennium multileaf collimator were applied, the CIMO algorithm resulted in a 26% reduction in the number of segments. For an Elekta multileaf collimator, the CIMO algorithm resulted in a 67% reduction in the number of segments. An average leaf sequencing time of less than one minute per beam was observed.

Algorithms↗

PubMed2000

Analysis of dose distribution in gamma knife radiosurgery for multiple targets.

PURPOSE: The aim of this study is to evaluate the actual effect of irradiation for other targets in dose planning for the treatment of multiple metastases with Gamma Knife. METHODS AND MATERIALS: We analyzed dose distributions for 51 targets in 10 patients with metastatic brain tumors who underwent radiosurgery with Gamma Knife for the treatment of more than one target in one session. We made dose plans with every attempt to include as many targets as possible and calculate dose distributions separately for each dose matrix. We also calculated the composite dose distribution by including the effect of all shots used. We compared these noncomposite and composite dose distributions. RESULTS: The differences in the mean target dose between the noncomposite dose distribution and the composite one ranged from 0.0 to 4.5 Gy with a mean of 1.5 Gy and was more than 2 Gy in 12 (24%) targets. The difference tended to be larger when targets were small in volume and/or the number of targets was large. CONCLUSIONS: The effect of irradiation from the shots for other targets was not negligible in some cases. This difference of dose distribution should be considered in the analysis of clinical outcomes of cases with multiple targets treated in one session.

Brain Neoplasms↗

PubMed1997

Calculation of the dose distribution in water from 71Ge K-shell x-rays.

The dose distribution in water from 71Ge K-shell x-rays (Eave = 9.44 keV) was calculated for various source configurations using both analytic and EGS4 Monte Carlo calculations. The point source kernel and the buildup factor are presented. The buildup factor for a point source in water has been found to increase up to about 1.1 as radial distance approaches 1 cm. Comparison between 71Ge and 90Sr/Y shows a similarity between their relative dose distribution in water. The dose distribution from a disc source was calculated using the EGS4 code and compared with the results from analytic calculation. Excellent agreement was observed, confirming the validity of analytic calculations. The dose rate at 0.01 cm from a 71Ge disc source was calculated to be about 1.3 x 10(-5) Gy MBq-1 s-1. Based on the results from this study, 71Ge activity of the order of 3.7 x 10(10) Bq (approximately 1 Ci) might be necessary to obtain dose rates typical of 90Sr/Y ophthalmic applicators. The possibility of using 71Ge as a source of radioactive stents was also investigated. A 71Ge stent was modelled as a cylindrical shell source and the dose rates were determined by Monte Carlo calculations. Some calculated results are compared with published values for a 32P-coated stent. The dose rate at 0.01 cm from a 71Ge stent has been calculated to be about 6.5 x 10(-3) Gy MBq-1 h-1, which is much lower than the reported dose rate at the same distance from a 32P-coated stent. However, an initial source activity of the order of 3.7 x 10(7) Bq (approximately 1 mCi) would easily result in a typical target dose (approximately 24 Gy) needed for intravascular stent applications. In conclusion, 71Ge sources could be used as alternatives to beta sources and, unlike high-energy (approximately MeV) beta sources, may provide easily predictable dose distributions in heterogeneous media and low dose rates, which might be beneficial for some clinical applications.

Beta Particles↗

PubMed2002

Pharmacodynamic modeling of muscle relaxants: effect of design issues on results.

BACKGROUND: Pharmacodynamic studies of muscle relaxants use different dosing regimens (such as administration by bolus vs. infusion and doses that produce complete vs. incomplete paralysis). The authors used published data to evaluate the effect of modeling assumptions on pharmacodynamic estimates. METHODS: The authors used a pharmacokinetic-pharmacodynamic dataset in which patients received cisatracurium, 75 or 300 microg/kg (1.5 or 6 x ED95), to generate plasma concentration (Cp) and twitch depression (effect) curves. They then evaluated the impact of the following: assuming that Cp decreased monotonically versus increasing initially before decreasing monotonically; misrecording effect data by 6 s or less; and doses targeting incomplete versus complete paralysis. Parameters evaluated were the steady state Cp depressing twitch tension 50% (C50) and the rate constant for equilibration between plasma and effect site concentrations (k(e0)). RESULTS: With the large dose, increasing the time at which Cp peaked from 0.0 to 1.5 min decreased C50 and increased k(e0) markedly; with the small dose, changes in both were small. Misrecording the timing of effect had a larger impact with the large dose compared with the small dose. Doses smaller than ED50 or those producing prolonged, complete twitch depression yielded biased and variable estimates. CONCLUSION: The erroneous assumption that Cp decreases monotonically after bolus administration affects accuracy of pharmacodynamic estimates with doses producing rapid, complete twitch depression. Other errors (e.g., misrecording the time of drug administration) impact on pharmacodynamic estimates, particularly with large doses. The authors' findings suggest that investigators performing neuromuscular (and other) pharmacodynamic studies should carefully consider the impact of study design on their parameter estimates.

Artifacts↗

PubMed1984

Results of testing fifteen glycol ethers in a short-term in vivo reproductive toxicity assay.

Fifteen glycol ethers were investigated for their potential to cause adverse reproductive toxic effects using an in vivo mouse screening bioassay. Pregnant mice were orally dosed once per day on days 7 through 14 of gestation at concentrations causing 0 to 41% maternal mortality. Reproductive endpoints included pup survival in utero (percent of live litters/pregnant survivors), pup perinatal and postnatal survival (number of live pups per litter, number of dead pups per litter, and pup survival to 2.5 days of age), and pup body weight statistics (weight at birth and weight at 2.5 days of age). The study was conducted in two phases: a dose range-finding phase using nonpregnant female mice, and a definitive reproductive phase using time-mated mice. The range-finding phase sought to identify, for each chemical, the maternal LD10 as the target dose. However, based upon reproductive phase results, such an exact dose was impractical to achieve. Thus, a range from the LD5 to the LD20 was considered a sufficient challenge dose that would not affect results due to high mortality, i.e., greater than the LD20. Glycol ethers were assigned to groups having different priorities for further testing based upon whether a sufficient challenge dose was administered and the degree of effects recorded for each chemical.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2002

Epidermal powder immunization with a recombinant HIV gp120 targets Langerhans cells and induces enhanced immune responses.

The recombinant envelope gp120 (rgp120) of human immunodeficiency virus (HIV) is a weak immunogen when administered by intramuscular (IM) injection. In the present study, we report that epidermal powder immunization (EPI) elicits robust antibody responses to the rgp120. EPI of mice with a dose 0.2-5 microg of rgp120 protein elicited geometric mean antibody titers that were 18- to 240-fold higher than that elicited by IM injection using a 5.0 microg dose. Targeting antigen to and mobilization of Langerhans cells (LCs) by EPI may explain the enhanced immunogenicity of the rgp120. EPI with rgp120 using sugar and gold particles as carrier resulted in differential antigen entry into the LCs and differential IgG subclass antibody and cellular immune responses. EPI may serve as a useful tool to evaluate vaccine potential of the rgp120 protein.

AIDS Vaccines↗