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Results for “Targeted dosing”

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PubMed1998

Dose escalation with three-dimensional conformal radiation therapy affects the outcome in prostate cancer.

PURPOSE: Three-dimensional conformal radiation therapy (3D-CRT) is a technique designed to deliver prescribed radiation doses to localized tumors with high precision, while effectively excluding the surrounding normal tissues. It facilitates tumor dose escalation which should overcome the relative resistance of tumor clonogens to conventional radiation dose levels. The present study was undertaken to test this hypothesis in patients with clinically localized prostate cancer. METHODS AND MATERIALS: A total of 743 patients with clinically localized prostate cancer were treated with 3D-CRT. As part of a phase I study, the tumor target dose was increased from 64.8 to 81 Gy in increments of 5.4 Gy. Tumor response was evaluated by post-treatment decrease of serum prostate-specific antigen (PSA) to levels of < or = 1.0 ng/ml and by sextant prostate biopsies performed > or = 2.5 years after completion of 3D-CRT. PSA relapse-free survival was used to evaluate long-term outcome. The median follow-up was 3 years (range: 1-7.6 years). RESULTS: Induction of an initial clinical response was dose-dependent, with 90% of patients receiving 75.6 or 81.0 Gy achieving a PSA nadir < or = 1.0 ng compared with 76% and 56% for those treated with 70.2 Gy and 64.8 Gy, respectively (p < 0.001). The 5-year actuarial PSA relapse-free survival for patients with favorable prognostic indicators (stage T1-2, pretreatment PSA < or = 10.0 ng/ml and Gleason score < or = 6) was 85%, compared to 65% for those with intermediate prognosis (one of the prognostic indicators with a higher value) and 35% for the group with unfavorable prognosis (two or more indicators with higher values) (p < 0.001). PSA relapse-free survival was significantly improved in patients with intermediate and unfavorable prognosis receiving > or = 75.6 Gy (p < 0.05). A positive biopsy at > or = 2.5 years after 3D-CRT was observed in only 1/15 (7%) of patients receiving 81.0 Gy, compared with 12/25 (48%) after 75.6 Gy, 19/42 (45%) after 70.2 Gy, and 13/23 (57%) after 64.8 Gy (p < 0.05). CONCLUSIONS: The data provide evidence for a significant effect of dose escalation on the response of human prostate cancer to irradiation and defines new standards for curative radiotherapy in this disease.

Aged↗

PubMed2003

Treatment history and treatment dose are important determinants of sulfadoxine-pyrimethamine efficacy in children with uncomplicated malaria in Western Kenya.

This study retrospectively studied amendable determinants of sulfadoxine-pyrimethamine (SP) efficacy involving 2869 treatments among 1072 Kenyan children <5 years old who had uncomplicated malaria. The dose was based on age: one-quarter tablet was given to infants <1 year old, one-half tablet was given to 1-3-year-old children, and a full tablet was given to 4-year-old children. Only 23.5% received the internationally recommended target dose of 25/1.25 mg of SP per kg of body weight. SP intake in the previous 15-35 days (adjusted relative risk, 1.67; 95% confidence interval, 1.35-2.07) and low SP dose (<27.5/1.375 mg/kg) (adjusted relative risk, 1.58; 95% confidence interval, 1.17-2.13) explained 38% of parasitological treatment failures by day 7. Patients with recent SP intake are likely to have recrudescent infections and may need close follow-up if treated with SP or alternative treatment. Applying our weight-for-age data to 31 existing age-based SP dose recommendations predicted that 22 of them would result in underdosing of >25% of children <5 years. Many age-based dose recommendations need urgent revision, because SP is increasingly used as first-line treatment in sub-Saharan Africa.

Age Factors↗

PubMed2002

Low dose--high dose: what is the right dose? Pharmacokinetic modeling of etoposide.

PURPOSE: Some clinical studies on etoposide (Eto) have shown marked schedule dependency of the effect (starting at about 1 mg/l) and toxicity (over about 10 mg/l) whereas other studies have not confirmed these results. What are the conclusions we can draw from these inconsistent results when developing new low-dose (LD) and high-dose (HD) Eto schedules? METHODS: A pharmacokinetic model for Eto based on individual pharmacokinetic data was used to simulate different LD (450 mg/m(2)) and HD (1800 mg/m(2)) schedules. The duration of exposure and the AUC of relevant concentration ranges (>1 mg/l, 1-10 mg/l, >10 mg/l) as well as peak levels were calculated in relation to the standard low dose (150 mg/m(2) over 2 h daily for 3 days). RESULTS: The fourfold dose increase from the LD to the HD schedule was associated with a complementary increase in total AUC. However, variations in infusion time for the HD schedule were associated with large differences in AUC distribution and drug exposure with constant total AUC. Short infusions (0.5 h and 4 h) resulted in extreme peak levels (factors of 17.6+/-1.5 and 8.7+/-0.4 compared to the standard LD schedule) and an AUC >10 mg/l (factors of 17.5+/-4.9 and 17.2+/-4.8, and 83+/-2.4% and 82+/-2.4% of the corresponding total AUC), and the 96-h infusion yielded a long duration of exposure to concentrations >10 mg/l (factor 7.9+/-2.6), whereas continuous i.v. infusion over 55+/-11 days was associated with a multiple increase in the duration of exposure to "standard" drug concentrations (1 mg/l ). CONCLUSIONS: According to evidence against schedule dependency, only target dose and pharmacokinetic variability would be appropriate rationales for Eto dosing. However, arguing for schedule dependency, simulated pharmacokinetic profiles for new Eto schedules over a wide range support that Eto-containing regimens should be designed on the basis of clear pharmacokinetic hypotheses of target levels, exposure times and AUC distributions, to allow subsequent development of pharmacokinetic/pharmacodynamic modeling.

Antineoplastic Agents, Phytogenic↗

PubMedDate not supplied

Toxicological evaluation of an electrically heated cigarette. Part 4: Subchronic inhalation toxicology.

The biological activity of mainstream smoke from an electrically heated cigarette (EHC) with controlled combustion and from the University of Kentucky Reference Cigarette 1R4F was determined in Sprague Dawley rats exposed nose-only for 90 days, 6 h a day, 7 days per week. For an equivalent response comparison between the two cigarette types, two doses were chosen for the EHC where the anticipated results were in the dynamic range of the 1R4F dose-response curve (four concentrations) for most end points. The number of cigarettes smoked per m(3) of diluted smoke resulted in total particulate matter concentrations of 40 and 90 microg l (-1) for the EHC and 40-170 microg l (-1) for the 1R4F. Biomonitoring indicated achievement of target doses. Mainstream smoke yields were lower for the EHC, with the exception of formaldehyde. No smoke-related mortality, remarkable in-life observations or abnormal gross pathological findings were observed. Smoke- and dose-related clinical pathology and organ weight changes included: increases in segmented neutrophils, some liver parameters and lung and adrenal weight relative to body weight; and decreases in lymphocytes, glucose concentration and spleen weight. Smoke-related histopathological findings in the respiratory tract included epithelial cell hyperplasia, squamous metaplasia, atrophy and accumulation of pigmented alveolar macrophages; they were mostly dose-dependent, more pronounced in the upper than lower respiratory tract and completely or partially reversed by 6 weeks post-inhalation. Qualitatively, the biological effects seen for the EHC and the 1R4F were comparable and similar to those observed in other mainstream smoke inhalation studies. Quantitatively, the biological activity of the EHC mainstream smoke was, on average, 65% lower than that of the 1R4F mainstream smoke on an equal cigarette basis and equivalent activity on an equal TPM basis.

Administration, Inhalation↗

PubMed2004

Safety and pharmacokinetic evaluation of intravenous vaccinia immune globulin in healthy volunteers.

BACKGROUND: Vaccinia immune globulin (VIG) administered via the intramuscular route has historically been used for the treatment of complications of smallpox vaccination. Intravenous formulations of VIG are required to improve tolerability and pharmacokinetic profile. METHODS: We conducted 2 separate studies to evaluate the feasibility of administration of an intravenous formulation of antivaccinia immune globulin (VIGIV). The first study assessed the pharmacokinetics and safety of a newly manufactured lyophilized VIG product for intravenous administration (VIGIV-lyo). Seventy-eight healthy volunteers received an intravenous infusion of VIGIV-lyo at doses of 100 mg/kg, 200 mg/kg, or 500 mg/kg. In the second study, we evaluated the safety of a liquid product of VIGIV (VIGIV-liq) in 33 healthy volunteers receiving an intravenous infusion of 100 mg/kg VIGIV-liq. RESULTS: The geometric mean titer of VIG at the target dose (100 mg/kg) after intravenous administration is 2.5 times higher than the predicted geometric mean titer after intramuscular injection (P<.001). The pharmacokinetics of VIGIV-lyo are linear for doses from 100 mg/kg through 500 mg/kg. Administration of the 200-mg/kg and 500-mg/kg doses of VIGIV-lyo does not result in markedly higher adverse event rates. The adverse event rates observed with the liquid product are comparable to those seen with the lyophilized product. CONCLUSIONS: These 2 studies suggest that intravenous administration of VIG is well tolerated and results in a more favorable pharmacokinetic profile than does VIG administered intramuscularly.

Antibodies, Viral↗

PubMed1996

Pharmacokinetic considerations of regional administration and drug targeting: influence of site of input in target tissue and flux of binding protein.

Hunt et al. introduced the concept of the Drug Targeting Index (DTI) to quantify the gain associated with regional drug administration and targeting and showed that for the ideal case of all drug first reaching the target DTI = l + CLs/(QT(l-ET)) where CL, is the total clearance of drug from the body (including the target tissue). QT is the target blood flow and ET is the steady-state extraction ratio of the drug in the target. In the model they portrayed the tissue as a homogeneous organ. A more general pharmacokinetic model has been developed that takes into account the three anatomical spaces (vascular, interstitial, and intracellular) of the target organ or tissue and that, in addition to unbound drug permeating the vascular and cellular membranes, protein-bound drug can also flux between the vascular and interstitial spaces. Elimination of unbound drug can take place from the cellular and interstitial spaces. An important parameter influencing the DTI is shown to be the fraction of targeted dose that is eliminated there before it reaches the systemic circulation, fT. Equations have been developed showing the relationship between fT and ET and for DTI when drug is administered at the various sites within the tissue and under a variety of conditions. Only when drug is administered into the target arterial blood stream or when distribution of drug within the target tissue is perfusion rate-limited, does fT = ET and DTI = 1 + CLs/x (QT (I - ET)). Otherwise consideration needs to be given to the permeabilities of both the unbound and bound drug and site of target administration, interstitial or intracellular. Then fT is greater than ET and DTI is greater than that expected had perfusion-rate limited distribution prevailed. The maximum benefit in DTI is seen for a drug of low cellular permeability but high cellular intrinsic clearance administered intracellularly.

Drug Delivery Systems↗

PubMed2000

Anticholinergic differences among patients receiving standard clinical doses of olanzapine or clozapine.

This study evaluated anticholinergic effects among patients with schizophrenia, schizoaffective disorder, or bipolar I disorder who were receiving either olanzapine (N = 12) or clozapine (N = 12) at standard clinical doses in a naturalistic setting. Serum anticholinergic levels were determined in adult male and female subjects using a radioreceptor binding assay. The Udvalg for Kliniske Undersogelser Scale was used to evaluate anticholinergic side effects clinically, and the Mini-Mental State Examination provided a global cognitive measure. Patients had achieved target doses that were stable at the time at which blood samples were obtained, and no other concomitant medicine with known anticholinergic potential was allowed. Patients receiving olanzapine (average dose, 15 mg/day) had serum anticholinergic levels of 0.96 (+/-0.55) pmol/ atropine equivalents compared with levels of 5.47 (+/-3.33) pmol/atropine equivalents for those receiving clozapine (average dose, 444 mg/day) (p < 0.001). Rates of increased and decreased salivation were significantly more common among the clozapine- and olanzapine-treated patients, respectively, whereas constipation, urinary disturbances, and tachycardia/palpitations were significantly more common among clozapine-treated patients. Neither group showed any global cognitive deficits. Olanzapine-treated patients had serum anticholinergic levels that were less than one fifth those of the clozapine-treated patients. Furthermore, clinical evaluations confirmed that clozapine-treated patients experienced more frequent and severe anticholinergic side effects (except dry mouth). However, none of the patients in either group expressed any desire to discontinue these medications as a result of the anticholinergic side effects.

Adult↗

PubMed2004

Relationship between the generalized equivalent uniform dose formulation and the Poisson statistics-based tumor control probability model.

The generalized equivalent uniform dose (GEUD) model uses a power-law formalism, where the outcome is related to the dose via a power law. We herein investigate the mathematical compatibility between this GEUD model and the Poisson statistics based tumor control probability (TCP) model. The GEUD and TCP formulations are combined and subjected to a compatibility constraint equation. This compatibility constraint equates tumor control probability from the original heterogeneous target dose distribution to that from the homogeneous dose from the GEUD formalism. It is shown that this constraint equation possesses a unique, analytical closed-form solution which relates radiation dose to the tumor cell survival fraction. It is further demonstrated that, when there is no positive threshold or finite critical dose in the tumor response to radiation, this relationship is not bounded within the realistic cell survival limits of 0%-100%. Thus, the GEUD and TCP formalisms are, in general, mathematically inconsistent. However, when a threshold dose or finite critical dose exists in the tumor response to radiation, there is a unique mathematical solution for the tumor cell survival fraction that allows the GEUD and TCP formalisms to coexist, provided that all portions of the tumor are confined within certain specific dose ranges.

Algorithms↗

PubMed2001

Room shielding for intensity-modulated radiation therapy treatment facilities.

PURPOSE: The traditional assumptions used in room-shielding calculations are reassessed for intensity-modulated radiation therapy (IMRT). IMRT makes relatively inefficient use of monitor units (MUs) when compared to conventional radiation therapy, affecting the assumptions used in room-shielding calculations. For the same single-fraction tumor dose delivered, the total number of MUs for IMRT is much greater than for a conventional treatment. Therefore, the exposure contribution from the linear accelerator head leakage will be significantly greater than with conventional treatments. METHODS AND MATERIALS: We propose a shielding calculation model that decouples the concepts of workload, MUs, and target dose when determining primary and secondary barrier thicknesses. The workload for primary barrier calculations for conventional multileaf collimator (MLC) IMRT treatments is determined according to patient tumor doses. The same calculation for accelerator-based serial tomotherapy IMRT requires scaling by the average number of treatment slices. However, rotational therapy yields a small use factor that compensates for this increase. We further define a series of efficiency factors to account for the small field sizes employed in IMRT. For secondary barrier calculations, the patient-scattered radiation is assumed to be the same for all IMRT modalities as for conventional therapy. The accelerator head leakage contribution is proportional to the number of MUs. Knowledge of the average number of MUs per patient is required to estimate the head leakage contribution. We used a 6-MV linear accelerator photon beam to guide the development of this technique and to evaluate the adequacy of conventional barriers for IMRT. Average weekly IMRT workload estimates were made based on our experience with 180 serial tomotherapy patients and published data for both "step and shoot" and dynamic MLC delivered treatments. RESULTS: We found that conventional primary barriers are adequate for both dynamic MLC and serial tomotherapy IMRT. However, the excessive head leakage produced by these modalities requires an increase in secondary barrier shielding. CONCLUSION: When designing shielding for an IMRT facility, increases in accelerator head leakage must be taken into account for secondary shielding. Adequacy of secondary shielding will depend on the IMRT patient load. For conventional facilities that are being assessed for IMRT therapy, existing primary barriers will typically prove adequate.

Facility Design and Construction↗

PubMed1999

Do typical clinical doses of methylphenidate cause tics in children treated for attention-deficit hyperactivity disorder?

OBJECTIVE: To determine whether typical clinical doses of methylphenidate (MPH) cause tics or exacerbate preexisting mild to moderate tics. METHOD: Ninety-one children with attention-deficit hyperactivity disorder, with and without comorbid tics (excluding severe tics and Tourette's syndrome), were randomly assigned to receive MPH or a placebo in a 1-year prospective study. The target dose was titrated to balance behavior change and side effects. Parents and teachers were the observers. RESULTS: Crossover from the placebo to MPH was common because of poor behavioral response. One MPH-treated subject dropped out; the final MPH group had 72 subjects; the placebo group, 18. The average dose of MPH was 0.5 mg/kg twice daily. Clinically significant tics developed in 19.6% of the subjects without preexisting tics receiving MPH and in 16.7% of those receiving the placebo (Fisher exact test, p = .59, not significant; relative risk = 1.17, confidence interval = 0.31-4.40). Deterioration of tics was observed in 33% of subjects with preexisting tics receiving MPH and in 33% of those receiving the placebo (Fisher exact test, p = .70, not significant; relative risk = 1.0, confidence interval = 0.40-1.85). CONCLUSIONS: Doses of MPH based on the typical clinical titration procedure did not produce significantly more tics than the placebo in children with or without preexisting (mild to moderate) tics.

Attention Deficit Disorder with Hyperactivity↗

PubMed2002

The effect of voxel size on the accuracy of dose-volume histograms of prostate 125I seed implants.

Cumulative dose-volume histograms (DVH) are crucial in evaluating the quality of radioactive seed prostate implants. When calculating DVHs, the choice of voxel size is a compromise between computational speed (larger voxels) and accuracy (smaller voxels). We quantified the effect of voxel size on the accuracy of DVHs using an in-house computer program. The program was validated by comparison with a hand-calculated DVH for a single 0.4-U iodine-125 model 6711 seed. We used the program to find the voxel size required to obtain accurate DVHs of five iodine-125 prostate implant patients at our institution. One-millimeter cubes were sufficient to obtain DVHs that are accurate within 5% up to 200% of the prescription dose. For the five patient plans, we obtained good agreement with the VariSeed (version 6.7, Varian, USA) treatment planning software's DVH algorithm by using voxels with a sup-inf dimension equal to the spacing between successive transverse seed implant planes (5 mm). The volume that receives at least 200% of the target dose, V200, calculated by VariSeed was 30% to 43% larger than that calculated by our program with small voxels. The single-seed DVH calculated by VariSeed fell below the hand calculation by up to 50% at low doses (30 Gy), and above it by over 50% at high doses (>250 Gy).

Algorithms↗

PubMed1993

Complex mixtures of air pollutants: characterizing the cancer risk of polycyclic organic matter.

Complex mixtures of polycyclic organic matter (POM) are used to illustrate the scientific problems and issues associated with characterizing the comparative risk of related complex mixtures. The complexity of mixtures in which the active components are not well characterized present special challenges, which include identifying the critical components of mixtures, their sources, and the appropriate biomarker(s) of exposure and dose; developing the appropriate experimental models for dose-response assessment; species extrapolation; and developing a scientific basis for predicting from one mixture to another. Strategies for addressing these issues include bioassay-directed chemical characterization of bioactive components of complex mixtures, apportionment methods to determine the source of biological activity and risk, DNA adduct methods to determine tissue exposure and target dose of mixtures, and comparative approaches to determining the relative similarity, potency, and risk of complex mixtures. Epidemiological data are available for humans exposed to POM from coke ovens, coal roofing tar, coal smoke, aluminum smelters, and cigarette smoke. These emissions are characterized and compared to POM from automotive emissions (diesel and gasoline), woodstove emissions, residential oil furnace emissions, and ambient air particles. The tumor potency and estimated cancer risks for these POM mixtures ranges over nearly three orders of magnitude.

Air Pollutants↗

PubMed2005

Immunogenicity of recombinant protective antigen and efficacy against aerosol challenge with anthrax.

Immunization with a recombinant form of the protective antigen (rPA) from Bacillus anthracis has been carried out with rhesus macaques. Rhesus macaques immunized with 25 mug or more of B. subtilis-expressed rPA bound to alhydrogel had a significantly increased immunoglobulin G (IgG) response to rPA compared with macaques receiving the existing licensed vaccine from the United Kingdom (anthrax vaccine precipitated [AVP]), although the isotype profile was unchanged, with bias towards the IgG1 and IgG2 subclasses. Immune macaque sera from all immunized groups contained toxin-neutralizing antibody and recognized all the domains of PA. While the recognition of the N terminus of PA (domains 1 to 3) was predominant in macaques immunized with the existing vaccines (AVP and the U.S. vaccine anthrax vaccine adsorbed), macaques immunized with rPA recognized the N- and C-terminal domains of PA. Antiserum derived from immunized macaques protected macrophages in vitro against the cytotoxic effects of lethal toxin. Passive transfer of IgG purified from immune macaque serum into naive A/J mice conferred protection against challenge with B. anthracis in a dose-related manner. The protection conferred by passive transfer of 500 mug macaque IgG correlated significantly (P = 0.003; r = 0.4) with the titers of neutralizing antibody in donor macaques. Subsequently, a separate group of rhesus macaques immunized with 50 mug of Escherichia coli-derived rPA adsorbed to alhydrogel was fully protected against a target dose of 200 50% lethal doses of aerosolized B. anthracis. These data provide some preliminary evidence for the existence of immune correlates of protection against anthrax infection in rhesus macaques immunized with rPA.

Administration, Intranasal↗

PubMed2004

Lack of pharmacokinetic or pharmacodynamic interaction between memantine and donepezil.

BACKGROUND: Memantine, a low- to moderate-affinity, uncompetitive N-methyl-D-aspartate receptor antagonist, was approved in the US for treatment of moderate to severe Alzheimer's disease in October 2003. OBJECTIVE: To determine whether an in vivo pharmacokinetic interaction exists between memantine and the acetylcholinesterase (AChE) inhibitor donepezil. METHODS: In this open-label, multiple-dose study, 24 healthy subjects (aged 18-35 y) received oral administration of memantine 10 mg on day 1. Following a 14-day washout period, subjects were orally administered donepezil 5 mg once daily for 7 days on an outpatient basis. Beginning on day 22, the donepezil dosage was doubled for 22 days to the target dose of 10 mg once daily, with the last donepezil dose concomitantly administered with memantine 10 mg on day 43. Assessments included pharmacokinetic as well as safety parameters. In addition, AChE inhibition was measured in red blood cells by radiolabeled-enzyme assay following administration of donepezil alone and after a single memantine dose. RESULTS: Data from 19 subjects who completed the study indicated no significant pharmacokinetic interactions between a single dose of memantine and multiple doses of donepezil. Percent maximum inhibition of AChE activity (mean +/- SD) by donepezil was 77.8 +/- 7.3% and not significantly different upon coadministration of a single dose of memantine (81.1 +/- 5.7%). Two subjects withdrew due to adverse events while taking donepezil alone. Single memantine doses administered with multiple donepezil doses were well tolerated. CONCLUSIONS: The pharmacokinetic and pharmacodynamic data from this study indicated a lack of interaction between memantine and donepezil, suggesting that memantine and donepezil may be safely and effectively used in combination.

Acetylcholinesterase↗

PubMedDate not supplied

Serum prolactin in subjects occupationally exposed to manganese.

To evaluate whether or not occupational exposure to manganese (Mn) affects basal levels of serum prolactin (PRL), a cross-sectional study was carried out in 31 occupationally-exposed workers, aged 39.2 years (DS 7.9) exposed to manganese (Mn) dusts for 14.5 years (range: 5 to 29 years) in a ferroalloy producing plant. Thirty-four industrial workers not exposed to neurotoxic chemicals and of comparable age composed the control group. Airborne Mn concentrations in dusts of the furnace area ranged 210 to 980 micrograms/m3, which is below the current American Conference of Governmental Industrial Hygienists (ACGIH)-recommended threshold limit value-time weighted average (TLV-TWA) of 1 mg/m3. Manganese concentrations in blood Mn (MnB) and in urine (MnU) were significantly higher in Mn-exposed workers as compared to control workers. The Mn-exposed workers showed significantly higher serum prolactin (PRL) levels with the geometric mean (GM) being 9.77 ng/ml with a geometric standard deviation (GSD) of 1.69 as compared to controls (GM 4.65 ng/ml, GSD 1.78, p < 0.001). Serum PRL was negatively related to age and positively correlated with both MnB and MnU. Dose-effect relationships were still significant in partial correlation analysis after control for age. The prevalence of abnormally high PRL values was consistent with a dose-response relationship. The observed increase in serum PRL among Mn-exposed workers suggests an impairment of tonic inhibition by tubero-infundibular dopaminergic neurons. The correlation between PRL and both MnB and MnU in samples collected at least 48 h from the last exposure suggests that such indices provide an estimation of the target dose.

Adult↗

PubMed2002

Dehydroepiandrosterone supplementation and bone turnover in middle-aged to elderly men.

In the present placebo-controlled, double-blind study, we assessed the effect of dehydroepiandrosterone (DHEA) supplementation (90 mg orally/d) on bone turnover in 43 healthy men, 56-80 yr old. Placebo or steroid was given for 6 months, followed by a 1-month washout period and then a further 6 months of the opposite agent. Serum samples were collected at baseline 3, 6, 7, and 13 months and assayed for procollagen peptide, bone-specific alkaline phosphatase, and osteocalcin, all markers of bone formation. Measurements were also made of serum cortisol, DHEA/DHEA-S, E2 and free and total T. First void, fasting urine was collected at baseline, 6, 7, and 13 months and assessed for deoxypyridinoline, a marker of bone resorption. Mean serum DHEA and DHEA-S levels in treated men were increased approximately 3-fold ( approximately 2.2 ng/ml to approximately 6 ng/ml) and 4.5-fold ( approximately 1000 ng/ml to approximately 4500 ng/ml), respectively, after 6 months and returned to baseline after washout. Similarly, circulating E2 concentrations were also increased 1.4-fold (from approximately 16-23 pg/ml; P < 0.001), a finding not observed with any other measured hormone. Bone marker levels remained remarkably constant at each sampling interval; procollagen peptide at approximately 8.0 ng/ml; bone-specific alkaline phosphatase at approximately 21.0 U/liter; deoxypyridinoline at approximately 4.5 nmol/mmol Cr. Osteocalcin showed a transient reduction from approximately 10.2- 6.2 ng/ml, P < 0.005 to P < 0.001, at 3 months, but this decline was observed in both treated and controls. Stratifying the marker levels by age or baseline DHEA/DHEA-S levels did not affect the findings. We conclude that oral DHEA does not affect bone turnover in middle-aged to elderly men when used for a 6-month period at doses targeted to restore circulating levels of the steroid to that seen in young adults.

Aged↗

PubMed2003

Topiramate, carbamazepine and valproate monotherapy: double-blind comparison in newly diagnosed epilepsy.

OBJECTIVES: To compare topiramate (TPM) with investigator's choice of carbamazepine (CBZ) or valproate (VPA) for initial treatment in patients with newly diagnosed epilepsy. MATERIAL AND METHODS: In patients with epilepsy diagnosed within previous 3 months, investigators selected CBZ (600 mg/day) or VPA (1250 mg/day) as preferred therapy based on the patient's clinical presentation. Based on investigators' treatment choice, patients (n=613) were assigned to the CBZ or VPA treatment branch. Within each branch, patients were randomized to double-blind treatment with the traditional antiepileptic drugs (CBZ or VPA), TPM 100 mg/day, or TPM 200 mg/day. Patients continued double-blind treatment until exiting the study or until 6 months after last patient randomized. RESULTS: No statistically significant differences between fixed doses of TPM and CBZ or VPA were observed in efficacy measures: time to exit, time to first seizure, and the proportion of patients seizure-free during the last 6 months of treatment. TPM 100 mg/day was associated with the fewest discontinuations due to adverse events. CONCLUSION: In patients with newly diagnosed epilepsy, an initial target dose of TPM 100 mg/day is at least as effective as therapeutic doses of CBZ and VPA.

Administration, Oral↗

PubMed2002

Carvedilol therapy in pediatric patients with congestive heart failure: a study investigating clinical and pharmacokinetic parameters.

OBJECTIVE: Our purpose was to evaluate the clinical effect of carvedilol among pediatric patients with congestive heart failure (CHF) who did not respond to standard therapy and to assess the pharmacokinetics of carvedilol among these children. METHODS: In this prospective, open intervention trial with blinded interpretation of selected end points, patients with CHF who did not improve on standard therapy, including digoxin, angiotensin-converting enzyme inhibitors, and diuretics, were treated with oral carvedilol in a ramped dosing scheme. Clinical parameters (ejection fraction, fractional shortening, and modified Ross score) were assessed before initiation of treatment and monthly for 6 months. Pharmacokinetic profiles of carvedilol were determined over the first 12-hour period after the initial dose in study patients, and for comparison, in 9 healthy adult volunteers. RESULTS: Fifteen patients (aged 6 weeks to 19 years) were enrolled in the study, including 10 patients with dilated cardiomyopathy and 5 with CHF secondary to congenital heart disease. All 15 patients tolerated carvedilol for the duration of the trial, and all achieved maximum target dosing. After 6 months of carvedilol therapy, ejection fraction increased (36% vs 54%; P <.05) and modified Ross Score improved (5 +/- 2 vs 3 +/- 3; P <.05). Elimination half-life was about 50% shorter in pediatric CHF patients compared with healthy adult volunteers (2.9 vs 5.2 hours; P <.05). CONCLUSIONS: Pediatric patients with CHF not responding to standard therapy may benefit from oral carvedilol treatment. The observed increased elimination of carvedilol in children suggests that optimal dosing strategies need to be further defined among the pediatric population.

Administration, Oral↗