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Drug Doses (drug + dose)
Selected AbstractsEvaluation of the Photosensitizer Tookad® for Photodynamic Therapy on the Syrian Golden Hamster Cheek Pouch Model: Light Dose, Drug Dose and Drug,light Interval Effects,PHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 4 2003François Borle ABSTRACT We have evaluated the efficacy of the new photosensitizer (PS) Tookad® in photodynamic therapy (PDT) in vivo. This PS is a palladium-bacteriopheophorbide presenting absorption peaks at 762 and 538 nm. The light dose, drug dose and drug injection,light irradiation interval (DLI), ranging between 100 and 300 J/cm2, 1 and 5 mg/kg and from 10 to 240 min, respectively, were varied, and the response to PDT was analyzed by staging the macroscopic response and by the histological examination of the sections of the irradiated cheek pouch. The level of PDT response, macroscopically and histologically, shows a strong dependence on the DLI, light dose and drug dose at the applied conditions in the normal hamster cheek pouch. A decay of the tissular response with increasing DLI is observed corresponding to a time of half-maximum response ranging from 10 to 120 min, depending on drug dose and light dose. The tissues affected at the lowest doses are predominantly the vascularized diffuse connective tissue situated between the inner and outer striated muscle (SM) layers as well as these muscle layers themselves. The highest response at the shortest DLI and the absence of a measurable response at DLI longer than 240 min at 300 J/cm2 and drug dose of 5 mg/kg are characteristics of a predominantly vascular effect of this PS. This observation suggests that Tookad® could be effective in PDT of vascularized lesions or pathologies associated with the proliferation of neovessels. [source] The Hill equation: a review of its capabilities in pharmacological modellingFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 6 2008Sylvain Goutelle Abstract The Hill equation was first introduced by A.V. Hill to describe the equilibrium relationship between oxygen tension and the saturation of haemoglobin. In pharmacology, the Hill equation has been extensively used to analyse quantitative drug,receptor relationships. Many pharmacokinetic,pharmacodynamic models have used the Hill equation to describe nonlinear drug dose,response relationships. Although the Hill equation is widely used, its many properties are not all well known. This article aims at reviewing the various properties of the Hill equation. The descriptive aspects of the Hill equation, in particular mathematical and graphical properties, are examined, and related to Hill's original work. The mechanistic aspect of the Hill equation, involving a strong connection with the Guldberg and Waage law of mass action, is also described. Finally, a probabilistic view of the Hill equation is examined. Here, we provide some new calculation results, such as Fisher information and Shannon entropy, and we introduce multivariate probabilistic Hill equations. The main features and potential applications of this probabilistic approach are also discussed. Thus, within the same formalism, the Hill equation has many different properties which can be of great interest for those interested in mathematical modelling in pharmacology and biosciences. [source] Medication accuracy and general practitioner referral lettersINTERNAL MEDICINE JOURNAL, Issue 2 2006S. L. Carney Abstract Prescriber medication communication is a Quality Use of Medicines barrier. Medication information in General Practice (GP) referral letters to a physician was evaluated. Accuracy of medications taken and drug dose was respectively 63% and 84%, an overall accuracy rate of 58%. Complementary/over-the-counter medication documentation occurred in 26% of the letters. To avoid medical mismanagement, physicians must validate all GP medication lists regardless of their apparent comprehensiveness. [source] Quetiapine indication shift in the elderly: diagnosis and dosage in 208 psychogeriatric patients from 2000 to 2006INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY, Issue 5 2007Lorenz Hilwerling Abstract Rationale Quetiapine was approved in Germany as an atypical antipsychotic for treatment of schizophrenia in 2000, followed by the approval as an antipsychotic for treatment of bipolar mania in 2003. The approval of quetiapine for treatment of bipolar depression is expected. We hypothesized that the psychogeriatric prescription pattern for quetiapine shifts from the psychotic to the affective spectrum. Methods Retrospectively we screened discharge reports of all geriatric inpatients of the psychiatric department of the Ruhr-University of Bochum in the period from January 2001 until March 2006 and identified 208 individual patients aged over 60 years, who had received quetiapine as final medication. Age, gender, daily drug dose, year of treatment and diagnosis (according to ICD-10) were recorded and analyzed. Results Over the six-year time span, the proportion of affective disorders (F3) as indication for quetiapine in the elderly increased, whereas the proportion of dementia (F0) as indication for quetiapine decreased significantly. The proportion of schizophrenic disorders (F2) treated with quetiapine did not change significantly. Discussion Since the decision of the German Federal Court in 2002 ,off label' use goes to the expenses of the prescriber. So the decrease of quetiapine in dementia is probably due to its ,off label' status in dementia. The psychogeriatric indication shift for quetiapine towards affective disorders could be the consequence of good clinical experiences with the drug and growing evidence for its antidepressant effect. Conclusion In addition to controlled pharmacological trials prospective clinical research is needed to evaluate the prescription attitudes of clinicians. Copyright © 2006 John Wiley & Sons, Ltd. [source] Volume of distribution at steady state for a linear pharmacokinetic system with peripheral eliminationJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 6 2004Leonid M. Berezhkovskiy Abstract The problem of finding the steady-state volume of distribution Vss for a linear pharmacokinetic system with peripheral drug elimination is considered. A commonly used equation Vss,=,(D/AUC)*MRT is applicable only for the systems with central (plasma) drug elimination. The following equation, Vss,=,(D/AUC)*MRTint, was obtained, where AUC is the commonly calculated area under the time curve of the total drug concentration in plasma after intravenous (iv) administration of bolus drug dose, D, and MRTint is the intrinsic mean residence time, which is the average time the drug spends in the body (system) after entering the systemic circulation (plasma). The value of MRTint cannot be found from a drug plasma concentration profile after an iv bolus drug input if a peripheral drug exit occurs. The obtained equation does not contain the assumption of an immediate equilibrium of protein and tissue binding in plasma and organs, and thus incorporates the rates of all possible reactions. If drug exits the system only through central compartment (plasma) and there is an instant equilibrium between bound and unbound drug fractions in plasma, then MRTint becomes equal to MRT,=,AUMC/AUC, which is calculated using the time course of the total drug concentration in plasma after an iv bolus injection. Thus, the obtained equation coincides with the traditional one, Vss,=,(D/AUC)*MRT, if the assumptions for validity of this equation are met. Experimental methods for determining the steady-state volume of distribution and MRTint, as well as the problem of determining whether peripheral drug elimination occurs, are considered. The equation for calculation of the tissue,plasma partition coefficient with the account of peripheral elimination is obtained. The difference between traditionally calculated Vss,=,(D/AUC)*MRT and the true value given by (D/AUC)*MRTint is discussed. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:1628,1640, 2004 [source] Development of a robust once-a-day glipizide matrix systemJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 6 2007Shahla Jamzad The robustness of a new hydroxypropylmethylcellulose (HPMC) based modified release glipizide (10 mg) formulation was studied. The tablet formulations were prepared by dry blending the ingredients and direct compression, incorporating a range of release modifying agents up to ± 20% w/w relative to an optimized formulation. The dissolution was assessed in 900 mL pH 6.8 buffer at 75 rev min,1 paddle speed. Calculated difference and similarity factors (f1 and f2) and results of analysis of variance suggest that the overall release profiles were similar. Compositional changes up to ± 20% w/w and a reduction of drug dose to half did not change the general release pattern of this low dose/pH-dependent drug in a significant way. It is concluded that the drug release from the developed matrix systems is highly dependent on the kinetics of hydration and erosion, and that the proposed compositional changes within ± 20% w/w did not alter this relationship. The particulate systems used were characterized by determining the Carr index, Hausner ratio and the rheological properties using a texture analyser. Results indicate that the release is reproducible and the system has potential for successful scale-up operation, while complying with recommended Food and Drug Administration guidelines "Scale Up and Post Approval Changes". [source] Intrathecal inflammatory masses: is the yearly opioid dose increase an early indicator?NEUROMODULATION, Issue 2 2010Rui V. Duarte BSc Objectives:, The objective of this study is to investigate the association between intrathecal drug, flow rate, drug concentration, and drug dose with the formation of intrathecal inflammatory masses. Methods:, A retrospective longitudinal study of 56 consecutive patients receiving long-term intrathecal analgesic administration was undertaken through screening of medical records. Data regarding drug flow rate, dose per day, and concentration of drugs administered were recorded for morphine, diamorphine, bupivicaine, clonidine and baclofen and averages computed. Results:, The average follow-up time post-implant was 91 ± 55 months (range: 9,209). Four of the 56 patients were diagnosed with intrathecal granuloma indicating a rate of 7%, the equivalent to 0.009 events per patient year. Twenty-one of the patients had received morphine either alone or combined; 22 had received diamorphine either alone or mixed; and 13 crossed over from morphine to diamorphine or the inverse. None of the patients with granuloma crossed over before diagnosis. A significant correlation was found between opioid dose (r= 0.275, p < 0.05), yearly increase of the opioid dose (r= 0.433, p < 0.05), and granuloma formation. Clonidine appeared to have a protective effect for the non-granuloma patients. No association was found with flow rate (r= 0.056) or opioid concentration (r= 0.214). Conclusion:, This is the first detailed study showing an association of diamorphine with granulomas. This study supports the previous finding of intrathecal opioid dose being a risk factor for intrathecal granulomas and clonidine being protective. In addition we have found that the yearly increase in opioid dose is a risk factor for granulomas and could serve as an indicator for closer surveillance. [source] Evaluation of the Photosensitizer Tookad® for Photodynamic Therapy on the Syrian Golden Hamster Cheek Pouch Model: Light Dose, Drug Dose and Drug,light Interval Effects,PHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 4 2003François Borle ABSTRACT We have evaluated the efficacy of the new photosensitizer (PS) Tookad® in photodynamic therapy (PDT) in vivo. This PS is a palladium-bacteriopheophorbide presenting absorption peaks at 762 and 538 nm. The light dose, drug dose and drug injection,light irradiation interval (DLI), ranging between 100 and 300 J/cm2, 1 and 5 mg/kg and from 10 to 240 min, respectively, were varied, and the response to PDT was analyzed by staging the macroscopic response and by the histological examination of the sections of the irradiated cheek pouch. The level of PDT response, macroscopically and histologically, shows a strong dependence on the DLI, light dose and drug dose at the applied conditions in the normal hamster cheek pouch. A decay of the tissular response with increasing DLI is observed corresponding to a time of half-maximum response ranging from 10 to 120 min, depending on drug dose and light dose. The tissues affected at the lowest doses are predominantly the vascularized diffuse connective tissue situated between the inner and outer striated muscle (SM) layers as well as these muscle layers themselves. The highest response at the shortest DLI and the absence of a measurable response at DLI longer than 240 min at 300 J/cm2 and drug dose of 5 mg/kg are characteristics of a predominantly vascular effect of this PS. This observation suggests that Tookad® could be effective in PDT of vascularized lesions or pathologies associated with the proliferation of neovessels. [source] The evaluation of the radioprotective effect of chyavanaprasha (an ayurvedic rasayana drug) in mice exposed to lethal dose of , -radiation: a preliminary studyPHYTOTHERAPY RESEARCH, Issue 1 2004Ganesh Chandra Jagetia Abstract The effect of various doses of 50% ethanolic extract of chyavanaprasha (an Ayurvedic rejuvenating herbal preparation) was studied on the survival of mice exposed to 10 Gy of , -radiation. Treatment with chyavanaprasha, consecutively for ,ve days before irradiation, delayed symptoms of radiation sickness and onset of mortality when compared with the non-drug treated irradiated controls. All doses of chyavanaprasha provided a signi,cant protection against gastrointestinal (GI) death (death of animals within 10 days after exposure to radiation), however, highest protection against GI death was observed for 15 mg/kg chyavanaprasha. Chyavanaprasha also provided a signi,cant protection against the bone marrow death after 10 to 40 mg/kg. However, the best protection was seen for 15 mg/kg, where the highest number of survivors was observed at the end of 30 days post-irradiation. The drug was non-toxic up to a dose of 6 g/kg b. wt., the highest drug dose that could be tested. Our study demonstrates that chyavanaprasha can provide good radioprotection at a very low non-toxic dose. Copyright © 2004 John Wiley & Sons, Ltd. [source] ORIGINAL ARTICLE: Can sugammadex save a patient in a simulated ,cannot intubate, cannot ventilate' situation?ANAESTHESIA, Issue 9 2010M. M. A. Bisschops Summary Recent studies have shown that the use of high dose rocuronium followed by sugammadex provides a faster time to recovery from neuromuscular blockade following rapid sequence induction than suxamethonium. In a manikin-based ,cannot intubate, cannot ventilate' simulation, we studied the total time taken for anaesthetic teams to prepare and administer sugammadex from the time of their initial decision to use the drug. The mean (SD) total time to administration of sugammadex was 6.7 (1.5) min, following which a further 2.2 min (giving a total 8.9 min) should be allowed to achieve a train-of-four ratio of 0.9. Four (22%) teams gave the correct dose, 10 (56%) teams gave a dose that was lower than recommended, four (22%) teams gave a dose that was higher than recommended, six (33%) teams administered sugammadex in a single dose, and 12 (67%) teams gave multiple doses. Our simulation highlights that sugammadex might not have saved this patient in a ,cannot intubate, cannot ventilate' situation, and that difficulties and delays were encountered when identifying, preparing and administering the correct drug dose. [source] Adenosine A1 Antagonism Attenuates Atropine-resistant Hypoxic Bradycardia in RatsACADEMIC EMERGENCY MEDICINE, Issue 9 2003Justin L. Kaplan MD Abstract Objectives: To test the following hypotheses: Hypoxia induces bradycardia and hemodynamic compromise that are resistant to atropine but responsive to selective antagonism of the adenosine A1 receptor (A1AdoR). The mechanism for such attenuation is independent of the vagus nerve. Methods: Ten minutes after sham or actual bilateral cervical vagotomy, paralyzed ventilated rats were made hypoxic (5% fractional inspired oxygen, continued until death). Five minutes after beginning hypoxia, intravenous treatment with BG-9719, a selective A1AdoR antagonist (0.1 mg/kg); atropine (0.1 mg/kg); BG-9719 vehicle; or saline was initiated. These drug doses were based on pilot studies. Of the eight treatment groups (eight possible combinations of vagotomy status and drug/vehicle treatment), n= 8 in all except nonvagotomized, vehicle-treated rats (where n= 7). Results: Heart rate and left ventricular contractility decreased rapidly with hypoxia. Atropine had minimal effects in prolonging survival (from mean ± SEM of 15.5 ± 2.1 minutes to 20.2 ± 2.5 minutes, p = 0.94) and attenuating posthypoxic decreases in heart rate (p = 0.89) and contractility (p = 0.83) compared with saline. BG-9719 prolonged survival, however, from 14.4 ± 1.9 minutes (with vehicle treatment) to 37.2 ± 6.8 minutes (p < 0.001). Survival, heart rate, and contractility were preserved with BG-9719 compared with atropine and vehicle (p < 0.05, all comparisons). Vagotomy prevented the effects of BG-9719 on survival prolongation (p = 0.003), heart rate (p = 0.01), and contractility (p < 0.001) but did not affect those outcomes in saline-treated rats. Conclusions: Survival, heart rate, and contractility were better preserved with BG-9719 than atropine. A1AdoR selective antagonism, possibly because of its multiple mechanisms for attenuating hypoxic cardiac insufficiency, resulted in better hemodynamic and clinical outcomes. That attenuation seems to have a component of vagal mediation. [source] Have newer cardiovascular drugs reduced hospitalization?HEALTH ECONOMICS, Issue 5 2009Evidence from longitudinal country-level data on 20 OECD countries Abstract This study examines the effect of changes in the vintage distribution of cardiovascular system drugs on hospitalization and mortality due to cardiovascular disease using longitudinal country-level data. The vintage of a drug is the first year in which it was marketed anywhere in the world. We use annual data on the utilization of over 1100 cardiovascular drugs (active ingredients) in 20 OECD countries during the period 1995,2003. Countries with larger increases in the share of cardiovascular drug doses that contained post-1995 ingredients had smaller increases in the cardiovascular disease hospital discharge rate, controlling for the quantity of cardiovascular medications consumed per person, the use of other medical innovations (computed tomography scanners and magnetic resonance imaging units), potential risk factors (average consumption of calories, tobacco, and alcohol), and demographic variables (population size and age structure, income, and educational attainment). The estimates also indicate that the use of newer cardiovascular drugs has reduced the average length of stay and the age-adjusted cardiovascular mortality rate, but not the number of potential years of life lost due to cardiovascular disease before age 70 per 100,000 population. The estimates indicate that if drug vintage had not increased during 1995,2004, hospitalization and mortality would have been higher in 2004. We estimate that per capita expenditure on cardiovascular hospital stays would have been 70% ($89) higher in 2004 had drug vintage not increased during 1995,2004. Per capita expenditure on cardiovascular drugs would have been lower in 2004 had drug vintage not increased during 1995,2004. However, our estimate of the increase in expenditure on cardiovascular hospital stays is about 3.7 times as large as our estimate of the reduction in per capita expenditure for cardiovascular drugs that would have occurred ($24). Copyright © 2008 John Wiley & Sons, Ltd. [source] Determinants of relapse after a short (12 weeks) course of antiviral therapy and re-treatment efficacy of a prolonged course in patients with chronic hepatitis C virus genotype 2 or 3 infection,HEPATOLOGY, Issue 2 2009Alessandra Mangia In hepatitis C virus (HCV) genotypes 2 and 3 patients, the high rate of relapse after 12 to 16 weeks of antiviral therapy is the main concern for shortening treatment duration. This study was undertaken to delineate predictors of relapse after short treatment in patients with undetectable HCV RNA at treatment week 4 (RVR), and to report in RVR patients with relapse the sustained virological response (SVR) after a second 24-week course of therapy. RVR patients received pegylated interferon (Peg-IFN) alfa-2b (1.5 ,g/kg) and ribavirin (1000-1200 mg/day) for 12 weeks; those who relapsed were re-treated with the same drug doses but for the extended standard duration of 24 weeks. Logistic regression analysis was applied to delineate predictors of relapse by using age, sex, route of transmission, body mass index (BMI), serum alanine aminotransferase (ALT), HCV genotypes, serum HCV RNA levels, and platelet counts as covariates. Of 718 patients with genotypes 2 and 3 who were started on therapy, 496 (69.1%) had undetectable HCV RNA at week 4. Of them, 409 patients (82.5%, CI 79.1-85.8) attained SVR, and 67 (14.1%, CI 10.4-16.5) relapsed. At regression analysis, only platelet count less than 140,000 mm3 [odds ratio, 2.51; confidence interval (CI), 1.49-4.20] and BMI 30 or higher (odds ratio, 1.7; CI, 1.03-2.70) were independently associated with relapse. Forty-three of 67 patients with relapse agreed to be re-treated, and an SVR was achieved in 30 (70.0%) of them. Conclusion: We recommend 12 weeks course of therapy for patients with undetectable HCV RNA at treatment week 4, providing they present with no advanced fibrosis and low BMI. (HEPATOLOGY 2008.) [source] A clinical prospective comparison of anesthetics sensitivity and hemodynamic effect among patients with or without obstructive jaundiceACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 7 2010L.-Q. YANG Background: To compare isoflurane anesthesia in patients with or without hyperbilirubinemia undergoing hepatobiliary surgery. Methods: Forty-two patients with obstructive jaundice and 40 control patients with normal liver function scheduled for hepatobiliary surgery under isoflurane anesthesia were studied. Anesthesia was induced with propofol (1.5,2 mg/kg) and remifentanil (2 ,g/kg). After tracheal intubation, anesthesia was titrated using isoflurane in oxygen-enriched air, adjusted to maintain a bispectral index (BIS) value of 46,54. Ephedrine, atropine and remifentanil were used to maintain hemodynamic parameters within 30% of the baseline. The mean arterial blood pressure (MAP), heart rate (HR), drug doses and the time taken to recover from anesthesia were recorded. Results: Demographic data, duration and BIS values were similar in both groups. Anesthesia induction and maintenance were associated with more hemodynamic instability in the patients with jaundice and they received more ephedrine and atropine and less remifentanil and isoflurane (51.1±24.2 vs. 84.6±20.3 mg/min; P for all <0.05) than control patients. Despite less anesthetic use, the time to recovery and extubation was significantly longer than that in control. Conclusion: Patients with obstructive jaundice have an increased sensitivity to isoflurane, more hypotension and bradycardia during anesthesia induction and maintenance and a prolonged recovery time compared with controls. [source] Stopping antipsychotic drug therapy in demented nursing home patients: a randomized, placebo-controlled study,,The Bergen District Nursing Home Study (BEDNURS)INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY, Issue 9 2008Sabine Ruths Abstract Background Despite modest efficacy, unpredictable individual utility, and a high rate of adverse effects, behavioural and psychological symptoms of dementia (BPSD) are common determinants for antipsychotic drug therapy in nursing home patients. Aims To explore the impact on BPSD of stopping long-term antipsychotic treatment in nursing home patients with dementia. Methods Fifty-five patients (43 women; mean age 84.1) taking haloperidol, risperidone, or olanzapine for BPSD were randomly assigned to cessation (intervention group, n,=,27) or continued treatment with antipsychotic drugs (reference group, n,=,28) for 4 consecutive weeks. The Neuropsychiatric Inventory (NPI) Questionnaire was used to examine changes in behavioural and psychological symptoms. Results By study completion, 23 of the 27 intervention group patients were still off antipsychotics. Symptom scores (NPI) remained stable or even improved in 42 patients (intervention group, 18 out of 27; reference group, 24 out of 28; p,=,0.18). As compared to patients with stable or improved symptom scores, patients with behavioural deterioration after antipsychotic cessation used higher daily drug doses at baseline (p,=,0.42). Conclusion A large share of elderly nursing home patients on long-term treatment with antipsychotics for BPSD, do well without this treatment. Standardized symptom evaluations and drug cessation attempts should therefore be undertaken at regular intervals. Copyright © 2008 John Wiley & Sons, Ltd. [source] A Prospective Case Series of Pediatric Procedural Sedation and Analgesia in the Emergency Department Using Single-syringe Ketamine,Propofol Combination (Ketofol)ACADEMIC EMERGENCY MEDICINE, Issue 2 2010Gary Andolfatto MD Abstract Objectives:, This study evaluated the effectiveness, recovery time, and adverse event profile of intravenous (IV) ketofol (mixed 1:1 ketamine,propofol) for emergency department (ED) procedural sedation and analgesia (PSA) in children. Methods:, Prospective data were collected on all PSA events in a trauma-receiving, community teaching hospital over a 3.5-year period, from which data on all patients under 21 years of age were studied. Patients receiving a single-syringe 1:1 mixture of 10 mg/mL ketamine and 10 mg/mL propofol (ketofol) were analyzed. Patients received ketofol in titrated aliquots at the discretion of the treating physician. Effectiveness, recovery time, caregiver and patient satisfaction, drug doses, physiologic data, and adverse events were recorded. Results:, Ketofol PSA was performed in 219 patients with a median age of 13 years (range = 1 to 20 years; interquartile range [IQR] = 8 to 16 years) for primarily orthopedic procedures. The median dose of medication administered was 0.8 mg/kg each of ketamine and propofol (range = 0.2 to 3.0 mg/kg; IQR = 0.7 to 1.0 mg/kg). Sedation was effective in all patients. Three patients (1.4%; 95% confidence interval [CI] = 0.0% to 3.0%) had airway events requiring intervention, of which one (0.4%; 95% CI = 0.0% to 1.2%) required positive pressure ventilation. Two patients (0.9%; 95% CI = 0.0% to 2.2%) had unpleasant emergence requiring treatment. All other adverse events were minor. Median recovery time was 14 minutes (range = 3 to 41 minutes; IQR = 11 to 18 minutes). Median staff satisfaction was 10 on a 1-to-10 scale. Conclusions:, Pediatric PSA using ketofol is highly effective. Recovery times were short; adverse events were few; and patients, caregivers, and staff were highly satisfied. ACADEMIC EMERGENCY MEDICINE 2010; 17:194,201 © 2010 by the Society for Academic Emergency Medicine [source] Population pharmacokinetics of isoniazid in the treatment of Mycobacterium tuberculosis among Asian and African elephants (Elephas maximus and Loxodonta africana)JOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 1 2005J. N. MASLOW We recently described the clinical presentation and treatment of 18 elephants from six herds infected with TB. Treatment protocols and methods varied between herds to include both oral and rectal dosing using multiple drug doses and formulations. In this paper we present information regarding the pharmacokinetics (PK) of isoniazid (INH) in elephants and provide suggestions regarding initial treatment regimens. Forty-one elephants received INH daily by either oral or rectal administration with different formulations. Population PK analysis was performed using Non-linear Mixed Effect Modeling (NONMEM). Results of oral administration indicated that compared with premixed INH solution, the drug exposure was highest with a suspension prepared freshly with INH powder. When INH was concomitantly given as an admixture over food, Tmax was delayed and variability in drug absorption was significantly increased. Compared with oral administration, similar drug exposures were found when INH was dosed rectally. The data generated suggest that a starting dose of 7.5 mg/kg of INH is appropriate for initial TB treatment in elephants when premixed solution is administered directly into the oropharynx or rectal vault and 4 mg/kg are when INH is administered following immediate suspension from powdered form. [source] Optimization of treatment parameters for Foscan®-PDT of basal cell carcinomasLASERS IN SURGERY AND MEDICINE, Issue 5 2008Christian S. Betz MD Abstract Background and Objective Basal cell carcinomas (BCCs) are the most common form of skin cancers with high and increasing incidence rates. Photodynamic therapy (PDT) with mTHPC (Foscan®) has shown to be a promising treatment alternative with good cosmetic results. The current study was aimed to determine optimal treatment parameters for this indication. Study Design/Materials and Methods mTHPC-PDT was performed in 117 patients with a total of 460 BCCs with diagnosis confirmed by scratch cytology. Treatment parameters were altered as follows: Foscan® dose 0.03,0.15 mg/kg, drug-light interval (DLI) 1,96 hours, total energy density 20,120 J/cm2. Outcomes were assessed 8 weeks post-PDT following WHO guidelines. Results The overall rate of complete remissions (CR) was 96.7% and the cosmetic outcome was very good. In the largest subgroup (n,=,80) where low-dose Foscan® was applied (0.05 mg/kg mTHPC; 48 hours DLI; 50 J/cm2 total energy density), a CR rate of 100% with a high and narrow 95% Confidence Interval of 0.955,1.000 was achieved. Smaller variations of the treatment parameters (i.e., reducing the photosensitizer dose to 0.04 mg/kg or shortening the DLI to 24 hours) yielded similarly good results. Side effects were encountered in 52 out of 133 PDT sessions. They were more common in patients who had received high drug doses (0.06,0.15 mg/kg) and comprised mostly pain and phototoxic reactions. Three patients developed severe sunburns with subsequent scarring at the injection site following bright sunlight exposure 15,19 days after photosensitizer administration. Conclusions The presented data suggest that mTHPC-PDT with the treatment parameters mentioned above seems to be an effective treatment option for BCCs. If sensibly applied, it is well tolerated and provides mostly excellent cosmetic results. Long-term results are yet to be evaluated. Lesers Surg. Med. 40:300,311, 2008. © 2008 Wiley-Liss, Inc. [source] Intrathecal Ziconotide for Neuropathic Pain: A ReviewPAIN PRACTICE, Issue 5 2009Richard L. Rauck MD Abstract Neuropathic pain is a considerable burden that affects activities of daily living. The management of neuropathic pain can be challenging because of multiple etiologies and complex manifestations. Ziconotide is a nonopioid intrathecal (IT) analgesic option for patients with neuropathic pain refractory to conventional treatments. The objective of this article is to review the published literature on ziconotide for the treatment of neuropathic pain. Relevant publications were identified through searches of all years of 6 databases, which included PubMed, EMBASE, and CINAHL. Search terms used were ziconotide, SNX-111, MVIIA, Prialt, and neuropathic pain. Publications were included if ziconotide was intrathecally administered (either alone or in combination with other IT agents) to treat neuropathic pain of any etiology and if pain assessment was an outcome measure. Data extracted included study design, IT drug doses, pain outcome measures, and adverse events (AEs). Twenty-eight articles met the inclusion criteria: 5 were preclinical studies and 23 were clinical studies. In the preclinical studies, ziconotide demonstrated antiallodynic effects on neuropathic pain. Data from double-blind, placebo-controlled (DBPC) trials indicated that patients with neuropathic pain reported a mean percent improvement in pain score with ziconotide monotherapy that ranged from 15.7% to 31.6%. A low starting dose and slow titration of ziconotide resulted in an improved safety profile in the aforementioned trials. Common AEs associated with ziconotide include nausea and/or vomiting, dizziness, confusion, urinary retention, and somnolence. Evidence from DBPC trials, open-label studies, case series, and case studies suggests that ziconotide, as either monotherapy or in combination with other IT drugs, is a potential therapeutic option for patients with refractory neuropathic pain. Additional studies are needed to establish the long-term efficacy and safety of ziconotide for neuropathic pain. [source] Changes in prescribed drug doses after market introductionPHARMACOEPIDEMIOLOGY AND DRUG SAFETY, Issue 6 2002Eibert R. Heerdink PhD Abstract Purpose The establishment of recommended dosing regimens has always been a difficult aspect of drug development. This paper examines the extent to which postmarketing prescribing deviates from initially recommended dosing regimens. We used the World Health Organization's (WHO) periodically updated compilation of the ,Defined Daily Dose' (DDD) to reflect prevailing patterns of prescribing in national markets. The aim of this study was to evaluate DDD changes over time (1982,2000) and to identify possible determinants of these changes. Methods Data on DDD changes were obtained from the WHO's Oslo Collaborating Centre. We performed a case,control analysis in which we compared drugs with (cases) and without (controls) postmarketing changes in DDD on possible determinants associated with DDD change. Results We found 115 instances of a change of DDD in the period 1982,2000 (45 (39.1%) increases and 70 (60.9%) decreases). Antibiotics showed the greatest number of changes in DDD: predominantly increases in the 1980s, while the 1990s were dominated by decreases in DDD of mostly cardiovascular drugs. Conclusion Changes in DDD reflect the outcome of a melange of forces, including misconceptions of dose requirements during pre-market development of drug and postmarketing changes in pharmacotherapeutic knowledge, clinical concepts, economic forces, and, in the case of anti-infective agents, changing patterns of resistance/sensitivity of target microorganisms to the anti-infective agent(s) in question. Copyright © 2002 John Wiley & Sons, Ltd. [source] Monitoring sedation in the critically ill childANAESTHESIA, Issue 5 2010A. Lamas Summary Sedation is an essential part of the management of the critically ill child, and its monitoring must be individualised and continuous in order to adjust drug doses according to the clinical state. There is no ideal method for evaluating sedation in the critically ill child. Haemodynamic variables have not been found to be useful. Clinical scales are useful when sedation is moderate, but are limited by their subjective nature, the use of stimuli, and the impossibility of evaluating profoundly sedated patients or those receiving neuromuscular blocking drugs; in addition, many of these scales have not been evaluated in children. The COMFORT scale is the most appropriate, as it was designed and validated for critically ill children requiring mechanical ventilation. Electroencephalography-derived methods permit continuous monitoring, provide an early indication of changes in the level of sedation, and facilitate a rapid adjustment of medication. However, these methods were designed and validated for patients under anaesthesia and their results cannot be fully extrapolated to the critically ill patient; in addition, some of them have not been validated in small children and there is still little experience in critically ill children. The main indications for the use of these methods are in patients with deep sedation and/or neuromuscular blockade. The bispectral index is the most widely used method at the present time. Analysis and comparison of the efficacy of the different methods for evaluating sedation in the critically ill child is required. [source] Model-based design of chemotherapeutic regimens that account for heterogeneity in leucopoeniaBRITISH JOURNAL OF HAEMATOLOGY, Issue 6 2006Markus Scholz Summary Patients treated with multicycle chemotherapy can exhibit large interindividual heterogeneity of haematotoxicity. We describe how a biomathematical model of human granulopoiesis can be used to design risk-adapted dose-dense chemotherapies, leading to more similar leucopoenias in the population. Calculations were performed on a large data set for cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP)-like chemotherapies for aggressive non-Hodgkin lymphoma. Age, gender, Eastern Cooperative Oncology Group performance status, lactate dehydrogenase and the degree of leucopoenia within the first therapy cycle were used to stratify patients into groups with different expected severity of leucopoenia. We estimated risk-specific bone marrow toxicities depending on the drug doses administered. These toxicities were used to derive risk-adapted therapy schedules. We determined different doses of cyclophosphamide and additional etoposide for patients treated with CHOP-14. Alternatively, the model predicted that further reductions of cycle duration were feasible in groups with low toxicity. We also used the model to identify appropriate granulocyte colony-stimulating factor (G-CSF) schedules. In conclusion, we present a method to estimate the potential of risk-specific dose adaptation of different cytotoxic drugs in order to design chemotherapy protocols that result in decreased diversity of leucopoenia between patients, to develop dose-escalation strategies in cases of low leucopoenic reaction and to determine optimal G-CSF support. [source] Hyperthermic intraoperative intraperitoneal chemotherapy with cisplatin and doxorubicin in patients who undergo cytoreductive surgery for peritoneal carcinomatosis and sarcomatosisCANCER, Issue 2 2002Phase I study Abstract BACKGROUND Hyperthermic intraperitoneal intraoperative chemotherapy (HIIC) combined with cytoreductive surgery (CS) has been proposed as a new multimodal treatment mainly for carcinomatosis of gastrointestinal origin. To evaluate whether this regimen could be used for other tumor types, the authors conducted a Phase I study on HIIC with doxorubicin and cisplatin in patients with peritoneal carcinomatosis or sarcomatosis. PATIENTS AND METHODS Thirty-one patients with peritoneal carcinomatosis or sarcomatosis (PCS) were enrolled for the study. After completion of CS, HIIC was administered with drug doses that were increased for each consecutive cohort following a three-patient cohort scheme. Thereafter, the accrual was stopped when Grade 4 locoregional or systemic toxicity was observed. The maximum tolerated dose (MTD) was considered the dose in the previous triplet. Drug pharmacokinetics and procedure costs also were analyzed. RESULTS After CS, residual tumors were not present or measured less than or equal to 3 mm (in dimension) in all cases. Maximum tolerated dose was 15.25 and 43.00 mg L,1 for doxorubicin and cisplatin, respectively. The perfusate/plasma area under the curve ratios were favorable for both drugs, at 162 ± 113 and 20.6 ± 6.0, respectively, for doxorubicin and cisplatin. Doxorubicin levels in the peritoneum were higher than in tumor or normal tissue samples. There were no postoperative deaths. Surgery-related complications were observed in 25% of cases. Findings at cost analysis showed that the length of stay in the operation room and intensive care unit were the major cost drivers. CONCLUSIONS Cytoreductive surgery combined with HIIC is an expensive but feasible therapeutic approach for locally advanced abdominal tumors. Because our preliminary findings for local disease control are encouraging, a Phase II study is now advisable to verify the activity of this promising treatment. Cancer 2002;94:492,9. © 2002 American Cancer Society. [source] A Cost-effectiveness Analysis of Propofol versus Midazolam for Procedural Sedation in the Emergency DepartmentACADEMIC EMERGENCY MEDICINE, Issue 1 2008Corinne Michèle Hohl MD Abstract Objectives:, To determine the incremental cost-effectiveness of using propofol versus midazolam for procedural sedation (PS) in adults in the emergency department (ED). Methods:, The authors conducted a cost-effectiveness analysis from the perspective of the health care provider. The primary outcome was the incremental cost (or savings) to achieve one additional successful sedation with propofol compared to midazolam. A decision model was developed in which the clinical effectiveness and cost of a PS strategy using either agent was estimated. The authors derived estimates of clinical effectiveness and risk of adverse events (AEs) from a systematic review. The cost of each clinical outcome was determined by incorporating the baseline cost of the ED visit, the cost of the drug, the cost of labor of physicians and nurses, the cost and probability of an AE, and the cost and probability of a PS failure. A standard meta-analytic technique was used to calculate the weighted mean difference in recovery times and obtain mean drug doses from patient-level data from a randomized controlled trial. Probabilistic sensitivity analyses were conducted to examine the uncertainty around the estimated incremental cost-effectiveness ratio using Monte Carlo simulation. Results:, Choosing a sedation strategy with propofol resulted in average savings of $17.33 (95% confidence interval [CI] = $24.13 to $10.44) per sedation performed. This resulted in an incremental cost-effectiveness ratio of ,$597.03 (95% credibility interval ,$6,434.03 to $6,113.57) indicating savings of $597.03 per additional successful sedation performed with propofol. This result was driven by shorter recovery times and was robust to all sensitivity analyses performed. Conclusions:, These results indicate that using propofol for PS in the ED is a cost-saving strategy. [source] Impact of treatment-related liver toxicity on the outcome of HCV-positive non-Hodgkin's lymphomas,AMERICAN JOURNAL OF HEMATOLOGY, Issue 1 2010Luca Arcaini We studied 160 Hepatitis C virus (HCV)-positive patients with NHL (59 indolent NHL, 101 aggressive). Median age was 67 years. HCV-RNA was present in 146. HBsAg was positive in seven patients. At diagnosis, ALT value was above UNL in 67 patients. One hundred and twenty patients received an anthracycline-based therapy, alkylators, 28 received chemotherapy plus rituximab. Cytotoxic drugs dose was reduced in 63 patients. Among 93 patients with normal ALT at presentation, 16 patients developed WHO grade II,III liver toxicity. Among 67 patients with abnormal ALT, eight patients had a 3.5 times elevation during treatment. Among 28 patients treated with rituximab and chemotherapy, five patients (18%) developed liver toxicity. Thirty four patients (21%) did not complete treatment (eight for liver toxicity). Median progression-free survival (PFS) for patients who experienced liver toxicity is significantly shorter than median PFS of patients without toxicity (respectively, 2 years and 3.7 years, P = 0.03). After a median F-UP of 2 years, 32 patients died (three for hepatic failure). A significant proportion of patients with HCV+ NHL develop liver toxicity often leading to interruption of treatment. This could be a limit to the application of immunochemotherapy programs. HCV+ lymphomas represent a distinct clinical subset of NHL that deserves specific clinical approach to limit liver toxicity and ameliorate survival. Am. J. Hematol., 2010. © 2009 Wiley-Liss, Inc. [source] Graves' disease in children and adolescents: Response to long-term treatmentACTA PAEDIATRICA, Issue 11 2005RAQUEL BARRIO Abstract Background: Optimal treatment of Graves' disease in paediatric patients is still a matter of controversy. Antithyroid drugs, radioiodine and thyroidectomy are the three therapeutic options available. Aim: To report our experience of long-term medical treatment and outcome of paediatric Graves' disease. Methods: A 5-y-long medical protocol was implemented in 20 children and adolescents with Graves' disease. All patients received antithyroid drugs as the first therapeutic option; patients who did not enter long-term remission received I131 and/or surgery as the definitive treatment. Results: The mean age at diagnosis was 12.1±4 y. Only two patients were males, both presenting concomitant type 1 diabetes. Mean follow-up was 13.8 ± 5.5 y. Forty per cent of patients achieved long-term remission with low antithyroid drugs doses (mean treatment time: 5.4± 1.4 y). Six patients received I131 as definitive treatment and another six underwent surgery after completing medical treatment for 6.8 ± 4.1 and 5.1 ± 2 y, respectively. No patients requiring high antithyroid drugs doses to maintain euthy-roidism reached long-term remission and needed I131 and/or surgery. Conclusion: Implementation of a long-term antithyroid drug protocol achieved 40% long-term remissions in paediatric patients with Graves' disease. Need for maintained high doses of antithyroid drugs could be considered a predictive factor for no remission. When permanent remission was not obtained by medical treatment, I131 and/or surgery allowed healing in all cases. [source] | |||||||||||||||||||||||||