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Abstract Boron Neutron Capture Therapy (BNCT) is performed using high-intensity neutron sources; however, the energy of the primary neutrons is too high for direct patient irradiation. Thus, neutron moderation is mandatory and is performed using a device known as a Beam Shaping Assembly (BSA). Due to the differences in flux and energy spectra between neutron sources, each facility needs a dedicated BSA design, whether it is based on a nuclear reactor or, more recently, on an accelerator. Since moderation involves the loss of neutrons, typically by a factor of 1000, it is necessary to generate a very high flux before neutrons pass through the BSA. We propose a novel approach that eliminates the necessity of a BSA, BSA-free, by generating neutrons suitable in flux and energy for direct patient irradiation through the $${}^{45}$$ Sc(p,n) $${}^{45}$$ Ti reaction using near-threshold protons. Our findings demonstrate that all IAEA quality factors for BNCT can be met with existing proton accelerators. Additionally, figures of merit studied provide similar results compared to real BNCT facilities. This breakthrough opens up new avenues in BNCT, among others, the control of the neutron penetration within the human body by small changing in the proton energy. Also, it is expected simplified accelerator-based facilities in terms of manufacturing and maintenance and operation. This work is a study based on experimental data and Monte Carlo simulations. Technical challenges and safety are addressed in Discussion section. This novel proposal is under evaluation as patent.

Boron Neutron Capture Therapy (BNCT) is performed using high-intensity neutron sources; however, the energy of the primary neutrons is too high for direct patient irradiation. Thus, neutron moderation is mandatory and is performed using a device known as a Beam Shaping Assembly (BSA). Due to the differences in flux and energy spectra between neutron sources, each facility needs a dedicated BSA design, whether it is based on a nuclear reactor or, more recently, on an accelerator. Since moderation involves the loss of neutrons, typically by a factor of 1000, it is necessary to generate a very high flux before neutrons pass through the BSA. We propose a novel approach that eliminates the necessity of a BSA, BSA-free, by generating neutrons suitable in flux and energy for direct patient irradiation through the Sc(p,n) Ti reaction using near-threshold protons. Our findings demonstrate that all IAEA quality factors for BNCT can be met with existing proton accelerators. Additionally, figures of merit studied provide similar results compared to real BNCT facilities. This breakthrough opens up new avenues in BNCT, among others, the control of the neutron penetration within the human body by small changing in the proton energy. Also, it is expected simplified accelerator-based facilities in terms of manufacturing and maintenance and operation. This work is a study based on experimental data and Monte Carlo simulations. Technical challenges and safety are addressed in Discussion section. This novel proposal is under evaluation as patent. [ABSTRACT FROM AUTHOR]

Abstract Background Adalimumab is currently considered the most efficacious anti-TNFα agent for childhood noninfectious uveitis (NIU). The objective of this study was to define a therapeutic range for adalimumab trough levels in the treatment of childhood NIU. Methods A retrospective, observational, pilot study of 36 children with NIU aged

Background: Adalimumab is currently considered the most efficacious anti-TNFα agent for childhood noninfectious uveitis (NIU). The objective of this study was to define a therapeutic range for adalimumab trough levels in the treatment of childhood NIU. Methods: A retrospective, observational, pilot study of 36 children with NIU aged < 18 years, treated with adalimumab. Serum adalimumab through levels and adalimumab anti-drug antibodies (ADA) were analysed at least 24 weeks after start adalimumab. Results: Adalimumab trough levels were significantly higher in complete responders 11.8 μg/mL (range 6.9–33.0) compared to partial or non-responders 9,2 μg/mL (range 0–13.6) (p = 0,004). Receiver–operator characteristics analyses with an area under the curve of 0,749 (95% CI, 0,561–0,937) defined 9.6 µg/mL as the lower margin for the therapeutic range. This cut-off corresponds with a sensitivity of 88% and a specificity of 56% (positive predictive value, 85%; negative predictive value, 62.5%). A concentration effect curve defined 13 µg/mL as the upper margin. Approximately one-third (30.5%) of patients had an adalimumab trough concentration exceeding 13 µg/mL. Free ADA were observed in 2 patients (5.5%). Conclusions: A therapeutic range of adalimumab trough levels of 9.6 to 13 µg/mL, which corresponds with an optimal clinical effect, was identified. Therapeutic drug monitoring may guide the optimisation of treatment efficacy in children with NIU in the treat-to-target era. [ABSTRACT FROM AUTHOR]

Carbamazepine is a drug with a narrow therapeutic range that requires clinical monitoring, since its toxic effects are not easily predictable, and the therapeutic level can vary. Our study aimed to monitor the serum level and determine the concentration/dose relationship of carbamazepine in people with epilepsy, analyzing its clinical implication. It is observed that 90.48% of the study volunteers present serum level values (4.3–10.4 mg/L) within the therapeutic range (4–12 mg/L); 7.14% present supratherapeutic levels (12.7–14.4 mg/L), 2.38% subtherapeutic (0.93 mg/L). The findings indicate a negative correlation (r = -0.616; r² = 0.379; p = 0.001), between the dose (mg/day) and the dose ratio (mg/L/mg/day); and a positive correlation (r = 0.544; r² = 0.296; p = 0.002), between the dose (mg/day)-serum concentration (mg/L). ANOVA and Tukey’s test mean difference is significant (p<0.05). It is concluded that there is a positive and significant linear correlation between daily doses and serum carbamazepine concentrations, which should be considered to individualize the dose and optimize clinical results. [ABSTRACT FROM AUTHOR]

In clinical practice, therapeutic drug monitoring (TDM) makes it possible to measure the concentration of drugs in serum or saliva, the purpose of which is to reduce adverse effects and optimize pharmacological therapy. The objective was to determine the concentrations of Phenytoin in saliva and serum of people with epilepsy. Cross-sectional, descriptive study with dynamic recruitment of 30 people with epilepsy (n = 30; 17 men, 56.7% and 13 women, 43.3%; mean age 33.9 ± 11.83 years). Serum and saliva samples were collected at trough levels from patients, who were under phenytoin treatment for at least three months. Drug levels were assessed by the Cloned Donor Enzyme Immunoassay method. Phenytoin levels were found in saliva between 0.01 to 3.56 mg/L and in serum between 0.09 to 36.60 mg/L. Pearson’s analysis showed an association between the estimated serum and saliva phenytoin concentrations (R2 0.7026; 95% CI 0.685-0.921), with a significant statistical correlation (p < 0.05). The Bland-Altman test broke concordance, the difference between the two saliva/serum methods is within 95% confidence. It is concluded that there is an association and concordance between the concentrations of phenytoin in serum and saliva, therefore, this technique can be useful in the clinical monitoring of phenytoin. [ABSTRACT FROM AUTHOR]

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Abstract Background Many medicines are dosed to achieve a particular therapeutic range, and monitored using therapeutic drug monitoring (TDM). The evidence base for a therapeutic range can be evaluated using systematic reviews, to ensure it continues to reflect current indications, doses, routes and formulations, as well as updated adverse effect data. There is no consensus on the optimal methodology for systematic reviews of therapeutic ranges. Methods An overview of systematic reviews of therapeutic ranges was undertaken. The following databases were used: Cochrane Database of Systematic Reviews (CDSR), Database of Abstracts and Reviews of Effects (DARE) and MEDLINE. The published methodologies used when systematically reviewing the therapeutic range of a drug were analyzed. Step by step recommendations to optimize such systematic reviews are proposed. Results Ten systematic reviews that investigated the correlation between serum concentrations and clinical outcomes encompassing a variety of medicines and indications were assessed. There were significant variations in the methodologies used (including the search terms used, data extraction methods, assessment of bias, and statistical analyses undertaken). Therapeutic ranges should be population and indication specific and based on clinically relevant outcomes. Recommendations for future systematic reviews based on these findings have been developed. Conclusion Evidence based therapeutic ranges have the potential to improve TDM practice. Current systematic reviews investigating therapeutic ranges have highly variable methodologies and there is no consensus of best practice when undertaking systematic reviews in this field. These recommendations meet a need not addressed by standard protocols.

Aims: Although cytochromeP450(CYP)3A5 gene polymorphism affects personalized tacrolimus doses, there is no consensus as to whether CYP3A5 genotypes should be determined to adjust the doses. The aims were to compare the therapeutic ranges and clinical outcomes between the conventional and genotype‐guided tacrolimus doses. Methods: This randomized controlled study compared 63 cases of the conventional tacrolimus dose group (0.1 mg/kg/day) with 62 cases of the genotype‐guided doses group of 0.125, 0.1 and 0.08 mg/kg for CYP3A5*1/*1, *1/*3, and *3/*3 genotypes for the initial 3 days of kidney transplantation. After day 3, dose adjustment occurred in both groups to achieve therapeutic concentrations. Results: The genotype‐guided group had an increased proportion of patients with tacrolimus concentrations in the therapeutic range at the steady state on day 3 (40.3 vs 23.8%, P =.048). A lower proportion of over‐therapeutic concentration patients was noted in the genotype‐guided group in the CYP3A5*3/*3 genotype (9.7 vs 27%, P = .013). Unexpectedly, more delayed graft functions (DGFs) were in the genotype‐guided group (41.9 vs 22.2%, P =.018) especially in the CYP3A5*1/*1 participants who might have had an aggravated DGF by a longer ischaemic time and higher serum donor creatinine levels than in the control group. There were no significant differences of glomerular filtration rates or graft or patient survivals over a median 37‐month follow‐up period. Conclusions: Determination of the CYP3A5 genotype improved therapeutic range achievement. CYP3A5*1/*1 patients who have high risks of DGF should be closely monitored because of an increased risk of DGF and reduced glomerular filtration rate with high tacrolimus doses. [ABSTRACT FROM AUTHOR]

To evaluate the cost of healthcare with respect to the quality of anticoagulation in patients with deep vein thrombosis (DVT) treated with warfarin in daily practice via the database analysis of a tertiary care center in the period 2010 to 2013. Of 258 307 records in total, 42 582 unique patients with DVT and 32 012 patients with international normalized ratio (INR) measurements were included. Overall, 6720 unique patients with DVT diagnosis and one or more INR measurements were identified, and the records of 4377 out of 6720 unique patients were validated and included in the analysis data set. The cost analysis was based on direct medical costs from the payer's perspective. Cost items were related to healthcare resource utilization (inpatient and outpatient services) during the study period, which provided a basis for calculation of per-patient, outpatient, inpatient, and total direct medical costs. Mean outpatient, inpatient, and total hospital admission costs were $578, $2195, and $2785, respectively, for patients with time in the therapeutic range of 70% or more, whereas the same costs were $571, $2163, and $3192, respectively, for patients with time in the therapeutic range of less than 70%. Our findings for a retrospective cohort of patients with DVT undergoing warfarin therapy reveal that patients spent 70% or more, as opposed to less than 70%, of follow-up time within the therapeutic INR range and that outpatient care, as opposed to inpatient care, was associated with lower healthcare costs. Given the significant contribution that hospital stay makes to the cost burden of DVT, our findings also highlight the association between poor warfarin anticoagulant control and increased hospitalization costs. • The efficacy and safety of warfarin are largely dependent on the maintenance of international normalized ratio (INR) within a narrow (2.0-3.0) therapeutic range and a minimum time in the therapeutic range (TTR) target threshold of at least 60% to 70%. This necessitates continual dose adjustment and routine INR monitoring, with the likelihood of poor anticoagulation, thus creating a considerable economic burden. • This database analysis provides, for the first time, data from Turkey on time spent in the therapeutic INR range and related healthcare costs among patients with DVT treated with warfarin. Our findings for a retrospective cohort of patients with DVT undergoing warfarin therapy reveal that only one-third of follow-up time was spent within the therapeutic INR range, whereas the INR monitoring frequency was 9.1 times/year, albeit with poor INR control. The total costs were $3192 and $2785 when TTR was less than 70% and 70% or more, respectively. • Overall, costs were higher for inpatient compared with outpatient DVT management, whereas a follow-up time of 70% or more within the therapeutic INR range was associated with lower healthcare costs. Our findings also highlight the association between poor warfarin anticoagulant control and increased hospitalization costs. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the international normalized ratio (INR) monitoring patterns in patients with deep vein thrombosis. Methods: Of 32,012 patients with -1 outpatient INR measurement and 42,582 patients with confirmed deep vein thrombosis diagnosis registered to our hospital between 1 January 2010 and 31 December 2013, 6720 records were identified to have both deep vein thrombosis and international normalized ratio measurement, and 4.377 out of 6.720 single patient records were determined to be statistically analyzable. Results: Median INR measurement frequency was 6.47 times/year and patients had INR levels of 2-3 in 34.3% of followup time. Having -70% vs. <70% of follow-up time within therapeutic range was associated with lower hospital admission frequency (9.7 vs. 10.3 times/year). Conclusion: Our study revealed only one-third of the follow-up time to be spent within therapeutic INR, association of INR therapeutic range with lesser number of hospital admissions and INR monitoring frequency of 6.47 times/year despite lack of stable INR control in most of the deep vein thrombosis patients. [ABSTRACT FROM AUTHOR]

Heparin-induced thrombocytopenia (HIT) is a not-uncommon adverse effect of heparin exposure, with potentially serious and/or fatal thrombotic consequences. Recent studies looking at the off-label use of fondaparinux for HIT show similar efficacy and adverse-effect profiles, as well as improved costs, compared with some commonly used direct thrombin inhibitors. Although routine laboratory monitoring of fondaparinux-specific anti-Xa levels typically is not recommended, we present a case report that suggests fondaparinux monitoring may be needed in patients with hepatic impairment causing acquired antithrombin deficiency. We performed daily assessment of antithrombin- and fondaparinux-specific anti-Xa levels in a 50-year-old female of unknown ethnicity to ensure that fondaparinux dosing was maintained within an acceptable range. With this management strategy, the patient experienced no thrombotic or hemorrhagic complications during the hospital admission or the following 2 months in outpatient treatment. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the significance of "subtherapeutic" vs "therapeutic" antiepileptic drug (AED) plasma levels with respect to treatment adherence. Material and methods: One hundred and seventy patients with refractory temporal lobe epilepsy who underwent video‐EEG monitoring in view of a surgical indication had their AEDs (carbamazepine, phenobarbital, phenytoin, and valproate) rapidly withdrawn following a standardized schedule. Plasma levels were measured at admission, and during the 2 days of drug withdrawal. Adherence and nonadherence were identified by the development of plasma levels from day 1 through day 3. Frequencies of an initial level below the reference range in both groups were compared. Results: Adherence was found in 73.2% of cases, and nonadherence in 26.8%. Low levels were seen equally often (about 1/4 of cases) in adherent and nonadherent cases. The vast majority (73.7%) of low levels had another explanation than nonadherence (eg low‐dose treatment or enzyme induction). Of 42 nonadherent cases, the vast majority of 76.2% had unsuspicious plasma levels at admission. Conclusions: "Subtherapeutic" AED plasma levels only rarely are caused by nonadherence whereas levels in the "therapeutic range" by no means prove that the patient is adherent to treatment. For meaningful interpretation, any level needs to be compared with other levels of the same patient. Our findings strongly emphasize the principle of individualized therapeutic AED monitoring as promoted by the Therapeutic Strategies Commission of the ILAE. [ABSTRACT FROM AUTHOR]

Background Elective cardioversion (ECV) for atrial fibrillation (AF) is associated with a relatively low risk of thromboembolic complications. However, the optimal intensity of anticoagulation for ECV is unknown. We sought to assess the risk of thromboembolism in low (INR 2.0–2.4) vs. high (INR ≥ 2.5) therapeutic range in a large retrospective cohort study. Methods This multi-centre “real world” study included 1424 ECVs in 1021 patients. The primary outcome was a stroke or a transient ischaemic attack (TIA) or a systemic embolus during the 30-day follow-up after ECV. Results Altogether 4 (0.3%) strokes, 2 (0.1%) TIAs and 2 (0.1%) bleeds were detected during the 30-day follow-up after ECV. No systemic emboli were detected. There were 2 deaths (0.1%), one associated with a stroke. Median time to stroke/TIA was 4 (IQR 9.5) days and the median CHA 2 DS 2 -VASc-score was 2 (IQR 1.25) among patients with thromboembolic events. Mean INR at ECV was 2.7 (SD 0.54) in the study cohort. Patients with INR 2.0–2.4 at ECV had more thromboembolic events compared with patients with INR ≥ 2.5 (5/529 (0.9%) vs. 1/895 (0.1%), p = 0.03). Comprehensive postprocedural INR data was available for 733 (71.8%) patients and 1007 cardioversions. At least one subtherapeutic (< 2.0) INR value was detected within 21 days after 230 (22.8%) ECVs and this drop in INR level was associated with a higher risk for thromboembolic events compared with continuous therapeutic post-cardioversion anticoagulation (1.7% vs 0.3%, p = 0.03). Conclusions Our results suggest that the intensity of periprocedural anticoagulation is associated with the risk of thromboembolic events after ECV. [ABSTRACT FROM AUTHOR]

In this research, we aim to investigate the influence of different materials, as a bolus, on the low-energy electron beam dose distributions and to develop equations for predicting surface dose based on bolus thickness, as well as the therapeutic interval based on surface dose. All the Monte Carlo (MC) calculations and measurements were conducted on a Siemens PRIMUS linac. Based on EGSnrc MC code, BEAMnrc system was used to model a Siemens linac and generate phase-space files for three electron beams (6, 8, and 10 MeV). The particles were transported from the phase-space files to the bolus materials and the simulated water phantom using DOSXYZnrc. Various materials with different thicknesses were examined as a bolus, and appropriate equations were determined for each material and electron beam. The comparison of percent depth dose (PDD) curves and beam profiles, using MC, with the measured data demonstrated that the calculated values properly matched with the measurements. The results indicated that the use of bolus materials with the density of higher than soft tissue can increase both surface dose and therapeutic interval simultaneously. This finding arises from the fact that the required bolus thickness for achieving the therapeutic surface dose decreases in the case of high-density materials. Two series of prediction equations were proposed for predicting the surface dose based on bolus thickness and the therapeutic interval based on surface dose. These equations are able to calculate properly the bolus thickness required for producing a therapeutic surface dose (above 90%) for any therapeutic interval. [ABSTRACT FROM AUTHOR]

Background: Many medicines are dosed to achieve a particular therapeutic range, and monitored using therapeutic drug monitoring (TDM). The evidence base for a therapeutic range can be evaluated using systematic reviews, to ensure it continues to reflect current indications, doses, routes and formulations, as well as updated adverse effect data. There is no consensus on the optimal methodology for systematic reviews of therapeutic ranges.Methods: An overview of systematic reviews of therapeutic ranges was undertaken. The following databases were used: Cochrane Database of Systematic Reviews (CDSR), Database of Abstracts and Reviews of Effects (DARE) and MEDLINE. The published methodologies used when systematically reviewing the therapeutic range of a drug were analyzed. Step by step recommendations to optimize such systematic reviews are proposed.Results: Ten systematic reviews that investigated the correlation between serum concentrations and clinical outcomes encompassing a variety of medicines and indications were assessed. There were significant variations in the methodologies used (including the search terms used, data extraction methods, assessment of bias, and statistical analyses undertaken). Therapeutic ranges should be population and indication specific and based on clinically relevant outcomes. Recommendations for future systematic reviews based on these findings have been developed.Conclusion: Evidence based therapeutic ranges have the potential to improve TDM practice. Current systematic reviews investigating therapeutic ranges have highly variable methodologies and there is no consensus of best practice when undertaking systematic reviews in this field. These recommendations meet a need not addressed by standard protocols. [ABSTRACT FROM AUTHOR]

Background A large proportion of the older population with non-valvular atrial fibrillation (NVAF) receive warfarin for stroke prevention, the safety and efficacy of which is affected by the time-in-therapeutic range (TTR). This has optimum effectiveness where the mean TTR is ≥70%, whilst no survival benefit is conferred if TTR is <40%. Objective To assess the TTR of patients aged 80 and over with NVAF on warfarin. Methods A retrospective analysis was performed on patients that had utilised an intermediate care service at a London hospital over one year. Patients were on warfarin for NVAF, aged ≥80 with a minimum of six continuous months of results. The therapeutic range was defined as an international normalised ratio of ≥2 and ≤3 and the TTR was calculated for each patient. Results 118 patients were identified with a mean age of 86.1 (80–107). 9 (7.6%) patients were within the therapeutic range for ≥70% of the time and 31 (26.3%) patients were within the therapeutic range for <40% of the time. The mean TTR was 47.5% (standard deviation 14.4%, range 12.5–81.8%). Those with a hospital admission had a significantly lower mean TTR versus those without an admission ( p -value = 0.013). Conclusion The TTR is extremely low in this cohort of patients aged 80 years and older who are on warfarin for NVAF. This exposes patients to significant risks of both bleeding and ischaemic stroke. Assessment of INR control should be carried out and consideration should be given as to whether novel oral anticoagulants should be more widely used in this population. [ABSTRACT FROM AUTHOR]

In recent clinical trials, the \“quality\“ of warfarin management has been characterized by the time in therapeutic range (TTR) - with the therapeutic range being an INR between 2.0 and 3.0. In many reviews of recent clinical trials, differences in the TTR have been used comparatively to critique and contrast the trials. However, TTR is a more complex measurement than is commonly appreciated, and many factors that underlie the TTR calculation, which can differ from trial to trial, have not been adequately addressed. This manuscript attempts to explain these issues so as to help the reader understand the factors that contribute to TTR and to understand the limitations of TTR so as to better understand anticoagulation trial results. It also addresses the issue of INRs below or above the therapeutic range, that can differ among trials, that are not provided simply by presenting a TTR value, but that can in a substantial way affect the bleeding risk and embolismprevention likelihood of anticoagulation in a trial. [ABSTRACT FROM AUTHOR]

Objective: To determine the therapeutic safety theoretically and experimentally, the biopharmaceutical equivalence parameters of two batches of multisource Digoxin tablets of 0.25mg. Material and Methods: Two batches, each of 200 tablets multisource digoxin 0.25 mg were studied, assigning code multisource TDH025 Lot 105031 and TDF025 Lot 10940431. The therapeutic range was determined by theoretical formula VT = aFraction pharmacokinetics / apredicted fraction by usual concentration x, then by the difference CmE and CME, the therapeutic range was obtained. The analytical method used for quantification of the active ingredient, was described in The International Pharmacopoeia of the World Health Organization (WHO); while the fretting test and the hardness was determined according to the USP. Results: The therapeutic index is 1.2 ng/ml; and evaluation of the parameters of the biopharmaceutical equivalence percentages of active ingredient of the two lots of multisource drugs are within the acceptance range (90-110%) given in the USP and WHO.The fretting of TDH025 fretting batch 105031 was 0.55% and TDF025 was 0.56%, both values are below 1% which is acceptable value; and hardness indicates an acceptable mechanical shock endurance. The 06 tablets were completely disintegrated, passing through a No. 10 (1700 uM) sieve, in a dissolution medium simulating gastric and intestinal pH in less than 5 min. Conclusion: Biopharmaceutical equivalence of multisource drugs digoxin 0.25 mg TDH025 TDF025 batch batch 105031 and 10940431 was demonstrated according to the acceptance criteria of the WHO and USP, the active ingredient (digoxin) quantified in each batch were within the range of 90-110%; attrition and hardness parameters indicate adequate stability in their lifetime. [ABSTRACT FROM AUTHOR]

Objective Tablet splitting is frequently performed to facilitate correct dosing, but the practice and implications in low-income settings have rarely been discussed. Methods We selected eight drugs, with narrow therapeutic indices or critical dosages, frequently divided in the Lao PDR (Laos). These were split, by common techniques used in Laos, by four nurses and four laypersons. The mean percentage deviation from the theoretical expected weight and weight loss of divided tablets/capsules were recorded. Results Five of eight study drugs failed, on splitting, to meet European Pharmacopoeia recommendations for tablet weight deviation from the expected weight of tablet/capsule halves with 10% deviating by more than 25%. There was a significant difference in splitting accuracy between nurses and laypersons ( P = 0.027). Coated and unscored tablets were less accurately split than uncoated ( P = 0.03 and 0.0019 for each half) and scored (0.0001 for both halves) tablets. Conclusion These findings have potential clinical implications on treatment outcome and the development of antimicrobial resistance. Investment by drug companies in a wider range of dosage units, particularly for narrow therapeutic index and critical dosage medicines, is strongly recommended. [ABSTRACT FROM AUTHOR]

We assessed whether prospective therapeutic drug monitoring to optimise the therapeutic range could prevent linezolid-induced thrombocytopenia. This prospective interventional study was conducted from September 2017 to October 2020 among 37 adult patients receiving linezolid. Patients were administered one of the following two initial dosages: 600 mg twice or once daily for patients with a creatinine clearance rate of ≥50 or <50 mL/min, respectively. Linezolid dosage adjustment was performed on days 3-5 based on the trough concentration. The serum linezolid levels in 22 and 15 patients were within and above the therapeutic range (2-7 µg/mL), respectively. The incidence of thrombocytopenia was significantly lower among patients whose linezolid levels were within the therapeutic range (4.5%;1/22) than in those whose levels were above the therapeutic range (80%; 12/15). It is important to maintain the linezolid level within the therapeutic range at the first therapeutic drug monitoring to prevent thrombocytopenia.

Backgrounds Limited evidence is available regarding pharmacist managed anticoagulation clinic in the Southeast Asian region where there is marked difference in terms of care model, genetic composition and patient demographics. Objectives This study aimed at comparing the anticoagulation clinic managed by the pharmacist with physician advisory and the usual medical care provided in Kuala Lumpur Hospital (KLH) in terms of anticoagulation control and adverse outcomes. Setting A 2,302 bedded government tertiary referral hospital in Malaysia. Methods A 6-month retrospective cohort study of the effectiveness of two models of anticoagulation care, the pharmacist managed anticoagulation clinic which is known as warfarin medication therapy adherence clinic (WMTAC) and usual medical clinic (UMC) in KLH was conducted, where a random number generator was used to recruit patients. The UMC patients received standard medical care where they are managed by rotational medical officers in the physicians' clinic. As for the WMTAC with physician advisory, the pharmacist will counsel and review the patients internationalised normalization ratio at each clinic visit and also adjust the patients' warfarin dose accordingly. Patients are referred to physicians if immediate attention is required. Main outcome measure The main therapeutic outcome is time in therapeutic range (TTR) both actual and expanded TTR and thromboembolic and bleeding complications. Results Each of the WMTAC and usual medical care recruited 92 patients, which totals to 184 patients. The patient demographics in terms of age, race and indication of treatment were comparable. At the end of the 6 months follow-up, patients in the WMTAC group had significantly higher actual-TTR (65.1 vs. 48.3 %; p < 0.05) compared to those in usual medical care group. Rates of admission were 6.5 versus 28.2 events per 100 person-years for the WMTAC and UMC groups, respectively. Though the bleeding incidences were not significantly different, it was reduced. Conclusions These findings will impact local warfarin patient management services and policies because there was no available evidence supporting the role of pharmacists in the management of warfarin patients prior to this study. [ABSTRACT FROM AUTHOR]

An increased slowing of cardiac conduction induced by sodium channel blockers is remarkably observed in carriers of an Asian-specific promoter haplotype [haplotype B (HapB)] of the cardiac sodium channel gene (SCN5A). We investigated the effect of HapB on the therapeutic range for serum flecainide concentration in Asian patients.We examined the serum concentration and antiarrhythmic efficacy of flecainide, together with the SCN5A promoter haplotype, in 146 patients with supraventricular tachyarrhythmias. Trough serum flecainide concentrations were determined by HPLC. The antiarrhythmic efficacy of flecainide was assessed for at least 2 months through examination of symptomatology, ECG, and Holter monitoring.The serum flecainide concentration did not differ between the wild-type HapA homozygotes and HapB carriers under treatment with the usual dose. A genetic difference in the antiarrhythmic efficacy of flecainide was observed between the HapA homozygotes and HapB carriers at serum flecainide concentrations less than 300 ng/ml (42.9 vs. 68.8%; P=0.022). PR prolongation and QRS widening were observed more commonly among the HapB carriers with serum flecainide concentrations of at least 300 ng/ml than in the HapA homozygotes (PR, 210±25 vs. 195±25 ms; P=0.036; and QRS, 112±10 vs. 105±9 ms; P=0.030).These findings suggest that the therapeutic range for serum flecainide concentration is lower in HapB carriers than in HapA homozygotes. [ABSTRACT FROM AUTHOR]

At present, we are using the proposed therapeutic range for monitoring unfractionated heparin therapy which is the aPTT ratio of 1.5-2.5. However, the aPTT value is influenced by reagents and methods of detection. The College of American Pathologists and the American College of Chest Physicians recommended that site-specific validation of heparin therapeutic range should be established. The aim of this study was to determine the appropriate therapeutic range of unfractionated heparin therapy of our aPTT system by ex vivo study. For comparison, two other commercial reagents were also determined to observe the differences. Blood samples were drawn from 21 healthy blood donors who were not taking any medication and from other 24 patients suffering from either arterial or venous thrombosis, receiving continuous intravenous infusion of unfractionated heparin without concomitant oral anticoagulant therapy. Correlation coefficients between aPTT ratios and plasma heparin concentration varied between 0.722 (Actin FSL) to 0.817 (Actin FS). Calculated therapeutic ranges of aPTT ratios corresponding to the heparin level of 0.29 - 0.47 U/ml were 1.8 - 2.5, 1.9 - 2.5 and 2.7 - 4.6 for Actin FS, Actin FSL and Pathromtin SL, respectively. Therefore, the appropriate therapeutic range of our system obtained from this study might be aPTT ratio between 1.8 and 2.5 which is very closed to the ratio that we are using now.

Abstract: We performed a retrospective study in patients with poorly controlled epilepsy treated with add-on lacosamide (LCM) to investigate the relationship of LCM-related adverse events with LCM serum concentration and weight-dependent dosage. We collected serum concentrations, weight-related dosages, and occurrences of the seven most frequent adverse events according to the randomized double-blind, placebo-controlled trials. Seventy of 131 patients could be sufficiently evaluated. LCM serum concentrations and weight-related dosages in patients with and without typical adverse events did not differ significantly. Closer analysis of the data suggested that dizziness as the leading adverse event occurred significantly more often if LCM was combined with classic sodium channel blockers. There was a significant correlation between LCM serum concentrations and co-medication, so there is still evidence for dependent variables that might have a relevant impact in individual cases. However, our data do not allow definition of a safety range for LCM. [Copyright &y& Elsevier]

Background: Mycophenolic acid (MPA), a selective inhibitor of lymphocyte proliferation, has lately been used to improve renal function and prolong graft survival in renal transplanted patients. Still, there is no consensus considering the recommended dosing and the therapeutic range of MPA. Methods: To estimate the safe therapeutic range of MPA, its plasma level and indicators of kidney function were measured in 216 patients (138 male, 78 female, age 46±12 years) 67±46 months after transplantation. Besides MPA, patients received cyclosporine (Group A, n=122) or tacrolimus (Group B, n=77). Seventeen patients (Group C) were treated with MPA in combination with everolimus or sirolimus. Plasma MPA was measured by enzyme inhibition assay. Results: In the whole study group MPA level increased with the dose of MPA (p=0.013). MPA level was below the therapeutic range in 40% (Group A) and 45% (Group B) of patients, respectively. MPA was 1.9±1.56 mg/L in Group A, 2.4±1.69 mg/L in Group B. In Group A MPA level increased and cyclosporine decreased with the progress of renal disease. Conclusions: Increasing MPA/cyclosporine ratio at more severe stages of chronic kidney disease was tolerable for the patients and rejection could be avoided. Tubular damage detected by urinary N-acetyl-β-D-glucosaminidase did not correlate with the MPA level. [ABSTRACT FROM AUTHOR]

Abstract: Objective: The hypothesis was that low grade variations of mixing ratios of luting agents have negligible influence, while high grade variations cause severe property changes independent from the cement type used. Material and methods: A zinc oxide phosphate, carboxylate, glass ionomer, resin-modified glass ionomer, dual-curing composite and self-adhesive composite cement were mixed using various mixing ratios. Beside the recommended ratio, samples were mixed with ratios between 10 and 25% (low grade) up to 60% (high grade) variation of powder/liquid, respectively base/catalyst pastes. The samples underwent a Vickers hardness, flexural strength and three-body abrasion test. Their extent of cure reaction was characterized using differential scanning calorimetry. Results: This study indicates that dual-curing composite cements and resin-modified glass ionomers have a wide therapeutic range, followed by zinc oxide phosphate, carboyxlate and classical glass ionomer cements. Dual-curing composite cement showed less property changes, if they were exclusively light-cured in contrast to dark-curing. The classic glass ionomer and the carboxylate cements reacted more sensible to higher liquid content than higher powder content, while zinc oxide phosphate cement was lower sensitive to higher powder content. The investigated self-adhesive composite cement reacted very sensitive even to low grade mixing errors. Conclusions: . Most of the established luting agents seem to tolerate low grade mixing errors, while this is not the case for recently developed self-adhesive composite cement. [Copyright &y& Elsevier]

The application of the clinical pharmacological approach to prescribing antiepileptic drugs has enhanced the efficiency of the drug treatment of epilepsy considerably. However, it would be possible to take the approach further in relation to this disorder by applying it to the more recently introduced antiepileptic drugs, to specific epileptic seizure syndromes and to seizure disorders of different degrees of activity. Similarly, the approach could be applied to the drug treatment of migraine attacks, to migraine prophylactic therapy and to the treatments of multiple sclerosis and Parkinsonism, with reasonable expectations that it would enhance the therapy of these disorders. [ABSTRACT FROM AUTHOR]

As a part of a program to develop an electron paramagnetic resonance (EPR) dosimeter suited for clinical use (doses in the cGy range), polycrystalline samples of lithium formate monohydrate (HCO2Li·H2O), magnesium formate dihydrate (C2H2O4Mg·2H2O), and calcium formate (C2H2O4Ca) have been examined. l-Alanine was included for comparison and reference. Samples were irradiated with 60Co γ-rays and 60–220 kV X-rays. The dosimeter response was assessed using the peak-to-peak amplitude of the first-derivative EPR spectrum. Dose–response curves for the 60Co γ-irradiated samples were constructed, and the dependences of the response on the photon energy, microwave power, and modulation amplitude were studied. Stability of the irradiation products upon storage (signal fading) was also investigated. Lithium formate monohydrate is by far the best candidate of the tested formates, suitable for measuring doses down to approximately 0.1 Gy. Lithium formate monohydrate is more sensitive than alanine by a factor of 5.6–6.8 in the tested photon energy range, it exhibits no zero-dose signal and shows a linear dose response in the dose range from 0.2 to 1000 Gy. Its EPR signal was found unchanged in shape and intensity 1 week after irradiation to 10 Gy. Various less favorable properties rendered the other formates generally unsuitable, although calcium formate exhibits some interesting EPR dosimetric properties. [Copyright &y& Elsevier]

The purpose of the present study was to determine therapeutic ranges for unfractionated heparin therapy using the activated partial thromboplastin time (APTT) by calibration against anti-Xa concentration. APTT assays were performed locally, i.e. at the institution of blood collection, on fresh plasma samples from patients treated with intravenous unfractionated heparin. The measurements were performed by 25 Dutch clinical laboratories using 11 different APTT reagents and 10 different types of coagulometers. After the local APTT measurement, the samples were frozen and transported to a central laboratory for measurement of anti-Xa activity. The number of samples from the participating laboratories ranged from 10 to 48. Local APTT results were correlated with the central anti-Xa measurements. Orthogonal regression analysis of log-transformed values was used to calculate APTT therapeutic ranges corresponding to anti-Xa concentrations of 0.29–0.47 IU/ml. The calculated APTT ranges were different between laboratories, even when the same reagent was used. In many laboratories, the therapeutic APTT range in use was much wider than the calculated range. Imprecision of the calculated APTT range was influenced by the wide scatter of the measurement points and by the selection of samples for the orthogonal regression equation. The present results show that, if anti-Xa concentrations of 0.29–0.47 IU/ml reflect the true therapeutic range, many laboratories do not use the proper therapeutic APTT range. [Copyright &y& Elsevier]

The aims of the study included: to explore the protein structure basis for the differences in digitalis sensitivity between isoforms of Na/K-ATPase from human and guinea-pig cardiac muscle; to determine the relative significance of the constituents of tripartite digitalis compounds in their inhibitory action on these Na/K-ATPase isoforms; to evaluate the potential significance of the receptor kinetics for pharmacological characteristics. The analytical method has been the recording of the inhibitory interaction of various digitalis derivatives with the Na/K-ATPase isoforms. The protein structure basis for the isoform differences in digitalis susceptibility has been explored by analysing in free-energy plots the kinetics of their inhibitory interaction with 53 digitalis derivatives of grossly different structure. The slope of the regression line and the parameters of the regression equation proved to be similar for the two isoforms in spite of the great difference in their digitalis susceptibilities. This surprising uniformity indicates that a uniform "macroscopic" mechanism underlies the inhibitory effect of the various derivatives on the two isoforms. On the other hand, the differences in the positions of Δ Gand Δ Gvalues for particular inhibitors relative to the regression line reveal differences in the 'microscopic' interaction energy surfaces of the two isoforms. In conclusion, the origin of the isoform distinctions in their susceptibility towards inhibition by various digitalis derivatives is essentially confined to differences in the chemotopology of the digitalis recognition matrix and binding cleft. Specific observations allowed to disentangle the impact of various steroid derivatizations at carbon atoms 3, 17, and diverse other positions on the kinetics of their interaction with the enzyme isoforms. The steroid nucleus of the cardiac glycosides, 5β,14β-androstane, proves to be the basal structural element for discrimination of Na/K-ATPase isoforms. This discrimination becomes much enlarged by steroid glycosidation at C3β-OH and/or by steroid substitution of C17β-H by a lactone ring. The higher inhibitory sensitivity of the human isoform is based either on an increased association rate or a decreased dissociation rate, depending on the nature of derivatization.-The significance of specific findings is discussed as to the following aspects: the types of intermolecular forces and the characteristics of the digitalis binding matrix; the nature of the rate-determining step in the formation and dissociation of the digitalis-enzyme complex; the receptor kinetics as a potential basis of the therapeutic range of cardiac glycosides; the potentiality of the use of 5β,14α-androstane as the newly discovered lead structure for the design of novel inotropic steroids possibly analogous in structure to the putative endogenous digitalis compounds. [ABSTRACT FROM AUTHOR]

In an open study, 18 patients suffering from an acute episode of schizophrenia and 18 patients with severe mania were given haloperidol at different dosage levels. Haloperidol plasma concentrations were measured and the status of the patients was evaluated at intervals using the Brief Psychiatric Rating Scale (BPRS). No correlation was found between the oral dose and the plasma concentrations in the schizophrenic group, but there was a low correlation for manic patients. In both groups, however, there was a correlation between these two parameters when the drug was given intramuscularly. There was no correlation between haloperidol plasma concentrations and the BPRS scores. Of the 36 patients 28 responded well to the treatment and were discharged from hospital. A good relationship between the clinical status as observed by the clinicians and the BPRS score was found. Plasma haloperidol concentration measurement was found to be a useful tool for the detection of non-compliance or excessive plasma levels. Accordingly, the present study indicates the value of drug level monitoring as a means to improve therapy. [ABSTRACT FROM AUTHOR]

37 patients on maintenance digoxin therapy were observed in hospital over an 8 day period. From day 1 to day 8 measurements of plasma digoxin and serum creatinine indicated that these patients were in the equilibrium state with regard to digoxin levels and renal function. Assuming a linear relationship between dose and plasma concentration, it was possible to calculate the doses which would have produced plasma concentrations of 1.5 ng/ml, and at the limits of the 'usual therapeutic range', 0.8 and 2.0 ng/ml. Doses obtained from six prescribing aids and those prescribed intuitively by the doctor were then compared. None of the methods used would have resulted in plasma digoxin concentrations within the 'usual therapeutic range' in more than 57% of the patients. The physicians' intuitive choice appeared to be better than the doses estimated from prescribing aids, in that they were correct as often as any assisted method, and when wrong tended to prescribe 'too low' rather than 'too high'. The prescribing aids tended to overestimate dosage in many patients, as high as 65% with one. Plasma digoxin concentration measurement would appear to be the only way to ensure adequate therapeutic efficacy and avoid toxicity in patients receiving maintenance digoxin. [ABSTRACT FROM AUTHOR]

In 11 patients with stable premature ventricular beats, the kinetics of single (150 and 300 mg) and multiple (150 mg t.i.d. and 300 mg t.i.d.) oral doses of propafenone were studied with reference to arrhythmia suppression. During the acute phase detectable plasma levels of the drug were achieved only with the higher dose. In 8 out of 10 patients the antiarrhythmic effect was obtained with the 300 mg dose, which was found to predict responsiveness at steady-state. During the chronic phase, antiarrhythmic efficacy was obtained with the lower dose regimen (150 mg t.i.d.) in half of those patients. A wide range of effective plasma levels was observed. The previously suggested therapeutic range (0.5-2.0 µg/ml) was not adequate in predicting either antiarrhythmic activity or adverse effects. The results show the role of propafenone metabolites in determining total antiarrhythmic action. [ABSTRACT FROM AUTHOR]

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