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Chloroquine and hydroxychloroquine have shown promising preliminary results and have been discussed as therapeutic options for patients with Covid-19. Despite the lack of robust evidence demonstrating the benefits and justifying the use of one of these drugs, the final decision is the responsibility of the attending physician and should be individualized and shared, whenever possible. This position statement recommends dosage adjustment for these drugs in the context of renal impairment.

Methotrexate (MTX) is a remarkable drug with a key role in the management of rheumatoid arthritis (RA) at every stage of its evolution. Its attributes include good overall efficacy for signs and symptoms, inhibition of structural damage and preservation of function with acceptable and manageable safety, a large dose-titratable range, options for either an oral or parenteral route of administration, and currently unrivalled cost-effectiveness. It has a place as a monotherapy and also as an anchor drug that can be safely used in combination with other conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or used concomitantly with biological DMARDs or targeted synthetic DMARDs. MTX is not without potential issues regarding toxicity, notably hepatotoxicity and bone marrow toxicity, as well as tolerability problems for some, but not all, patients. But many of these issues can be mitigated or managed. In the face of a welcome expansion in available targeted therapies for the treatment of RA, MTX looks set to remain at the foundation of pharmacotherapy for the majority of people living with RA and other inflammatory rheumatic diseases. In this article, we provide an evidence-based discussion as to how to achieve the best outcomes with this versatile drug in the context of a treat-to-target strategy for the management of RA.

Drugs fulfilling the criterion of a standard drug will always become panacea provided, if they are used properly. On the other hand, a poorly manufactured drug however used skillfully, will prove to be a poison. Texts of Ayurveda, do mention hazards of drugs, which are not properly manufactured or administered. Art of drug administration is unique in this ancient medical science that cautions towards concentrating on dose, indications, contra-indications, suitable vehicle, specific diet, certain restrictions etc., while administering medicines in suitable individuals. Though a huge amount of information is available and evidences are being generated on the usefulness of traditional practices in global healthcare; there is a need of generating awareness on Promoting rational use of traditional medicines in particular to Ayurvedic drugs. Conventional researchers wish to work on traditional formulations have to understand traditional principles and involve traditional physicians in their researches in the benefit of mankind.

Background Combination analgesics are effective in acute pain, and a theoretical framework predicts efficacy for combinations. The combination of dexketoprofen and tramadol is untested, but predicted to be highly effective. Methods This was a randomised, double-blind, double-dummy, parallel-group, placebo-controlled, single-dose trial in patients with moderate or severe pain following third molar extraction. There were ten treatment arms, including dexketoprofen trometamol (12.5 mg and 25 mg) and tramadol hydrochloride (37.5 mg and 75 mg), given as four different fixed combinations and single components, with ibuprofen 400 mg as active control as well as a placebo control. The study objective was to evaluate the superior analgesic efficacy and safety of each combination and each single agent versus placebo. The primary outcome was the proportion of patients with at least 50 % max TOTPAR over six hours. Results 606 patients were randomised and provided at least one post-dose assessment. All combinations were significantly better than placebo. The highest percentage of responders (72 %) was achieved in the dexketoprofen trometamol 25 mg plus tramadol hydrochloride 75 mg group (NNT 1.6, 95 % confidence interval 1.3 to 2.1). Addition of tramadol to dexketoprofen resulted in greater peak pain relief and greater pain relief over the longer term, particularly at times longer than six hours (median duration of 8.1 h). Adverse events were unremarkable. Conclusions Dexketoprofen trometamol 25 mg combined with tramadol hydrochloride 75 mg provided good analgesia with rapid onset and long duration in a model of moderate to severe pain. The results of the dose finding study are consistent with pre-trial calculations based on empirical formulae. Trial registration EudraCT (2010-022798-32); Clinicaltrials.gov (NCT01307020). Electronic supplementary material The online version of this article (doi:10.1186/s10194-015-0541-5) contains supplementary material, which is available to authorized users.

Background: Exogenous doses of 60 mg/kg α 1 -antitrypsin (AAT) every 7 days are recommended in patients with severe AAT deficiency. However, long term administration of weekly doses is not well accepted by patients. Using pharmacokinetic simulations, we evaluated whether steady state minimum concentrations of total AAT can be maintained above the threshold of 0.5 g/l with longer intervals between doses. Methods: Several sets of exogenous AAT versus time simulations were studied using a non-linear mixed effect approach with dosage regimens every 7, 14, 21, and 28 days. For each regimen the mean exogenous AAT trough concentrations and 5/95th percentiles were determined. The results obtained were applied to estimate the individual optimal dose at 7, 14, and 21 days in six patients using Bayesian analysis. Results: The simulations showed that a dose of 50 mg/kg AAT every 7 days was sufficient to obtain nadir concentrations. Doses of 120 and 100 mg/kg every 14 days were also adequate, but 180 mg/kg given every 21 days required total AAT monitoring to avoid underdosage. Longer intervals were inappropriate. Dosage individualisation confirmed that AAT infusions given every 14 days maintained the nadir level of 0.5 g/l without a significant dose increase compared with current practice. When the time span between doses was fixed at 21 days, a mean relative AAT dose enhancement of 91% and 13%, respectively, was required to achieve sustained total AAT concentrations above the target level for 100% and 85% of the interval between doses. Conclusions: It is feasible to extend the interval between doses of AAT to 14 or 21 days to achieve adequate trough total AAT concentrations. This study might be used as a starting point for clinical evaluation of the regimens described.

Els valors d’exposició sistèmica (àrea sota la corba de concentracions plasmàtiques=AUC) terapèutica a ganciclovir són 40-50 μg·h/mL. L’avaluació de l’exposició assolida amb el règim de dosificació recomanat en fitxa tècnica va mostrar que només un 16% dels pacients assoleixen l’objectiu terapèutic. La optimització de la posologia en base a un model predictiu ajustant la dosi segons les característiques individuals de cada pacient, per assolir l’exposició adequada a ganciclovir, seria de gran utilitat. Per aquest motiu es va dissenyar un assaig clínic de superioritat (marge de superioritat del 40%), randomitzat en dos grups segons l’estratègia de dosificació en pacients transplantats d’òrgan sòlid sota tractament profilàctic o de la infecció per citomegalovirus. La dosificació en el grup A fou segons fitxa tècnica i en el grup B per predicció bayesiana utilitzant el model poblacional prèviament desenvolupat i en base a les concentracions assolides. L’objectiu principal de la tesi va ser optimitzar la posologia de ganciclovir i valganciclovir, assessorada per l’exposició al fàrmac segons l’AUC. Els objectius secundaris van incloure 1) la validació de la metòdica analítica, 2) establir un disseny d’estratègia limitada d’extracció de mostres per poder estimar paràmetres farmacocinètics, entre ells valors d’AUC de GCV i 3) avaluar l’impacte de l’optimització de la posologia en la resposta i tolerància clínica. La metòdica analítica per a la determinació de GCV mitjançant UHPLC/UV i UHPLC/MS/MS va resultar precisa i exacte complint les guies de la FDA i EMA respectivament. El valor del límit de quantificació (LLOQ) va ser de 0.5 µg/mL. Es va reduir el temps de retenció (5 minuts amb HPLC vs 0.7 min amb UHPLC) i el volum de mostra injectat (200 µL). Amb el detector MS/MS el temps de retenció va ser de 0.51 min i el LLOQ de 0.06 µg/mL. L’especificitat i correlació d’ambdós mètodes es va confirmar demostrant la intercanviabilitat de les dues tècniques. Es següent pas va ser el desenvolupament d’una estratègia de mostreig limitat. Les finestres de mostreig que es van seleccionar foren el disseny amb 3 punts (0.5-1.5, 4-5h i 6-8h post-dosi) seguit del de 2 punts (2-3h i 6-8h post-dosi) perquè presentaven la major exactitud i precisió per a l’estimació d’aclariment (CL) i volum de distribució (V2). La població per intenció de tractar inclosos en l’assaig van ser de 53 pacients (27 grup A i 26 grup B) i no es van observar diferències estadísticament significatives en els característiques basals. L’objectiu principal de percentatge d’assoliment de l’AUC diana es va avaluar mitjançant les medianes d’AUC per pacient (18.5% Grup A vs 88.4% Grup B) i analitzant totes les determinació d’AUC aïllades (18.7% Grup A vs 65.9% in Grup B). Es va demostrar la superioritat de l’estratègia de dosificació per predicció bayesiana vs la dosificació segons la fitxa tècnica, assolint el criteri de superioritat del 40%. Considerant els diferents talls de CLCR, les diferències van ser significatives pels pacients amb CLCR60 mL/min. Els resultats clínics van mostrar que els pacients tractats per la infecció per CMV i dosificats segons predicció bayesiana tenien una tendència a un eradicació viral més precoç (17.6 dies Grup A i 12.5 dies Grup B). El nombre de recidives i primoinfeccions va ser major en el grup A vs el grup B (66.67% vs 9.01% i 33.3% vs 8.3%, respectivament). La potencia del l’estratègia de dosificació per predir la probabilitat de recidiva o primoinfecció va mostrar ser significativa per a la recidiva (p=0.007). No es van observar diferències en la incidencia d’efectes adversos hematològics. La present tesi demostra l’efecte de l’ajust de dosi de GCV/VGCV per predicció bayesiana en base al model poblacional en l’assoliment de la diana terapèutica., A previous study of our group showed that solid organ transplant (SOT) patients treated with ganciclovir/valganciclovir following dosage manufacturer’s recommendations were either over or underexposed. The main objective of the doctoral thesis was dose adjustment by Bayesian prediction based on population pharmacokinetic model to optimize treatment according to a target value (area under the curve [AUC]=40-50µg·h/mL). Secondary objectives were: 1) developed and validate a chromatographic method coupled with ultraviolet (UV) and mass spectrometry (MS/MS) detection, 2) develop a clinically applicable limited sampling strategy (LSS) and 3) evaluate the impact of dose optimization in clinical efficacy and safety. The method UHPLC/UV and UHPLC/MS/MS were precise and accurate and the retention time was 0.7 and 0.51 min, respectively. The limit of quantification was 0.5 mg/L for UV and 0.06 mg/L for MSMS detection method. There was a good correlation between both techniques. An LSS was developed and sampling windows were designed. Predicted exposure using 3 sampling times (0.5–1.5, 4–5, and 6–8 hours) showed the best predictive performance. Finally a two arm, randomized and open-label, superiority trial (margin of 40%) in adult SOT recipients treated with ganciclovir/valganciclovir, either as prophylaxis or treatment of CMV infection, was carried out. (Group A: manufacturer’s recommended doses. Group B: dose adjustment based on target exposure by Bayesian prediction). Results of 53 SOT patients were analyzed. CGV dose adjustment by Bayesian prediction optimized exposure as the 88.4% of patients were within the therapeutic AUC range vs the 18.7% in the group following the manufacturer's recommendations, fulfilling the 40% of superiority margin (p=1.7x10-6). The time required to reach AUC was delayed in Group A (p=0.000029). A trend towards shorter time to viral clearance was seen for Group B vs group A (17.6 vs 12.5 days, p=0.125). The incidence of relapse (66.67% vs 9.01%) and the late CMV disease (33.3% vs 8.3%) were both higher in Group A vs B. No relevant differences in toxicity were observed. Results showed that dose adjustment based on target exposure by Bayesian prediction contributes to optimize the ganciclovir/valganciclovir treatment achieving the therapeutic AUC from the early stages of the treatment

Objectives: The study is aimed to assess whether the information contained in standard pharmacology, endocrinology, and diabetology textbooks regarding timings of administration, frequency and dose of various insulins is adequate and also to see whether the information contained in these texts is concordant with product inserts. Materials and Methods: Four standard textbooks of pharmacology, two of diabetology and three of endocrinology were assessed for the published information regarding dose, timing, and frequency of insulin administration. The product inserts of commonly available insulins in India were also studied for the same. Results: Various omissions and disparities could be seen in the coverage of insulins in standard textbooks. Posology information about premixed insulins and basal insulins have been omitted by the majority of the textbooks. Details about dose, frequency and timings of ultra-short acting insulins have also not been covered by all textbooks. Some discrepancies regarding prescribing information was also noted in product inserts, especially in case of newer insulins. Conclusions: Thus, this article stresses upon the need of a uniform source of information for providing adequate and standardized knowledge regarding timing, frequency, and dose of insulins.