Literature and experimental data relevant to waiver of in vivo bioequivalence (BE) testing for the approval of immediate-release solid oral dosage forms containing amoxicillin trihydrate are reviewed. Solubility and permeability characteristics according to the Biopharmaceutics Classification System (BCS), therapeutic uses, therapeutic index, excipient interactions, as well as dissolution and BE and bioavailability studies were taken into consideration. Solubility and permeability studies indicate that amoxicillin doses up to 875 mg belong to BCS class I, whereas 1000 mg belongs to BCS class II and doses of more than 1000 mg belong to BCS class IV. Considering all aspects, the biowaiver procedure can be recommended for solid oral products of amoxicillin trihydrate immediate-release preparations containing amoxicillin as the single active pharmaceutical ingredient at dose strengths of 875 mg or less, provided (a) only the excipients listed in this monograph are used, and only in their usual amounts, (b) the biowaiver study is performed according to the World Health Organization-, U.S. Food and Drug Administration-, or European Medicines Agency-recommended method using the innovator as the comparator, and (c) results comply with criteria for "very rapidly dissolving" or "similarly rapidly dissolving." Products containing other excipients and those containing more than 875 mg amoxicillin per unit should be subjected to an in vivo BE study.

Background:No pricing formula has been implemented from November 2002 to date in Sri Lanka. Therefore, we initiated a study in 2003 to determine the prices, availability and affordability of medicines in the private sector of Sri Lanka in the absence of a price control.Materials and Methods:The World Health Organization/Health Action International methodology was used. The study was conducted in retail pharmacies (Rajya Osu Sala) of State Pharmaceuticals Corporation (semigovernment) and privately owned retail pharmacies (n = 15) in 2003, 2006 and 2009 in a geographical area. Essential medicines (n = 28) were studied and, for each medicine, innovator, most sold generic and cheapest generic were monitored. The medicine’s median price was compared with the international reference prices (IRP) to obtain the median price ratio. The daily wage of the lowest-paid government worker was used to calculate affordability.Results:Innovators were five to six-times the IRP at privately owned pharmacies and four to seven-times at the Rajya Osu Sala. The prices of generics were ≤1 the IRP during 6 years in privately owned and Rajya Osu Sala pharmacies. Cheapest generics were high in availability (>80%) throughout the study period. Innovators cost more than a day’s wage of the lowest-paid government worker; in contrast, generics were always less than one day’s wage. There seems to be no difference in affordability between privately owned or semigovernment pharmacies.Conclusion:In Sri Lanka, generic medicines have effective pricing and are available and affordable. No drastic changes in prices of medicine in the private sector were observed over the 6 years despite removal of price control.

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Aims The parasite, Leishmania donovani is responsible for lethal visceral leishmaniasis (VL) in humans. There is a need to investigate novel medicines as antileishmanial drugs, as medication currently introduced for leishmaniasis may cause resistance, serious side-effects, chemical instability and high cost. Therefore, this computational study was designed to explore potential phytochemical inhibitors against Leishmania donovani squalene synthase (LdSQS) enzyme, a drug target. Main methods Multiple sequence alignment was carried to detect conserved regions across squalene synthases from different Leishmania spp. Their evolutionary relationships were studied by generating phylogenetic tree. Homology modeling method was used to build a three dimensional model of the protein. The validated model was explored by docking simulation with the phytochemicals of interest to identify the most potent inhibitors. Two reported inhibitors were used as references in the virtual screening. The top hit compounds (binding energy less than -9 kcal/mol) were further subjected to intermolecular interaction analysis, pharmacophore modeling, pharmacokinetic and toxicity prediction. Key findings Seven phytochemicals displayed binding energies less than -9 kcal/mol hence demonstrating ability to be strongly bound to the active site of LdSQS to inhibit the enzymatic activity. Ancistrotanzanine B demonstrated the lowest binding affinity of -9.83 kcal/mol superior to reported inhibitors in literature. Conserved two aspartate rich regions and two signatory motifs were found in the L. donovani squalene synthase by multiple sequence alignment. In addition, study of pharmacophore modeling confirmed that top hit phytochemicals and the reported inhibitor (E5700) share common chemical features for their biochemical interaction with LdSQS. Among seven phytochemicals, 3-O-methyldiplacol showed admissible physicochemical, pharmacokinetic and toxicity predictions compared to the reported inhibitors. All seven phytochemicals satisfied in silico prediction criteria for oral bioavailability. Significance Based on the current study, these hits can be further structurally optimized and validated under laboratory conditions to develop antileishmanial drugs.

Bioequivalence studies are the usually accepted method to determine the therapeutic equivalence of two drug products. Because in-vivo bioequivalence studies are time consuming and expensive to conduct, major regulatory authorities have introduced biowaivers for some selected medicines belonging to BCS class 1 and III drugs. Comparative dissolution tests are used in biowaiver procedure to waiver the bioequivalence requirement. We performed this study to see whether two brands of paracetamol tablets are bioequivalent using the in-vitro methodology. In the first stage of this research study, British Pharmacopeia 2012 quality tests were performed on the two selected paracetamol tablet products to determine whether they are pharmaceutically equivalent. In the second stage in-vitro equivalence of the two products was determined using the biowaiver testing procedure given by the World Health Organization. Dissolution profiles were generated at pH values, 1.2, 4.5 and 6.8. Results were compared through two model independent methods, difference factor (f 1) and similarity factor (f 2). The two paracetamol tablet products tested, complied with all the quality requirements of the British Pharmacopeia 2012. For the two products, the difference factor (f 1) was below the 15 and similarity factor (f 2) was above the 50 in all dissolution test conditions. These results confirm that the two products are pharmaceutically equivalent. The test product is also bioequivalent to the reference product in-vitro, and therefore they can be interchangeable during clinical use. This study shows that in-vivo bioequivalence testing can be waived using the in-vitro method, for some pharmaceutical products such as paracetamol tablets.

BackgroundLithium is a first line drug used to treat bipolar affective disorder requiring frequent monitoring due to its narrow therapeutic index. Flame photometry is a reliable quick and cost-effective method of serum lithium estimation. ObjectiveWe aimed to validate a flame photometry method for serum lithium estimation to compare the results with a different model flame photometer and an ionselective electrode. MethodSherwood 410 flame photometer was used for the analysis. Serum samples were diluted 1:2 using a lithium blank solution containing sodium and potassium. Aqueous lithium standards were prepared using the same blank. The method was validated for the concentration range 0.2-1.5mmol/l. Linearity, recovery, accuracy, precision and stability were determined by standard lithium serum samples representing the lower limit of quantification (LLOQ) 0.2mmol/l, median level of quantification (MLOQ) 0.8mmol/l and the upper limit of quantification (ULOQ) 1.5mmol/l. Five replicates of serum and aqueous lithium samples were used to determine linearity in the range between LLOQ and ULOQ using the coefficient of determination (R2). Five standard serum replicates were used for recovery, accuracy and precision studies. Precision was determined by the coefficient of variation (CV%) on three different days. Results of the flame photometric method were compared with those of a different flame photometric method and an ion-selective electrode method. Results:The R2 for the aqueous samples and the serum samples was >0.995 demonstrating linearity. The matrix effect ranged between 92.5% and 105% for the LLOQ, MLOQ and ULOQ. The accuracy and precision for LLOQ, MLOQ of and ULOQ were below 15%. Similar results were obtained for the QC samples with the different model flame photometer and ion-selective electrode method.

Rationale, aims and objectives: The Morisky Medication Adherence Scale (MMAS-8) is a self-reported scale used in assessing medication adherence in patients on chronic therapy. Medication adherence is a neglected area of research in Sri Lanka and in this study we have attempted to validate the Sinhala translation of the MMAS-8 to determine medication adherence among patients stabilized on lithium therapy for bipolar disorder (BD).Methods: The MMAS-8 was translated to Sinhala with standard forward and backward translations from English to Sinhala. Patients with BD on stable doses of lithium were administered the Sinhala version of the MMAS-8. During the same visit, the serum lithium concentration was measured. Criterion validity was assessed using therapeutic serum lithium concentrations as the gold standard. Internal consistency was assessed using Cronbach’s alpha and Spearman’s rank correlation was used to assess test-retest reliability.Results: From a sample of 240 patients, 82.1% were considered adherent, with serum lithium concentration >0.4 mmol/L. The mean MMAS-8 score was 6.95±1.3. According to the MMAS-8 scale, 13.3% reported low adherence while 43.3% reported medium and high adherence equally using MMAS cut offs <6, 6 to<8 and 8 respectively. The scale sensitivity to identify adherence at a cut-off score of 6 was 86.3%. The test–retest reliability value was 0.708 (p<0.001). Internal consistency was found with a Cronbach’s alpha value of 0.608 for the 8 items of the scale.Conclusion: The Sinhala version of MMAS-8 can be used as a sensitive instrument to identify medication adherence in patients with bipolar disorders.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative pathogen for the novel COVID-19 disease. SARS-CoV-2 papain-like protease (PLpro) is responsible for viral replication and host innate immunity suppression. Thus, this study aimed to explore potential phytochemical inhibitors against this dual therapeutic target using virtual screening methods. Thirty-one phytochemicals with reported anti-SARS-CoV-1 PLpro activity were used to construct the phytochemical library along with two positive controls. Molecular docking using AutoDock 4.2 was employed to calculate binding affinity and inhibition constant of each compound within the S3/S4 binding pocket of SARS-CoV-2 PLpro. Based on the docking results, twelve compounds were subjected to non-covalent interaction analysis utilizing the Discovery Studio Visualizer software. Further, their physicochemical, pharmacokinetics and toxicity descriptors were evaluated using molinspiration and pkCSM web servers, respectively. Hirsutenone from Alnus japonica and broussoflavan A from Broussonetia papyrifera, displayed the strongest binding affinity (-8.23 kcal/mol and -8.13 kcal/mol), lowest inhibition constant (920.39 nM and 1.1 μM) and highest ligand efficiency (0.34 and 0.26) among all phytochemicals towards the binding pocket of SARS-CoV-2 PLpro, demonstrating superiority to PLpro inhibitors, 3k and GRL0617 which were used as positive controls. Additionally, hirsutenone, broussoflavan A and broussochalcone A (from Broussonetia papyrifera) possessed favorable physicochemical properties for oral drug development, satisfying Lipinski’s and Veber’s rules. Furthermore, in silico pharmacokinetics and toxicity predictions revealed that the three aforementioned phytochemicals are water soluble, non-mutagenic, non-hepatotoxic and biologically safe. Hence these lead compounds might be exploited to accelerate the drug discovery process against the ongoing COVID-19 infection.