Optimization and Quest of HPMC loaded Stavudine Controlled Release Dosage Development by Central Composite Design utilizing Reduced Factorial Screening Technique

Abstract The current research focused on screening and finding the significant independent variables in stavudine loaded tablet, followed by optimizing the best formulation using central composite design. The objective of the study to develop stavudine loaded controlled release tablet utilizing reduced factorial design, followed by optimization technique as well as characterization of prepared tablets. Preliminary trial batches were prepared using different grades of hydroxypropyl methylcellulose. The resolution-IV reduced factorial design was selected to screen the significant independent variables in the dosage form design. A total number of eight runs were prepared and responses were recorded. The signified factors identified by half-normal and Pareto chart. The prepared tablets are evaluated for various physiochemical characterizations. Three dependent responses such as hardness, dissolution at 6 hour and 12 hours are considered in optimization process. Later on, drug-polymer interaction study was carried out. The principal of the study design based on finding the best formulation with prefixed set parameter values utilizing the concept of screening technique. It observed that HPMC K15M (57.18 %), HPMC K100 (66.32 %) and PVP K30 (7.97 %) as best composition in a formulation batch would fulfill the predetermined parameter with specific values.

Acceptability of small-sized oblong tablets in comparison to syrup and mini-tablets in infants and toddlers: A randomized controlled trial.

OBJECTIVE: There is limited evidence for the acceptability of various drug formulations holding the potential to improve medicines administration to children. Suitable formulations need to meet the requirements of pediatric patients. Previous studies have demonstrated the acceptance of mini-tablets. Oblong tablets may carry more active ingredient content per unit than mini-tablets and could be an important alternative when the drug substance requires administration of higher doses. The primary objective was to demonstrate non-inferiority of acceptability of oblong tablets in comparison to 3 ml glucose syrup in children aged 1 to 5 years. Secondary objectives were investigation of acceptability, swallowability and palatability of mini-tablets, oblong tablets and glucose syrup in children between 1 and 5 years. METHODS: An open, randomized, single dose two-way cross-over design in two parallel study arms was applied. 280 children were stratified to one of five age groups and randomized to receiving one oblong tablet (2.5 × 6 mm) in comparison either to 3 ml glucose syrup or to three mini-tablets (2 × 2 mm). Acceptability and swallowability were assessed according to pre-defined evaluation criteria. The application of the formulations was video documented to evaluate the palatability. RESULTS: As primary objective, non-inferiority was observed regarding acceptability of the oblong tablet compared to syrup in all age groups (84.4% vs 80.1%, difference 4,29% points with 95% CI of -3.00%,11.57%). For swallowability, superiority of the oblong tablet compared to syrup could be shown (74.5% vs. 53.2%, difference 21.26% points, 95% CI of 11.29%, 31.23%). Regarding palatability, <10% of children demonstrated unpleasant reaction after intake of the oblong tablet or mini-tablets as graded by both raters, however, in contrast up to 40% of children after intake of syrup. CONCLUSION: Oblong tablets are a promising, safe alternative to liquid drug formulations and administration of multiple mini-tablets in children.

Cutaneous foreign body microemboli-induced occlusive vasculopathy: A complication of illicit intravenous injection of oral opioid tablets.

Occlusive nonvasculitic vasculopathy is a process characterized clinically by retiform purpura and potential ulceration and necrosis of affected areas, secondary to blockage of small vessels without associated inflammatory vasculitis. Intravascular injection of foreign material is known to cause distal ischemia and necrosis due to thrombosis, local vasoconstriction, or microemboli formation. A 27-year-old male presented with retiform purpura and worsening distal fingertip necrosis of the right upper extremity accompanied by suspicious intravascular polarizable foreign material identified on skin, muscle, and vascular biopsies. We report a case that highlights concerning complications and dermatopathologic findings of intravascular injection of oral opioid tablets.

Uterine fibroids treatment: do we have new valid alternative? Experiencing the combination of vitamin D plus epigallocatechin gallate in childbearing age affected women.

OBJECTIVE: Uterine myomas are the most common benign tumors in females, and at least 25% of affected patients experience symptoms severe enough to need treatment, like heavy hemorrhage, pelvic pain, and infertility. Currently, a non-invasive approach is preferred in women of childbearing age who desire pregnancy. The aim of our study was to determine the effect of oral supplementation with a combination of vitamin D plus epigallocatechin gallate (EGCG) and vitamin B6 in women with myomas. PATIENTS AND METHODS: Between April and December 2020, we enrolled 95 women of childbearing age, afferent to our hospital, displaying at least one myoma with a diameter <4 cm. Patients were divided in two groups: 41 women were treated daily with two tablets of 25 µg vitamin D + 150 mg EGCG + 5 mg vitamin B6 for 4 months; 54 women, representing the control group, received no treatment. Total volume and vascularization of myomas were analyzed ultrasonographically. Bleeding and pelvic pain was also evaluated, as well as patients' quality of life and health through questionnaire Short Form Health Survey (SF-36) and Patient Global Impression of improvement (PGI-I). RESULTS: After treatment myomas' total volume and peripherical vascularization significantly decreased respectively by 37.9% (p<0.001) and 7.7%. On the other hand, we observed an increase in myomas' volume by 5.5 % and of peripherical vascularization by 5% in the control group. The treated group reported an improvement in SF-36 (p<0.001) and PGI-I (85.4%) questionnaire scores. CONCLUSIONS: We demonstrated, in young women who want to preserve fertility, that the combined supplementation of vitamin D, EGCG, and vitamin B6 reduced myomas' volume and improved patients' quality of life, without side effects.

Association between pill burden and interdialytic weight gain in patients with hemodialysis: A multi-center cross-sectional study.

High daily pill burden affects quality of life and mortality. High interdialytic weight gain (IDWG) is associated with increased mortality. We examined the association between pill burden and IDWG in hemodialysis patients. This cross-sectional study was conducted in six dialysis centers in Japan in June 2017. The exposure was the number of daily tablets, and outcome was defined as 1 day of relative IDWG divided by post-dialysis weight from the previous session. Among 188 outpatients (mean age, 68.7 [SD, 10.3] years; men, 67.0%; median dialysis vintage, 76.0 [interquartile range, 36.5, 131.5] months), the mean number of daily tablets was 19.7 ± 9.9, and mean relative weight gain was 3.5 ± 1.2%. Multiple linear regression analysis showed a regression coefficient of 0.021 (95% confidence interval: 0.004-0.039), indicating that one additional tablet prescription increased the IDWG by 0.021%. In hemodialysis patients, the daily pill burden was a significant, independent risk for increased relative IDWG.

Initial posaconazole dosing to achieve therapeutic serum posaconazole concentrations among children, adolescents, and young adults receiving delayed-release tablet and intravenous posaconazole.

Posaconazole is a broad-spectrum antifungal used for prophylaxis and treatment of invasive fungal diseases. There are limited data on the optimal dosing, safety, and efficacy of the DRT and IV formulations in immunocompromised pediatric and adolescent patients. We describe our experience including dosing, plasma trough concentrations, safety, and tolerability. Plasma concentrations ≥.7 µg/mL were considered therapeutic for prophylaxis and ≥1.0 µg/mL for treatment. Fifty-four patients (median age of 16 years) received DRT or IV formulations of posaconazole. Thirty-one (57%) patients received posaconazole for treatment and 23 (43%) for prophylaxis. Overall, 36 (67%) patients achieved targeted initial plasma trough concentrations (median 1.3 µg/mL) (Figure 1). The median daily dose among patients <13 years of age who achieved the targeted initial concentrations was 7.3 mg/kg/day for the DRT formulation and 9.8 mg/kg/day for the IV formulation. The median daily dose among patients ≥13 years of age who achieved the targeted initial concentrations was 4.9 mg/kg/day for the DRT formulation and 5.6 mg/kg/day for the IV formulation. Thirty-six patients (67%) developed transaminitis, mostly grade 1. Our observations show that DRT and IV formulations are safe and effective in immunocompromised children, adolescents, and young adults. Higher dosing per body weight of DRT and IV posaconazole may be required in patients <13 years of age compared with patients 13 years of age and older to achieve therapeutic plasma concentrations. [Figure: see text].

Population Pharmacokinetics of Vemurafenib in Children With Recurrent/Refractory BRAF Gene V600E-Mutant Astrocytomas.

Vemurafenib (Zelboraf) is an orally available BRAFV600E inhibitor approved for the treatment of unresectable or metastatic BRAFV600E -mutant melanoma. The primary objective of this work was to characterize the pharmacokinetics (PK) of vemurafenib in pediatric patients with recurrent/refractory astrocytomas harboring the BRAFV600E mutation. The study was also designed to evaluate the feasibility of replacing whole vemurafenib tablets with crushed tablets in young children unable to swallow tablets. Twenty-five pediatric patients (median age, 8.8 years; range, 3.3-19.2) with recurrent/refractory BRAFV600E -mutant astrocytomas received whole (n = 19) or crushed (n = 6) vemurafenib tablets twice daily. Plasma samples were collected on days 1, 15, and 22 in cycle 1 of vemurafenib treatment. Descriptive PK analyses demonstrated significant variability (approximately 6-fold) in drug exposure. A 1-compartment model with first-order absorption and elimination was developed by adjusting the vemurafenib PK model previously validated in adults with mutant BRAFV600E melanoma. After inclusion of allometric scaling on total body weight, the model adequately described the PK of vemurafenib in children between a wide age range of 3 to 19 years old. In the crushed-tablet cohort, relative bioavailability was approximately 96% (95% confidence interval, 49%-142%) compared to that seen in pediatric patients receiving whole tablets based on the preliminary comparison analysis results. Moderate intrapatient variability (48%) of vemurafenib clearance was observed. There was significant correlation (R2 = 0.83) between area under the plasma concentration-time curve and trough concentration at steady state. These results will help increase the number of pediatric patients for whom vemurafenib is accessible and facilitate improved dosing in pediatric patients with recurrent/refractory BRAFV600E astrocytomas.

Pharmacokinetics of tablet and liquid formulations of oral 6-mercaptopurine in children with acute lymphoblastic leukemia.

PURPOSE: Mercaptopurine (6MP) is essential to cure childhood acute lymphoblastic leukemia (ALL). A liquid 6MP formulation was recently introduced to facilitate oral 6MP administration, especially to children. Its approval and bioequivalence with 6MP tablet were based on comparative pharmacokinetics in 60 healthy adults. Due to potential pharmacokinetic differences between healthy adults and children with ALL, we compared pharmacokinetics of tablet and liquid 6MP formulations in children with ALL. METHODS: Pharmacokinetics of 50 mg 6MP tablet (Puri-Nethol®) and 20 mg/ml 6MP liquid suspension (Xaluprine®) were compared in a non-blinded, random order, single-dose, cross-over study in 16 children with ALL (eight males). 6MP was administered after a 12 h fast, and 6MP plasma concentrations measured consecutively over seven hours post-dose. Pharmacokinetic outcomes were as follows: Area under the curve (AUC), maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), and terminal half-life (T½). RESULTS: Liquid 6MP formulation resulted in a 26% lower AUC (p = 0.02) compared with tablet (median 1215 vs. 1805 h × nmol/l). No significant differences were observed for Cmax,Tmax and T½ (p = 0.28, p = 0.09, p = 0.41, respectively). Based on criteria declared by the World Health Organization the results did not establish non-inferiority of liquid 6MP formulation compared with 6MP tablet. CONCLUSION: Non-inferiority of liquid 6MP formulation compared with 6MP tablet was not demonstrated. Yet, maintenance therapy doses are adjusted by degree of myelosuppression and not by 6MP dose. Thus, in spite of a lower bioavailability, a liquid 6MP formulation is still desirable in a clinical setting, especially for children. However, if shifting between 6MP formulation is indicated, dose adjustments should be anticipated to maintain equivalent treatment intensity in children with ALL. The study is registered on clinicaltrials.gov (NCT01906671). Date of registration: 24.07.13.

Posaconazole delayed-release tablets in paediatric haematology-oncology patients.

BACKGROUND: To date, there are few studies that describe pharmacokinetics, safety and efficacy of posaconazole delayed-release tablet (DRT) formulation in the paediatric population. OBJECTIVES: We evaluated retrospectively posaconazole plasma concentrations and safety of posaconazole DRT in paediatric haematology-oncology patients. PATIENTS AND METHODS: Posaconazole DRT was assessed in 28 haematological paediatric patients with a median age 15 of years (range 5-18) and a median body weight of 50 kg (range 22-83 kg). Twenty-one patients received posaconazole DRT as prophylaxis and 7 patients as therapy. RESULTS: As prophylaxis, the median daily dose was 5.5 mg/kg/day (range 2.2-22.2) with posaconazole trough level ≥ 0.7 µg/mL in 80% by first week, 62.5% by second week and 87.5% by fourth week. As therapy, the median daily dose was 4 mg/kg/day (range 3.3-4.5) with trough level ≥ 1 µg/mL 100% by first week, 80% by second week and 33.4% by fourth week. CONCLUSIONS: Posaconazole DRT is feasible in paediatric patients capable to swallow tablets. Specific pharmacokinetic studies are needed.

Effectiveness of Risk Minimization Measures for Fentanyl Buccal Tablet (FENTORA) in Canada: A Mixed-Methods Evaluation Using Surveys, Medical Chart Records and Web Surveillance.

BACKGROUND: Fentanyl buccal tablet (FBT), a potent opioid, was approved in Canada in 2013 for breakthrough pain in opioid-tolerant adult cancer patients. Additional risk minimization measures (aRMMs), consisting of communications to patients and healthcare providers (HCPs), were implemented from November 2014 through September 2015. OBJECTIVES: The aim of this study was to assess the effectiveness of FBT aRMMs as measured by prescriber knowledge, understanding, and behavior regarding key safety concerns (off-label use, use in non-opioid-tolerant patients, misuse/abuse/diversion, and drug-drug interaction) and to evaluate illicit FBT use. METHODS: The study included three components: (1) a knowledge and understanding (KAU) survey of FBT prescribers conducted in two waves: November 2016-February 2017 and April-September 2018; (2) a retrospective prescription study of medical records of patients treated with FBT by a subgroup of prescribers from the KAU survey; and (3) Web surveillance of illicit FBT use in Canada using the search term FENTORA (May 2014-September 2018). The aRMMs were considered effective if the lower bound of the 95% confidence interval indicated that at least 65% of respondents met or partly met the knowledge objective for each key safety concern. RESULTS: KAU survey: Of 46 eligible HCPs, 97.8% met or partly met the knowledge objective on use in breakthrough pain cancer patients, 97.8% on use in opioid-tolerant patients, 89.1% on dose and titration, 100% on abuse/addiction, and 58.7% on drug-drug interaction. Retrospective prescription study: Of 22 FBT-treated patients identified from 14 HCPs, 45.5% had cancer, 50.0% recorded a breakthrough pain indication, and 36.4% reported opioid tolerance; however, only 13.6% of patients were prescribed FBT according to the approved indication. Web surveillance: Of 932 FBT posts in Canada, only 40 (4.3%) mentioned illicit use. CONCLUSIONS: The aRMMs as measured by the prescriber KAU were effective for most key safety messages; however, not all key messages of the aRMMs were stringently followed in routine practice.

Partição de Comprimidos Antineoplásicos Utilizados no Tratamento de Leucemias Agudas em Crianças e Adolescentes / Splitting of Antineoplastic Tablets Used in Acute Leukemias Treatment in Children and Adolescents / Partición de Comprimidos Antineoplásicos Empleados en el Tratamiento de Leucemias Agudas en Niños y Adolescentes

Introdução: A manipulação de antineoplásicos para ajuste de dose, como partição de comprimidos, é comum no tratamento de leucemias agudas de crianças e adolescentes. Objetivo: Identificar a frequência e descrever a prática da partição domiciliar de comprimidos antineoplásicos utilizados no tratamento oral de crianças e adolescentes com leucemias agudas na fase de manutenção. Método: Trata-se de um estudo transversal descritivo, realizado em um hospital pertencente à rede de saúde pública do Distrito Federal com assistência especializada em pediatria. Foram incluídos no estudo crianças e adolescentes entre 1 e 18 anos, diagnosticados com leucemias agudas e em fase de manutenção do tratamento no período de estudo. Foi aplicado um questionário semiestruturado ao responsável principal pela administração dos medicamentos quimioterápicos via oral, podendo ser o cuidador ou a própria criança/adolescente. Foram coletadas variáveis sociodemográficas dos pacientes e cuidadores e variáveis sobre a prática de partição de medicamentos antineoplásicos no domicílio. Resultados: Todos os 48 entrevistados no período do estudo relataram ter partido comprimidos antineoplásicos ao longo do tratamento de leucemias agudas, sendo estes mercaptopurina (n=45 [93,75%]) e tioguanina (n=3 [6,25%]). Conclusão: A partição de comprimidos antineoplásicos foi uma prática unânime em virtude da necessidade referida de ajuste de dose individual para o tratamento de leucemias agudas de crianças e adolescentes, considerando a indisponibilidade de formulações adequadas. Os resultados reforçam a necessidade de a partição ser uniformizada e realizada de maneira a minimizar os riscos e a garantir a segurança para as crianças e adolescentes e seus cuidadores.

Introduction: Antineoplastic drug manipulation for dose adjustment, such as tablet splitting, is standard in acute leukemia treatment for children and adolescents. Objective: To identify the frequency and describe the practice of household splitting of antineoplastic tablet for oral treatment of children and adolescents with acute leukemias in the maintenance phase. Method: Cross-sectional descriptive study performed in a public health system hospital from Distrito Federal (Brazil) with specialized pediatric assistance. Children and teenagers between 1 and 18 years old, diagnosed with acute leukemia and in treatment maintenance phase during the study period were included. A semi-structured questionnaire was applied to the main responsible for administering oral chemotherapy drugs, which could be the caregiver or the child/adolescent themselves. Sociodemographic variables of patients and caregivers and variables on the practice of splitting antineoplastic drugs at home were collected. Results: All 48 interviewees in the study period reported having split antineoplastic tablets during the treatment for acute leukemias, such as mercaptopurine (n = 45 [93.75%]) and thioguanine (n = 3 [6.25%]). Conclusion: The splitting of antineoplastic tablets was a unanimous practice due to the reported need to adjust the individual dose for acute leukemia treatment in children and adolescents, considering the unavailability of adequate formulations. The results reinforce the need for splitting to be standardized and performed in a way that minimizes risks and ensures safety for patients and their caregivers

Introducción: La manipulación de fármacos antineoplásicos para el ajuste de dosis, como las particiones de comprimidos, es frecuente en el tratamiento de las leucemias agudas en niños y jóvenes. Objetivo: Identificar la frecuencia y describir la práctica de la división domiciliaria de medicamentos antineoplásicos utilizados en el tratamiento oral de niños y adolescentes con leucemias agudas en la fase de mantenimiento. Método: Se trata de un estudio transversal descriptivo realizado en un hospital de la red de salud pública del Distrito Federal (Brasil) con asistencia especializada en pediatría. El estudio incluyó a niños y jóvenes de entre 1 y 18 años de edad diagnosticados con leucemia aguda y en fase de mantenimiento del tratamiento en el período del estudio. Se aplicó un cuestionario semiestructurado a la persona principal responsable de la administración de fármacos quimioterapéuticos por vía oral, que puede ser el cuidador o el propio niño/joven. Fueron colectadas variables sociodemográficas de los pacientes y cuidadores y variables sobre la práctica de la división de los medicamentos antineoplásicos en domicílios. Resultados: Los 48 entrevistados en el período de estudio informaron haber roto las pastillas antineoplásicas durante el tratamiento de la leucemia aguda, siendo éstas mercaptopurina (n=45 [93,75%]) y tioguanina (n=3 [6,25%]). Conclusión: La partición de comprimidos antineoplásicos fue una práctica unánime debido a la necesidad mencionada de ajustar la dosis individual para el tratamiento de las leucemias agudas de niños y adolescentes, considerando la falta de formulaciones apropiadas. Los resultados refuerzan la necesidad de estandarizar y realizar la partición para minimizar los riesgos y garantizar la seguridad de los niños, jóvenes y sus cuidadores.

Efficacy And Safety Of Apatinib Treatment In Platinum-Resistant Recurrent Epithelial Ovarian Cancer: A Real World Study.

OBJECTIVE: To evaluate real-world use and outcomes of apatinib treatment in platinum-resistant recurrent epithelial ovarian cancer. METHODS: This is an observational study. Patients with platinum-resistant recurrent epithelial ovarian cancer initiating apatinib treatment from January 2016 to December 2018 were included. The primary end point was progression-free survival. Other end points included overall survival, objective response rate, disease control rate, and toxicity. RESULTS: A total of 28 platinum-resistant epithelial ovarian cancer patients were enrolled in this study. Thirteen cases received apatinib as maintenance therapy following chemotherapy with a median progression-free survival of 6.0 months and a medium overall survival of 11.0 months. Four patients received apatinib as palliative following chemotherapy with 2 cases in progressive disease and 2 cases in stable disease. Eleven cases received apatinib alone as salvage therapy with a disease control rate of 81.8% and a median progression-free survival of 3.0 months. The most common adverse effects were hand-foot syndrome (53.57%), secondary hypertension (46.43%) and fatigue (14.29%). Five patients discontinued treatment due to grade 3 toxicities and 4 patients required dose reduction because of adverse effects. CONCLUSION: Apatinib produced moderate improvements in progression-free survival in patients with platinum-resistant epithelial ovarian cancer both as maintenance therapy following chemotherapy and as single-agent salvage therapy. Our study suggests that apatinib may be effective for women with platinum-resistant recurrent epithelial ovarian cancer.

Effects of Renal Impairment on the Pharmacokinetics of Once-Daily Amantadine Extended-Release Tablets.

BACKGROUND: An extended-release formulation of amantadine (Osmolex ER™, Osmotica Pharmaceutical US LLC) was approved in February 2018 to treat Parkinson's disease and drug-induced extrapyramidal reactions in adults. OBJECTIVES: To determine the pharmacokinetic profile of extended-release amantadine in subjects with varying degrees of renal impairment. METHODS: Adults with normal renal function (creatinine clearance > 89 mL/min/1.73 m2), moderate renal impairment (creatinine clearance 30-59 mL/min/1.73 m2), or severe renal impairment (estimated glomerular filtration rate < 30 mL/min/1.73 m2) received a single 129-mg dose (160 mg amantadine hydrochloride) of extended-release amantadine. Blood and urine samples for pharmacokinetic analysis were taken at scheduled intervals. A two-compartment pharmacokinetic population model was employed to determine optimum extended-release amantadine dosing in subjects with renal impairment. RESULTS: Following a single oral dose of the 129-mg extended-release amantadine tablet, amantadine plasma concentration increased slowly, reaching a peak at approximately 11 h. Amantadine elimination was reduced in subjects with renal impairment. Renal clearance decreased from 10,965 to 2618 mL/h in subjects with severe renal impairment compared to those with normal renal function. Pharmacokinetic modeling and simulation methods were used to recommend the oral administration of 129-mg extended-release amantadine tablets at intervals of 24, 48, 72, 96, 120, or 168 h depending on the degree of renal function. CONCLUSIONS: Renal impairment was associated with reduced amantadine clearance. Based on pharmacokinetic modeling and simulations, dose regimens were recommended for subjects with impaired renal function to provide systemic amantadine exposure similar to subjects with normal renal function taking a once-daily extended-release amantadine tablet.

Effects of Lactobacillus reuteri-containing lozenges on healing after surgical removal of mandibular third molars: a randomised controlled trial.

We investigated the effect of probiotic supplements on oral wound healing, swelling, pain and discomfort after surgical removal of mandibular third molars. A second aim was to evaluate if the intervention could influence the concentrations of oxytocin in saliva. Sixty-four consecutive volunteers (18-34 years) were enrolled to a double-blind randomised placebo-controlled trial with two parallel arms. Following surgery, the patients were asked to take three lozenges per day containing two strains of Lactobacillus reuteri (DSM 17938 and ATCC PTA 5289) or placebo for two weeks. The clinical healing and extra-oral swelling were scored two weeks post-operatively. Samples of wound exudate were cultivated for the presence of Staphylococcus aureus and ß-haemolytic streptococci. Salivary oxytocin concentrations were analysed from pre- and post-surgery samples using ELISA technique. Compliance and the subjective perception of swelling, pain and discomfort were reported daily through visual analogue scales in a logbook. All patients except three completed the protocol and the postoperative course was uneventful in most cases. Minor extra-oral swellings were noted in five patients, but none required antibiotic treatment. At the 2-week follow-up, there were no significant differences in clinical wound healing index, extra-oral swelling, bacterial growth or salivary oxytocin levels between the groups. The self-reported data unveiled, however, a significantly reduced sense of swelling, in particular during the second week after surgery in the probiotic test group (P<0.05). Likewise, significantly fewer nights with disturbed sleep and fewer days with sick-leave from work were reported among the participants in the test group (P<0.05). No differences were found in the post-operative use of analgesics. In conclusion, we found no significant influence of probiotic supplements on objective wound healing after surgical extraction of impacted mandibular third molars. However, since the patients' perceived significant post-operative ameliorations, further studies are needed to explore the patient's value of the intervention.

Effects of Age Among Elderly Cancer Patients on Breakthrough Pain Management with Sublingual Fentanyl Tablets.

INTRODUCTION: Sublingual fentanyl tablets (SFTs) have been shown to be a safe and effective option in controlling breakthrough cancer pain (BTcP). However, further examination is required to investigate the use of SFTs among the elderly. The aim of this study was to examine the influence of age in BTcP management with SFTs in the elderly population. METHODS: We performed subgroup analyses of a recently completed trial in two subsets of individuals: patients aged 65-74 years (low age group) and patients ≥ 75 years (high age group). Pain intensity (PI), onset of pain relief, frequency and duration of BTcP episodes, and adverse events (AEs) were assessed at 3, 7, 15, and 30 days. Health status instruments used were the Hospital Anxiety and Depression Scale (HADS-A and HADS-D) and the Short Form 12, version 2 (SF-12v2) questionnaire. RESULTS: Levels of PI at the end of the study improved significantly as compared with baseline in both the low and the high age groups (30.0% and 27.7% reduction, respectively). The onset of analgesia at the end of the study began in < 10 min in 85.0% of young-old subjects and in 62.5% of patients ≥ 75 years, but no significant differences were found. BTcP episodes lasted < 15 min in 75.0% of patients in the low age group and 58.3% in the high age group (p = 0.24). Most of patients in both groups experienced one to five BTcP daily episodes, at all assessment points. HADS-D decreased from 10.78 (± 4.33) to 8.21 (± 3.57) in the low age group, and from 10.96 (± 4.26) to 9.36 (± 3.35) in the high age group (p = 0.02). Significant differences in HADS-A scores from baseline to the end of the study were also observed in both subgroups (p < 0.05). Patients in the low age group had less favorable mental component summary (MCS) and physical component summary (PCS) scores than patients in the high age group. At the end of the study, 10.0% of young-old patients and 29.2% of patients aged ≥ 75 years reported AEs related to their treatment. The most commonly reported AEs included nausea, vomiting, constipation, somnolence, and skin disorders and they were generally mild to moderate in severity. CONCLUSIONS: The results of this study showed that SFTs provided safe and clinically meaningful pain relief in both elderly subgroups. Clinical implications of these findings await validation in large, confirmatory studies to identify age subgroup divergences among elderly cancer patients treated with SFTs.

Challenges and Lessons From Conducting A Paediatric Clinical Trial in Sub-Saharan Africa: The Case of the Praziquantel Oral Dispersible Tablets Phase II Study in Côte d'Ivoire.

The importance of implementing paediatric clinical trials for neglected tropical diseases (NTDs) in compliance with the Good Clinical Practices of the International Conference of Harmonisation (ICH-GCP) and other applicable regulatory and ethics guidelines is increasingly being recognised as an essential pathway to provide safe and effective medicines for millions of untreated children living in sub-Saharan Africa (SSA). This paper describes the learnings and challenges faced by the Pediatric Praziquantel Consortium team during the implementation of an industry-sponsored Phase II clinical study in pre-school-aged children infected with schistosomiasis, conducted in remote rural settings in Côte d'Ivoire. The importance of close interactions with the ethics committee, the regulatory and administrative authorities and the rural communities are highlighted. The difficulties faced included obtaining a valid informed consent from the child's parent or guardian, the collection of blood samples from children during the study while respecting cultural beliefs as well as the weak medical research infrastructure. The paper illustrates how a public-private collaborative partnership can promote capacity-building and high-quality NTD paediatric clinical research in SSA.

Dosimetry of 177Lu-PSMA-617 after Mannitol Infusion and Glutamate Tablet Administration: Preliminary Results of EUDRACT/RSO 2016-002732-32 IRST Protocol.

Radio-ligand therapy (RLT) with177Lu-PSMA-617 is a promising option for patients with metastatic castration-resistant prostate-cancer (mCRPC). A prospective phase-II study (EUDRACT/RSO,2016-002732-32) on mCRPC is ongoing at IRST (Meldola, Italy). A total of 9 patients (median age: 68 y, range: 53⁻85) were enrolled for dosimetry evaluation of parotid glands (PGs), kidneys, red marrow (RM) and whole body (WB). Folic polyglutamate tablets were orally administered as PGs protectors and 500 mL of a 10% mannitol solution was intravenously infused to reduce kidney uptake. The whole body planar image (WBI) and blood samples were acquired at different times post infusion (1 h, 16⁻24 h, 36⁻48 h and 120 h). Dose calculation was performed with MIRD formalism (OLINDA/EXM software). The median effective half-life was 33.0 h (range: 25.6⁻60.7) for PGs, 31.4 h (12.2⁻80.6) for kidneys, 8.2 h (2.5⁻14.7) for RM and 40.1 h (31.6⁻79.7) for WB. The median doses were 0.48 mGy/MBq (range: 0.33⁻2.63) for PGs, 0.70 mGy/MBq (0.26⁻1.07) for kidneys, 0.044 mGy/MBq (0.023⁻0.067) for RM and 0.04 mGy/MBq (0.02⁻0.11) for WB. A comparison with previously published dosimetric data was performed and a significant difference was found for PGs while no significant difference was observed for the kidneys. For PGs, the possibility of reducing uptake by administering glutamate tablets during RLT seems feasible while further research is warranted for a more focused evaluation of the reduction in kidney uptake.

Health-related quality of life among HIV-infected patients initiating treatment in Brazil in the single-tablet regimen era.

Health-related quality of life (HRQoL) is a multidimensional concept involving an individual's self-perception about how a disease or treatment impacts their daily life. In this study, we evaluated the HRQoL and factors associated with this outcome in 366 patients initiating combination Antiretroviral Therapy (cART) in Belo Horizonte, Brazil.We measured HRQoL using the EuroQoL-5D 3 level (EQ-5D) and the HIV instrument of the World Health Organization (WHOQOL-HIV BREF) and identified factors associated with HRQoL using multilevel linear regression. Participants had been on cART treatment a median of 65.5 days at the time the instruments were completed. The median HRQoL of patients on the single-tablet regimen containing efavirenz/ tenofovir/ lamivudine and the multi-tablet regimen containing dolutegravir and tenofovir/ lamivudine were high, with no significant difference between groups. Factors consistently associated with lower HRQoL were being single (unmarried), having a lower educational level, recent cigarette smoking, recent signs and symptoms of anxiety or depression, comorbid disease and the occurrence of adverse drug reactions. We observed high levels of HRQoL in cART-treated people and no differences between dolutegravir and efavirenz-based regimens. This study provides inputs to future economic analysis and identifies opportunities to increase the HRQoL of patients by targeting modifiable factors.

A phase I/II trial of olaparib tablet in combination with eribulin in Japanese patients with advanced or metastatic triple-negative breast cancer previously treated with anthracyclines and taxanes.

BACKGROUND: We conducted a multicenter phase I/II trial of olaparib plus eribulin in Japanese patients with advanced or metastatic triple-negative breast cancer (TNBC) to determine the recommended phase II dose (RP2D) (phase I) and to examine the efficacy and safety (phase II) (UMIN00009498) of the combined therapy. PATIENTS AND METHODS: In phase I, olaparib tablet was orally administered twice daily from level 1:25 mg BID to level 7:300 mg BID, with 1.4 mg/m2 of eribulin on days 1 and 8. In phase II, patients were treated with RP2D to assess the response rate (independent review). The planned sample size was 24 with a threshold of 10%. RESULTS: One of the 24 patients enrolled in phase I experienced dose-limiting toxicity. The RP2D was established as 300 mg twice daily for olaparib and 1.4 mg/m2 for eribulin. Among the 24 patients in phase II, the median number of administered courses was 5.5 (range: 1-28). Grade ≥III adverse events included neutropenia (83.3%), leucopenia (83.3%), anaemia (41.7%), febrile neutropenia (33.3%) and thrombosis (8.3%). The response rate was 29.2% (independent; N = 7/24; 90% confidence interval [CI]; 14.6-47.9). Median progression-free survival and overall survival were 4.2 (95% CI, 3.0-7.4) and 14.5 (95% CI, 4.8-22.0) months, respectively. Germline BRCA1/2 mutation status was observed in three patients in phase I and 2 patients in phase II, respectively. The Cmax and area under the curve for olaparib increased in a dose-dependent manner, and these parameters for eribulin and olaparib were not influenced by each other. CONCLUSIONS: Combination therapy of olaparib with eribulin shows antitumour activity against advanced or metastatic TNBC, but caution must be exercised in the presence of febrile neutropenia.

Randomized, Open-Label, Crossover Studies Evaluating the Effect of Food and Liquid Formulation on the Pharmacokinetics of the Novel Focal Adhesion Kinase (FAK) Inhibitor BI 853520.

BACKGROUND: BI 853520 is a potent inhibitor of focal adhesion kinase and is currently under clinical development for the treatment of non-hematological malignancies. OBJECTIVE: The objective of this study was to evaluate the effect of food and liquid dispersion on the pharmacokinetics of BI 853520 in two open-label, crossover substudies. PATIENTS AND METHODS: Sixteen patients with advanced solid tumors were enrolled in each substudy. The order of administration was randomized, and pharmacokinetic samples were collected for 48 h after administration of a 200 mg dose of BI 853520. Lack of effect would be demonstrated if the 90% confidence interval (CI) of the ratio of the adjusted geometric mean (GMR) of the area under the plasma curve (area under the plasma concentration-time curve from time zero to the last quantifiable concentration at tz [[Formula: see text]] and observed area under the plasma concentration-time curve extrapolated from time zero to infinity [AUC0-∞,obs]) and maximum plasma concentration (Cmax) did not cross the 80-125% (bioequivalence) boundaries. RESULTS: Adjusted GMRs (90% CIs) for the fed versus fasted state were 92.46% (74.24-115.16), 98.17% (78.53-122.74), and 87.34% (71.04-107.38) for [Formula: see text], AUC0-∞,obs, and Cmax, respectively. Although the 90% CIs were not within bioequivalence limits for the food-effect study, the limited reductions in these pharmacokinetic parameters after administration with a high-fat meal are unlikely to be clinically relevant. Compared with a tablet, administration of BI 853520 as a liquid dispersion did not strongly affect [Formula: see text], AUC0-∞,obs, or Cmax, resulting in adjusted GMRs (90% CIs) of 1.00 (0.92-1.09), 0.98 (0.90-1.07), and 0.93 (0.86-1.01), respectively. CONCLUSIONS: These studies demonstrate that BI 853520 can be given with no food restrictions, and as a liquid dispersion, without strongly impacting pharmacokinetics. These pharmacokinetic properties may help make BI 853520 dosing more convenient and flexible, improving treatment compliance. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov identifier: NCT01335269.