Pharmacokinetic profile of liposome-encapsulated ropivacaine after maxillary infiltration anaesthesia

The aim of this study was to determine the pharmacokinetic parameters of liposomal ropivacaine after dental anesthesia in 14 healthy volunteers. In this randomized, double-blind and crossover study, the volunteers received maxillary infiltration of liposome-encapsulated 0.5% ropivacaine and, 0.5% ropivacaine with 1:200,000 epinephrine in two different sessions. Blood samples were collected before and after (from 15 to 1440 min) the administration of either ropivacaine formulation. HPLC with UV detection was used to quantify plasma ropivacaine concentrations. The pharmacokinetic parameters AUC(0-24) (area under the plasma concentration x time curve from baseline to 24 h), AUC(0-infinity) (area under the plasma concentration-time curve from baseline to infinity), C-max (maximum drug concentration), CL (renal clearance), T-max (maximum drug concentration time), t(1/2) (elimination half-life) and Vd (volume of distribution) were analyzed using the Wilcoxon signed-rank test. No differences (p > 0.05) were observed between both formulations for any of the pharmacokinetic parameters evaluated and plasma ropivacaine concentrations, considering each period of time. Both formulations showed similar pharmacokinetic profiles, indicating that the liposomal formulation could be a safer option for use of this local anesthetic, due to the absence of a vasoconstrictor

Pharmacokinetic Profile of Liposome-Encapsulated Ropivacaine after Maxillary Infiltration Anaesthesia

O objetivo do presente estudo foi determinar os parâmetros farmacocinéticos da ropivacaína encapsulada em lipossomas após anestesia local em 14 voluntários sadios. Neste estudo randomizado, cruzado e duplo-cego, os voluntários receberam anestesia infiltrativa na maxila de ropivacaína a 0,5% encapsulada em lipossomas e ropivacaína 0,5% com epinefrina a 1:200.000 em duas sessões distintas. Amostras de sangue foram coletadas antes e após (de 15 a 1440 min) a administração das formulações de ropivacaína. A quantificação da concentração plasmática de ropivacaína foi feita por meio de HPLC com detecção por UV. Os parâmetros farmacocinéticos AUC 0-24 (área sob a curva de concentração × tempo do tempo 0 até 24 horas) , AUC 0-∞ (área sob a curva de concentração x tempo do tempo 0 até o infinito), C max (concentração máxima da droga), CL (clearance renal), T max (tempo em que ocorre a concentração máxima); t 1/2 (meia vida de eliminação) e V d (volume de distribuição) foram analisados pelo teste de Wilcoxon. Nenhuma diferença (p > 0,05) foi observada entre as duas formulações em cada parâmetro farmacocinético avaliado e as concentrações plasmáticas de ropivacaína, considerando cada período de tempo. Ambas as formulações apresentaram perfil farmacocinético semelhante, indicando que a formulação lipossomal poderia ser uma opção mais segura para o uso deste anestésico local, devido à ausência de vasoconstritor. The aim of this study was to determine the pharmacokinetic parameters of liposomal ropivacaine after dental anesthesia in 14 healthy volunteers. In this randomized, double-blind and crossover study, the volunteers received maxillary infiltration of liposome-encapsulated 0.5% ropivacaine and, 0.5% ropivacaine with 1:200,000 epinephrine in two different sessions. Blood samples were collected before and after (from 15 to 1440 min) the administration of either ropivacaine formulation. HPLC with UV detection was used to quantify plasma ropivacaine concentrations. The pharmacokinetic parameters AUC 0-24 (area under the plasma concentration × time curve from baseline to 24 h), AUC 0-∞ (area under the plasma concentration-time curve from baseline to infinity), C max (maximum drug concentration), CL (renal clearance), T max (maximum drug concentration time), t 1/2 (elimination half-life) and Vd (volume of distribution) were analyzed using the Wilcoxon signed-rank test. No differences (p > 0.05) were observed between both formulations for any of the pharmacokinetic parameters evaluated and plasma ropivacaine concentrations, considering each period of time. Both formulations showed similar pharmacokinetic profiles, indicating that the liposomal formulation could be a safer option for use of this local anesthetic, due to the absence of a vasoconstrictor. Keywords: ropivacaine, local anesthesia, dentistry, liposome, pharmacokinetic Pharmacokinetic Profile of Liposome-encapsulated Ropivacaine after Maxillary Infiltration Anaesthesia J. Braz. Chem. Soc. 1946 Introduction Prolonged-action local anesthetic is required when postoperative pain and discomfort are expected, especially after major surgical procedures. 1 In many countries, bupivacaine, the racemic mixture of S-and D-bupivacaine, is the only long-acting local anesthetic available in dental practice. Ropivacaine (RVC), another long-acting local anesthetic of the cyclic aminoamide family, is synthesized in the S-enantiomer form and presents lower toxicity to the cardiovascular and central nervous systems, compared to bupivacaine. 2 Traditionally, most of local anesthetic formulations are administered together with a vasoconstrictor in order to increase anesthesia duration and to reduce systemic absorption rate. 3 It was recently demonstrated that the use of these formulations increased, especially those containing epinephrine 1:100.000. 5 Alternative drug delivery systems, such as liposomes, have been used to prolong the duration of action of many drugs, including local anesthetics. 6-10 These vesicles are nontoxic and nonimmunogenic because their components (phosphatidyl choline and cholesterol) are also found in biological membranes. 17 Previous authors have shown that liposomal encapsulation of bupivacaine altered its pharmacokinetic profile after extradural injection in rabbits, resulting in lower concentrations of the drug in plasma, liver and myocardium. 18 Grant and co-workers 16 observed that when encapsulated in liposomes, bupivacaine remained at the injection site for a significantly longer period of time after subcutaneous injection in mice. Attempting to simulate an accidental intravascular injection of a local anesthetic, Boogaerts and coworkers 8 assessed the acute CNS (central nervous system) and cardiac toxicities induced by intravenous infusion in rabbits of 0.25% bupivacaine, with and without epinephrine (1:200,000), compared to liposomeencapsulated bupivacaine. They demonstrated a reduction of CNS and cardiac toxicities using liposome-encapsulated bupivacaine. The addition of epinephrine to the plain solution did not decrease the CNS and cardiac toxicities induced by bupivacaine. It was recently demonstrated in animal studies, which used sciatic and infraorbital nerve blockades, that encapsulation of ropivacaine into unilamellar vesicles increased the duration and the intensity of analgesic effects. 6 Although long-acting local anesthetics are normally used in low doses in dentistry, high doses may be required for removal of four impacted third molars in a single session. The present study is the first attempt to measure the pharmacokinetic parameters of ropivacaine after maxillary infiltration anesthesia using a liposome-encapsulated formulation in healthy volunteers. The pharmacokinetic parameters of an RVC formulation containing epinephrine (vasoconstrictor) were also assessed for comparison. Experimental Materials RVC hydrochloride was donated by Cristalia Prod. Quim. Farm. Ltda (Itapira, SP, Brazil). Egg phosphatidylcholine (EPC), cholesterol (Ch) and α-tocopherol (α-T) were purchased from Sigma Chemical Company (St Louis, MO). All other reagents used were of analytical grade. RVC-liposome formulation The liposomal RVC formulations were prepared as described by Araújo and co-workers. 10 The following liposomal characterization was previously determined by Araújo and co-workers. Subjects This research was approved by the Ethical Committee of Piracicaba Dental School, University of Campinas (approval #164/2006). Fourteen healthy volunteers (seven males and seven females) aged 24 (± 3.1) years old were selected, and signed a written informed consent. The volunteers presented no systemic or oral disorders, had no history of allergy to any of the local anesthetics used, and were not taking any medication, as determined by oral questioning and by their documented health histories. Prior to the beginning and right after the end of the study, all the subjects were submitted to laboratory tests to confirm that they were in good health and that the females were not pregnant. The same tests were performed at the end of the study to ensure that all results previously obtained were not altered by the anesthetic formulations tested. These tests included cross-reactive protein, blood-hemoglobin, lymphocyte count, platelet count, erythrocyte sedimentation rate, serum (S)-sodium, S-potassium, S-chloride, S-albumin, S-alkaline phosphate, S-gamma-glutamyl-transferase, S-aspartate transaminase, S-alanine transaminase, S-creatine, plasma glucose, urea, cholinesterase, total protein, bilirubin, uric acid, urine glucose, urine leukocyte count, urine protein, and urine hemoglobin. Serology tests for human immunodeficiency virus and hepatitis B and C were also performed. Female subjects underwent a urine bHCG pregnancy test. Ambulatory procedures Anesthetic procedures In this double-blind and crossover study, the volunteers randomly received 1.8 mL of 0.5% ropivacaine with 1:200,000 epinephrine, and liposome-encapsulated 0.5% ropivacaine, for infiltration anesthesia at the apex of the right maxillary canine, in two different sessions spaced one week apart. Ropivacaine with 1:200,000 epinephrine was obtained by simple dilution of the commercially available solution of ropivacaine (Naropin ® 10 mg mL -1 , AstraZeneca, São Paulo, Brazil) immediately before application. Under sterile conditions, 5 mL of 1% ropivacaine was diluted with 5 mL of 1:100,000 (v/v) epinephrine (Drenalin ® , Ariston Ind. Quim. Farm. Ltda, São Paulo, SP, Brazil). The local anesthetics (1.8 mL) were placed into coded sterile 3 mL Luer-Lok syringes (Becton Dickinson, Curitiba, Brazil) fitted with disposable needles (30G, one-inch, Becton-Dickinson Company, Franklin Lakes, NJ, USA). After topical anesthesia on the injection site with 20% benzocaine, the formulations were injected at the maxillary buccal fold of the right-canine region at an injection rate of 1 mL min -1 . The same operator performed the maxillary infiltration anesthesia in all the subjects. Blood sampling and drug analysis Blood samples (4.5 mL) from a forearm vein were collected with a heparinized cannula before and 15, Pharmacokinetic and statistical analyses The following pharmacokinetic parameters were evaluated by computer software (PK Solutions, noncompartmental pharmacokinetics data analysis, 2001; Summit Research Services, Montrose, CO, USA): C max (maximum drug concentration); T max (maximum drug concentration time); AUC 0-24 , (area under the plasma concentration-time curve from baseline to 24 h); AUC 0-∞ (area under the plasma concentration-time curve from baseline to infinity); CL (renal clearance); t 1/2 (elimination half-life) and Vd (volume of distribution). Statistical analysis was performed using the Student's t-test in order to compare the ropivacaine concentrations between the groups at each time interval. Pharmacokinetic parameters were compared using the Wilcoxon signed-rank test. The significance level was set at 5%, and the tests were performed with BioEstat 5.0 (Fundação Mamirauá, Belém, PA, Brazil) Results and Discussion In an earlier study, Araújo and co-workers 6 demonstrated that the size distribution of liposomal formulations containing RVC presented two modes, one with a maximum at 371 nm (85%), and another with a peak at 128 nm (15%). The efficiency of encapsulation was around 24%, which was sufficient to modify the release profile of the pharmaceutical, with a reduction of the release rate over a one-hour period from 76 to 58%. In the same study it was also shown that, compared to RVC alone, the liposomal RVC formulation increased the duration and intensity of analgesic effects in sciatic and infraorbital nerve blocking experiments. Extending the earlier work of Araújo and co-workers 6 here we report on the first attempt to assess the pharmacokinetic parameters of ropivacaine after maxillary infiltration anesthesia using a liposome-encapsulated ropivacaine formulation in healthy volunteers, comparing the results with a commercial RVC formulation containing epinephrine vasoconstrictor. The calibration curve for determination of plasma ropivacaine ( 22 The detection limit for ropivacaine observed in our study (30 ng mL -1 ) was close to the limit observed by those authors (25 ng mL -1 )

Pharmaceutical policies : effects of policies regulating drug marketing

Objectives: This is a protocol for a Cochrane Review (intervention). The objectives are as follows:. Main objective To assess the effects of policies that regulate drug promotion on drug utilization, coverage or access, healthcare utilization, patient outcomes, adverse events and costs. Secondary objective(s) To assess whether the effects of policies that regulate drug promotion to patients/consumers, healthcare professionals, regulators and third-party payers differ according to drug class, clinical indication, target groups and country (high-, middle- or low-income countries)

Systematic survey of randomized trials evaluating the impact of alternative diagnostic strategies on patient-important outcomes

Objectives: To provide a perspective on the current practice of randomized clinical trials (RCTs) of diagnostic strategies focusing on patient-important outcomes. Study Design and Setting: We conducted a comprehensive search of MEDLINE and included RCTs published in full-text reports that evaluated alternative diagnostic strategies. Results: Of 56,912 unique citations, we sampled 7,500 and included 103 eligible RCTs, therefore suggesting that MEDLINE includes approximately 781 diagnostic RCTs. The 103 eligible trials reported on: mortality (n = 41; 39.8%); morbidities (n = 63; 61.2%); symptoms/quality of life/functional status (n = 14; 13.6%); and on composite end points (n = 10; 9.7%). Of the studies that reported statistically significant results (n = 12; 11.6%), we judged 7 (58.3%) as at low risk of bias with respect to missing outcome data and 4 (33.3%) as at low risk of bias regarding blinding. Of the 41 RCTs that reported on mortality, only one (2.4%) reported statistically significant results. Of 63 RCTs addressing morbidity outcomes, 11 (17.5%) reported statistically significant results, all of which reported relative effects of greater than 20%. Conclusion: RCTs of diagnostic tests are not uncommon, and sometimes suggest benefits on patient-important outcomes but often suffer from limitations in sample size and conduct. (C) 2017 Elsevier Inc. All rights reserved.Peer reviewe

Data sources for drug utilization research in Latin American countries—A cross-national study: DASDUR-LATAM study

Purpose: Drug utilization research (DUR) contributes to inform policymaking and to strengthen health systems. The availability of data sources is the first step for conducting DUR. However, documents that systematize these data sources in Latin American (LatAm) countries are not known. We compiled the potential data sources for DUR in the LatAm region. Methods: A network of DUR experts from nine LatAm countries was assembled and experts conducted: (i) a website search of the government, academic, and private health institutions; (ii) screening of eligible data sources, and (iii) liaising with national experts in pharmacoepidemiology (via an online survey). The data sources were characterized by accessibility, geographic granularity, setting, sector of the data, sources and type of the data. Descriptive analyses were performed. Results: We identified 125 data sources for DUR in nine LatAm countries. Thirty-eight (30%) of them were publicly and conveniently available; 89 (71%) were accessible with limitations, and 18 (14%) were not accessible or lacked clear rules for data access. From the 125 data sources, 76 (61%) were from the public sector only; 46 (37%) were from pharmacy records; 43 (34%) came from ambulatory settings and; 85 (68%) gave access to individual patient-level data. Conclusions: Although multiple sources for DUR are available in LatAm countries, the accessibility is a major challenge. The procedures for accessing DUR data should be transparent, feasible, affordable, and protocol-driven. This inventory could permit a comparison of drug utilization between countries identifying potential medication-related problems that need further exploration.Fil: Lopes, Luciane C.. University Of Sorocaba; BrasilFil: Salas, Daiana Maribel. University of Pennsylvania; Estados UnidosFil: Osorio de Castro, Claudia Garcia Serpa. Fundación Oswaldo Cruz; BrasilFil: Freitas Leal, Lisiane. McGill University; CanadáFil: Doubova, Svetlana V.. Mexican Institute of Social Security; MéxicoFil: Cañás, Martín. Universidad Nacional Arturo Jauretche; Argentina. Federación Médica de la Provincia de Buenos Aires; ArgentinaFil: Dreser, Anahi. Instituto Nacional de Salud Pública; MéxicoFil: Acosta, Angela. Universidad ICESI; ColombiaFil: Oliveira Baldoni, Andre. Federal University of São João Del-Rei; BrasilFil: de Cássia Bergamaschi, Cristiane. University of Sorocaba; BrasilFil: Marques Mota, Daniel. Brazilian Health Regulatory Agency; BrasilFil: Gómez Galicia, Diana L.. Universidad Autónoma del Estado de Morelos; MéxicoFil: Sepúlveda Viveros, Dino. Universidad de Chile; ChileFil: Narvaez Delgado, Edgard. No especifíca;Fil: da Costa Lima, Elisangela. Universidade Federal do Rio de Janeiro; BrasilFil: Chandia, Felipe Vera. Pontificia Universidad Católica de Chile; ChileFil: Ferre, Felipe. Universidade Federal de Minas Gerais; BrasilFil: Marin, Gustavo Horacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Universidad Nacional de La Plata; ArgentinaFil: Olmos, Ismael. State Health Services Administration; UruguayFil: Zimmermann, Ivan R.. Universidade do Brasília; BrasilFil: Fulone, Izabela. University of Sorocaba; BrasilFil: Roldán Saelzer, Juan. Instituto de Salud Pública; ChileFil: Sánchez Salgado, Juan Carlos. No especifíca;Fil: Castro Pastrana, Lucila I.. Universidad de Las Américas de Puebla; MéxicoFil: de Souza, Luiz Jupiter Carneiro. Fundación Oswaldo Cruz; BrasilFil: Machado Beltrán, Manuel. Universidad Nacional de Colombia; ColombiaFil: Tolentino Silva, Marcus. University of Sorocaba; BrasilFil: Mena, María Belén. Universidad Central del Ecuador; EcuadorFil: de França Fonteles, Marta Maria. Universidade Federal do Ceara; BrasilFil: Urtasun, Martín Alejandro. Universidad Nacional Arturo Jauretche; Argentina. Federación Médica de la Provincia de Buenos Aires; Argentin

Obesity: A New Adverse Effect of Antibiotics?

Since the introduction of antibiotics, they have been used freely, with their prescription occurring almost always when they were not necessary. The other major form of contact between humans and antibiotics, now unintentionally, is with the large amount of these drugs in the environment and in our food. The relationship between antibiotic use and the development of obesity has become increasingly evident and apparent in humans, with some authors clearly establishing the relationship between the large-scale use of antibiotics in the past 70 years and the “epidemic” of obesity that has occurred in parallel, almost as an adverse epidemiological effect. In the research effort entertained herein, a correlation between the use and abuse of antibiotics and the onset of obesity was investigated

Oral streptococci growth on aging and non-aging esthetic restorations after radiotherapy

The aim of this study was to examine Streptococcus mutans biofilm growth on both aged and non-aged restorative dental resins, which were submitted to therapeutic irradiation. Sixty-four disks of an esthetic restorative material (Filtek Supreme) were divided into 2 groups: aged group (AG) and a non-aged group (NAG). Each group was subdivided into 4 subgroups: non-irradiated and irradiated with 10Gy, 35Gy, and 70Gy. The biofilms were produced by Streptococcus mutans UA159 growing on both AG and NAG surfaces. The colony-forming units per mL (CFU/mL) were evaluated by the ANOVA and the Tukey LSD tests (&#945;=0.05). AG presented smaller amounts of CFU/mL than the NAG before irradiation and after 10Gy of irradiation (p<0.05). AG irradiated with 35 and 70Gy showed increased amount of bacterial biofilm when compared to non-irradiated and 10Gy-irradiated disks (p<0.05). The exposure to ionizing radiation at therapeutic doses promoted changes in bacterial adherence of aged dental restorative material

Editorial : new horizons in health-promoting: from methods to implementation science

New technologies with the potential to improve population health are being continually introduced through research and innovation. To improve care with available resources, it is necessary to promote the most cost-effective technologies, respecting organizational, social and ethical issues. This can be a concern in recent years with the growth in pharmaceutical expenditure being driven by new medicines for complex diseases, including cancer and orphan diseases, often though with limited health gain (Cohen, 2017; Luzzatto et al., 2018; Moreira et al., 2021; Godman et al., 2021c). This calls for greater evidence-based approaches to healthcare especially in countries with universal healthcare systems faced with rising costs and continued unmet need (Camargo et al., 2016; Fulone et al., 2016; Godman et al., 2021b)

Brazilian oral herbal medication for osteoarthritis: a systematic review protocol

Abstract Background Osteoarthritis affects 1 % of the world’s population and is the most common cause of musculoskeletal impairment in the elderly. Herbal medications are commonly used in Brazil to manage symptoms associated with osteoarthritis, and some of them are financed by the Brazilian government; however, the effectiveness of most of these agents is uncertain. The aim was to systematically review the efficacy and safety of 13 oral herbal medications used in Brazil for the treatment of osteoarthritis. Methods Randomized clinical trials eligible for our systematic review will enroll adults with osteoarthritis treated by a Brazilian herbal medication or a control group (placebo or active control). Using terms to include all forms of osteoarthritis combined with herbal medications, we will search the following electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; EMBASE; CINAHL; Web of Science; Health Star; AMED, the database of the Cochrane Complementary Medicine Field, LILACS; CAB abstracts, Clinical trial.gov, WHO trials registry, and Bank of Brazil Thesis (CAPES), to 31 January 2016, without restrictions concerning language or status of publication. Outcomes of interest include the following: symptom relief (e.g., pain), adverse events (gastrointestinal bleeding, epigastric pain, nausea, and allergic reactions), discontinuation due to adverse events, quality of life, and the satisfaction with the treatment. Dichotomous data will be summarized as risk ratios; continuous data will be given as standard average differences with 95 % confidence intervals. A team of reviewers will assess each citation independently for eligibility and in duplicate it. For eligible studies, the same reviewers will perform data extraction, bias risk assessment, and determination of the overall quality of evidence for each of the outcomes using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) classification system. Discussion This is the first study that will evaluate the use of herbal medications used in Brazil for the treatment of pain caused by osteoarthritis. The results could guide prescribers in decision-making in clinical practice, to inform the patients with pain caused by osteoarthritis in relation to effective and safe treatment options and to inform the managers of the public health system which of the plants could actually be financed by the Brazilian government. Systematic review registration PROSPERO 4201501979