Analysis of extemporaneous oral liquid from commercially available drugs in hospital

The objective of this study was to identify drugs that received dose adjustments (DA) and pharmaceutical alternatives (PA) that avoid DA, and calculate the economic percentage of this replacement. A descriptive, observational and cross-sectional study was performed in a second level hospital. The pharmacy and nursing services was accompanied to identify the drugs that received DA and the compounding techniques. After identifying all the drugs that received DA, was identified in the Brazilian market the corresponding pharmaceutical alternative, with the Drugs Price List of Brazilian Health Regulatory Agency. For those drugs that was not available any PA, was performed a research of studies that describe compounding techniques in international scientific databases. Was identify 88 drugs that received DA, and these, 50 do not have any PA. Were identified compounding techniques to 40 drugs. Although any drug has your own particularity of compounding, the compounding techniques can be grouped in five categories. The standardization of 29 drugs can reduce in 28% the DA procedure and cost saving of 34,85%/month. We can conclude that every three drugs prescribed, one received DA and every three DA, one can be avoided by the selection of 29 PA, saving cost as well. The use and standardization of five techniques would attend the pharmaceutics recommendations for better dissolution, bioavailability and patient safety

The role of organic cation transporter 2 inhibitor cimetidide, experimental diabetes mellitus and metformin on gabapentin pharmacokinetics in rats

O transportador de cátions orgânicos 2 (OCT2), expresso na membrana basolateral do túbulo proximal dos rins, promove a eliminação de compostos endógenos e de vários fármacos em uso na clínica. A gabapentina (GAB), anticonvulsivante utilizado para tratamento de dor neuropática, é eliminada principalmente por excreção renal e estudos sugerem participação da secreção ativa via OCT2. Dados experimentais observados em ratos com diabetes mellitus experimental (DME) induzido por estreptozotocina (STZ) sugerem que a hiperglicemia e/ou a redução dos níveis circulantes de insulina reduzem a expressão do OCT2. O objetivo do estudo é investigar a influência do DME, e do DME após administração de insulina, da cimetidina (inibidor de OCT2) e da metformina (substrato de OCT2) na disposição cinética da GAB em ratos. Ratos machos Wistar (n = 6 por tempo de coleta) foram divididos em cinco grupos: controle, cimetidina (dose única de cimetidina 100 mg/kg via intraperitonial), diabético (dose única de STZ 40 mg/kg via intravenosa), diabético tratado com insulina (dose única de STZ 40 mg/kg via intravenosa e doses de insulina 2 UI duas vezes por dia, por 15 dias) e metformina (dose única de metformina 100 mg/kg). Todos os animais receberam dose única de GAB (50 mg/kg, via gavagem). Amostras de plasma e urina foram coletadas até 12 horas após a administração da GAB. As concentrações plasmáticas e urinárias de GAB foram determinadas por cromatografia líquida de alta eficiência com detecção por espectrometria de massas e ultravioleta, respectivamente. A área sob a curva concentração plasmática versus tempo extrapolado ao infintito (ASC0-?) da GAB foi calculada pela quadratura de Gauss-Laguerre. A administração de dose única de GAB 50 mg/kg em ratos Wistar machos resultou em valores (média ± desvio padrão) de ASC0-?, Cmáx, Tmáx, CLT/F, t1/2, CLr e Fel de 96,31 ± 12,28 ?g.h/mL, 24,75 ± 9,26 ?g/mL, 3,66 ± 1,11 h, 0,52 ± 0,07 L/h.kg, 0,25 ± 0,07 L/h.kg e 0,48 ± 0,13, respectivamente. A disposição cinética da GAB não foi alterada após a administração simultânea de cimetidina ou metformina. O grupo diabético apresentou maiores valores de Fel quando comparado com o grupo controle (0.83 ± 0.25 × 0.48 ± 0.13, respectivamente). O Grupo Diabético tratado com insulina também apresentou maior Fel (0.85 ± 0.10) e CLr quando comparado ao grupo controle (0.55 ± 0.10 L/h.kg × 0.25 ± 0.07 L/h.kg). As diferenças encontradas podem ser explicadas pela hiperfiltração glomerular induzida pelo diabetes e pelo tratamento com insulina, devido ao aumento no fluxo sanguíneo renal. Conclui-se que o transporte ativo por OCT2 não é relevante para a disposição cinética da GAB em ratos. A hiperfiltração glomerular induzida pela diabetes mellitus experimental e pela administração de insulina sugerem que a filtração glomerular é o principal processo na eliminação renal da GAB.The organic cation transporter 2 (OCT2), expressed on the basolateral membrane of the proximal kidney tubule, promotes the elimination of endogenous compounds and various drugs in clinical use. Gabapentin (GAB), an anticonvulsant used to treat neuropathic pain, is eliminated primarily by renal excretion, and studies suggest participation of active secretion via OCT2. Experimental data observed in mice with streptozotocin (STZ) induced experimental diabetes mellitus (EDM) suggest that hyperglycemia and/or reduction of circulating insulin levels reduce OCT2 expression. The aim of the study is to investigate the influence of EDM, EDM after insulin administration, cimetidine (OCT2 inhibitor) and metformin (OCT2 substrate) on the kinetic dispostion of GAB in rats. Male Wistar rats were divided into five groups: control, cimetidine (single dose of cimetidine 100 mg/kg intraperitoneally), diabetic (single dose of STZ 40 mg/kg intravenously), diabetic treated (single dose of STZ 40 mg/kg intravenously and 2 IU twice daily for 15 days) and metformin (single dose metformin 100 mg/kg). All animals received a single dose of GAB (50 mg/kg, via gavage). Plasma and urine samples were collected up to 12 hours after GAB administration. Plasma and urine concentrations of GAB were determined by high performance liquid chromatography with detection by mass spectrometry and ultraviolet, respectively. The area under the plasma concentration versus time-extrapolated to infinity (ASC0-?) curve of GAB was calculated by the Gauss-Laguerre quadrature. Single dose administration of 50 mg/kg GAB in male Wistar rats resulted in values (mean ± standard deviation) of ASC0-?, Cmax, Tmax, CLT / F, T1/2, CLr and Fel of 96.31 ± 12.28 ?g.h/mL, 24.75 ± 9.26 ?g/mL, 3.66 ± 1.11 h, 0.52 ± 0.07 L/h.kg, 0.25 ± 0.07 L/h.kg and 0.48 ± 0.13, respectively. The kinetic disposition of GAB was not altered after the simultaneous administration of cimetidine or metformin. The diabetic group had higher Fel values when compared to the control group (0.83 ± 0.25 × 0.48 ± 0.13, respectively). The Diabetic Group treated with insulin also had higher Fel (0.85 ± 0.10) and CLr when compared to the control group (0.55 ± 0.10 L/hr.kg × 0.25 ± 0.07 L/hr.kg). The differences found may be explained by glomerular hyperfiltration induced by diabetes and by insulin treatment, due to increased renal blood flow. We concluded that the active transport by OCT2 is not relevant for the GAB kinetic disposition. Glomerular hyperfiltration induced by EDM and by insulin administration suggest that glomerular filtration is the main process in the renal elimination of GAB

Impacts of pregnancy and acute pyelonephritis on in vivo activity of organic anion transporters 1 and 3 employing furosemide pharmacokinetics

Os transportadores de ânions orgânicos (OAT) 1 e 3 são de fundamental importância na excreção renal e consequentemente no regime de dosagem de medicamentos. No entanto, pouco se conhece sobre a influência da inflamação associada à infecção renal, principalmente em gestantes, na expressão/atividade dos referidos transportadores. Assim, este estudo desenvolveu protocolos para investigação da inflamação e da gravidez na atividade in vivo dos OAT 1 e 3 pela avaliação da farmacocinética do marcador furosemida (FUR). No primeiro protocolo, o impacto da inflamação foi investigado em gestantes diagnosticadas com pielonefrite aguda (modelo de inflamação), nos segundos e terceiros trimestres da gestação. As pacientes foram tratadas com cefuroxima (CER) endovenosa 750 mg TID e receberam dose única oral de FUR 40 mg antes (n = 10) e 40 mg após (n = 7) o término do tratamento com o antibiótico, alta hospitalar e redução da inflamação. As concentrações de citocinas plasmáticas foram avaliadas nas duas etapas deste protocolo. Adicionalmente, buscou-se descrever a farmacocinética e a relação PK-PD da CER contra 3 possíveis MIC para Escherichia coli (2, 4 e 8 µg/mL) nesta população. O segundo protocolo deste estudo investigou o impacto da gestação em 10 participantes gestantes saudáveis e 12 participantes não gestantes saudáveis que receberam dose única oral de FUR 40 mg. Em todos os grupos e fases, as amostras seriadas de sangue e urina foram colhidas até 24h após a administração da FUR. Os métodos de quantificação de FUR, glicuronídeo de FUR e CER em matrizes biológicas foram desenvolvidos e validados em LC-MS/MS. A disposição cinética da FUR foi avaliada pelo modelo não compartimental. O impacto da inflamação (antes e após tratamento com CER) na farmacocinética da FUR foi avaliado pelo teste de Wilcoxon, enquanto o impacto da gravidez (grávidas e não grávidas) foi avaliado pelo teste de Mann-Whitney. O nível de significância foi fixado em 5% para ambos os testes. Os métodos bioanalíticos apresentaram sensibilidade e limites de confiança adequados para estudos de farmacocinética, possibilitando a quantificação de FUR, glicuronídeo de FUR e CER em até 24 h após as doses administradas. Quando comparado ao período pós-infecção/inflamação, as gestantes diagnosticadas com pielonefrite aguda apresentaram concentrações de citocinas plasmáticas de 2 até 100 vezes maiores para a MCP-1, TNF-α, IFN-γ, IL-6 e de até 10 vezes para a proteína C reativa. Além disso, apresentaram maiores valores medianos (intervalo interquartil) de Tmax 1,88 (1,38 - 4,52) h e menores valores de CLR 4,08 (2,36 - 6,35) L/h e CLSEC 3,95 (2,29 - 6,21) L/h de FUR. Ainda, após a primeira dose de CER, as pacientes gestantes apresentaram valores de Cmax: 43,0 (32,1 - 51,7) µg/mL, Tmax: 0,34 (0,29 - 0,46) h, AUC0-6: 66,7 (45,1 - 77,4) µgh/mL, AUC0-∞: 66,7 (45,1 - 77,4) µgxh/mL, t1/2: 1,71 (1,32 - 1,82) h, CLss: 10,3 (8,65 - 15,6) L/h, Fe: 28,2 (13,2 - 43,6) %, CLR: 3,01 (2,41 - 4,24) L/h, Vdc: 24,2 (20,3 - 29,8) L, Vdss: 23,7 (19,4 - 26,6) L e Fu 0,67 (0,59 - 0,74). O tratamento com CER empregado mostrou-se efetivo para 9 pacientes para MIC = 2 µg/mL, para 5 pacientes para MIC = 4 µg/mL e para nenhuma paciente para MIC = 8 µg/mL. Já no segundo protocolo, as participantes gestantes saudáveis apresentaram menores valores de AUC0-∞ 1110,48 (1033,88 - 1362,50) ng×h/mL, Ae 7,75 (5,67 - 10,04) mg e Fe 19,39 (14,50 - 25,11) %, como também maiores valores de CL/F 38,17 (34,83 - 45,17) L/h e CLNR 31,64 (27,91 - 41,16) L/h quando comparadas as participantes não gestantes saudáveis. Assim, conclui-se que a inflamação, avaliada pela pielonefrite aguda, reduziu a atividade in vivo dos OAT 1 e 3 em aproximadamente 50%. O estudo de PK-PD sugere que ajuste de dose de pelo menos 30% (dose total de aproximadamente 1 g) seria suficiente para que 8 das 10 pacientes investigadas apresentassem efetividade (fT>MIC ≥ 50%) para os MIC de 2 e 4 µg/mL. Finalmente, não se observou impacto da gestação na atividade in vivo dos OAT 1 e 3. No entanto, o aumento de aproximadamente 40% no CLNR e de aproximadamente 50% no CL/F das gestantes sugere que outra via de eliminação e/ou de absorção pode estar alterada nesta condição.Organic anion transporters (OAT) 1 and 3 are of fundamental importance in renal excretion and consequently in the drug dosage regimen. However, little is known about the influence of inflammation associated with kidney infection, especially in pregnant women, on the expression/activity of these transporters. Thus, this study developed protocols to investigate inflammation and pregnancy in the in vivo activity of OAT 1 and 3 employing furosemide (FUR) pharmacokinetics. In the first protocol, the impact of inflammation was investigated in pregnant women diagnosed with acute pyelonephritis (inflammation model), in the second and third trimesters of pregnancy. Patients were treated with intravenous cefuroxime (CER) 750 mg TID and received a single oral dose of FUR 40 mg before (n = 10) and 40 mg after (n = 7) the end of antibiotic treatment, hospital discharge and reduction of inflammation. Plasma cytokine concentrations were evaluated in the two phases of this protocol. Additionally, we sought to describe the pharmacokinetics and PK-PD relation of CER against 3 possible MIC for Escherichia coli (2, 4 and 8 µg/mL) in this population. The second protocol of this study investigated the impact of pregnancy in 10 healthy pregnant participants and 12 healthy non-pregnant participants who received a single oral dose of FUR 40 mg. In all groups and phases, serial blood and urine samples were collected up to 24h after FUR administration. Methods for the quantification of FUR, FUR glucuronide and CER in biological matrices were developed and validated in LC-MS/MS. The kinetic disposition of the FUR was evaluated by the non-compartmental model. The impact of inflammation (before and after CER treatment) on FUR pharmacokinetics was assessed by the Wilcoxon test, while the impact of pregnancy (pregnant and non-pregnant) was assessed by the Mann-Whitney test. The significance level was set at 5% for both tests. The bioanalytical methods showed adequate sensitivity and confidence limits for pharmacokinetic studies, allowing the quantification of FUR, FUR glucuronide and CER within 24 h after the administered doses. When compared to the post-infection/inflammation period, pregnant women diagnosed with acute pyelonephritis had plasma cytokine concentrations from 2 to 100-fold higher for MCP-1, TNF-α, IFN-γ, IL-6 and up to 10-fold for the C-reactive protein. In addition, they had higher median values (interquartile range) of Tmax 1.88 (1.38 - 4.52) h and lower values of CLR 4.08 (2.36 - 6.35) L/h and CLSEC 3.95 (2.29 - 6.21) L/h of FUR. Also, after the first dose of CER, pregnant patients had Cmax values: 43.0 (32.1 - 51.7) µg/mL, Tmax: 0.34 (0.29 - 0.46) h, AUC0-6: 66.7 (45.1 - 77.4) µg×h/mL, AUC0-∞: 66.7 (45.1 - 77.4) µg×h/mL, t1/2: 1.71 (1.32 - 1.82) h, CLss: 10.3 (8.65 - 15.6) L/h, Fe: 28.2 (13.2 - 43.6) %, CLR: 3.01 (2.41 - 4.24) L/h, Vdc: 24.2 (20.3 - 29.8) L, Vdss: 23.7 (19.4 - 26.6) L and Fu 0.67 (0.59 - 0.74). The CER treatment used was effective for 9 patients for MIC = 2 µg/mL, for 5 patients for MIC = 4 µg/mL and for no patient for MIC = 8 µg/mL. In the second protocol, healthy pregnant participants had lower AUC0-∞ 1110.48 (1033.88 - 1362.50) ng×h/mL, Ae 7.75 (5.67 - 10.04) mg and Fe 19.39 (14.50 - 25.11) %, as well as higher values of CL/F 38.17 (34.83 - 45.17) L/h and CLNR 31.64 (27.91 - 41.16) L/h when compared to healthy non-pregnant participants. Thus, we concluded that inflammation, assessed by acute pyelonephritis, reduced the in vivo activity of OAT 1 and 3 by approximately 50%. The PK-PD study suggests that a dose adjustment of at least 30% (total dose of approximately 1 g) would be sufficient for 8 of the 10 investigated patients to be effective (fT>MIC ≥ 50%) for MIC of 2 and 4 µg/mL. Finally, there was no impact of pregnancy on the in vivo activity of OAT 1 and 3. However, the increase of approximately 40% in CLNR and approximately 50% in CL/F in pregnant women suggests that another route of elimination and/or absorption may be altered in this condition

Analysis of extemporaneous oral liquid from commercially available drugs in hospital

ABSTRACT The objective of this study was to identify drugs that received dose adjustments (DA) and pharmaceutical alternatives (PA) that avoid DA, and calculate the economic percentage of this replacement. A descriptive, observational and cross-sectional study was performed in a second level hospital. The pharmacy and nursing services was accompanied to identify the drugs that received DA and the compounding techniques. After identifying all the drugs that received DA, was identified in the Brazilian market the corresponding pharmaceutical alternative, with the Drugs Price List of Brazilian Health Regulatory Agency. For those drugs that was not available any PA, was performed a research of studies that describe compounding techniques in international scientific databases. Was identify 88 drugs that received DA, and these, 50 do not have any PA. Were identified compounding techniques to 40 drugs. Although any drug has your own particularity of compounding, the compounding techniques can be grouped in five categories. The standardization of 29 drugs can reduce in 28% the DA procedure and cost saving of 34,85%/month. We can conclude that every three drugs prescribed, one received DA and every three DA, one can be avoided by the selection of 29 PA, saving cost as well. The use and standardization of five techniques would attend the pharmaceutics recommendations for better dissolution, bioavailability and patient safety