The white-coat effect is an independent predictor of myocardial ischemia in resistant hypertension.

White-coat hypertension (WCH), commonly found in pseudoresistant hypertension, does not pose higher cardiovascular risk than hypertensive status. However, when the decrease of the out-of-office blood pressure does not reach normal levels - the white-coat effect (WCE) - the repercussions are still obscure. We investigated the repercussions of the WCE in myocardial perfusion in resistant hypertension (RHTN). We enrolled 129 asymptomatic RHTN subjects - divided into WCE (n = 63) and non-WCE (n = 66) - to perform rest and stress myocardial perfusion scintigraphy and biochemical tests. Groups were equal regarding age, gender and body mass index. There was a high prevalence of WCE (49%). WCE was associated with higher prevalence of myocardial ischemia (49.2% vs 7.6%, p < 0.001), microalbuminuria (60.3% vs 36.4%, p = 0.01) and higher heart rate (72 [64-80] vs 64 [60-69], p < 0.001), compared with non-WCE patients. On an adjusted logistic regression, heart rate was considered a predictor of WCE (OR = 1.10, 95% CI 1.04-1.15; p < 0.001), but not MA (OR = 1.8, 95% CI 0.8-3.9; p = 0.15). On a second model of adjusted logistic regression, WCE was an independent predictor of myocardial ischemia (OR = 14.7, 95% CI 4.8-44.8; p < 0.001). We found a high prevalence of WCE in RHTN, and this effect may predict silent myocardial ischemia in this subset of hypertensive patients. In this group of hypertensives special attention should be given to the WCE.

Hemodynamic effects of bupropion in anesthetized dogs.

Bupropion is a non-nicotinic drug used in smoking cessation therapy. However, its acute effects remain unclear. In this study, we investigated the effects of bupropion on hemodynamic parameters in pentobarbital-anesthetized mongrel dogs. Bupropion administered either in bolus injections (3 or 6 mg/kg, i.v.) or in cumulative doses of 0.01, 0.1, 1, 3 and 10 mg/kg showed, in both studies, a significant increase of mean pulmonary arterial pressure and pulmonary vascular resistance index. These results show that bupropion can elevate the pulmonary pressure. Further investigations should be done to test this effect in smokers with chronic obstructive pulmonary disease.

Hemodynamic effects of a combination of bupropion and nicotine in anesthetized dogs.

Bupropion has been used to treat psychic depression and as a therapy for smoking cessation, the latter mainly in association with nicotine. However, there have been no detailed studies of the hemodynamic effects of the association of bupropion with nicotine during replacement therapy. In this study, we evaluated the effects of such an association on the cardiovascular parameters in anesthetized dogs. Bupropion, either alone or together with nicotine, had no significant effect on the cardiac index (CI; 4.7 +/- 0.2 vs 4.3 +/- 0.1 and 3.5 +/- 0.3 vs 3.4 +/- 0.3 L x min(-1) x m(2), respectively; mean +/- SEM) and mean arterial pressure (MAP; 134 +/- 5.0 vs 145 +/- 11.0 and 118 +/- 5.0 vs 133 +/- 10.5 mmHg, respectively). There was a slight but significant increase in the systemic vascular resistance index (SVRI; 2,165 +/- 93 vs 2,645 +/- 126 and 2,335 +/- 100 vs 2,737 +/- 200 dyn x cm(-5)m(-2), respectively). However, there was a significant increase in the mean pulmonary artery pressure (MPAP; 20 +/- 0.8 vs 25 +/- 1.6 and 18 +/- 1.3 vs 25 +/- 1.6 mmHg, respectively; p < 0.05) and pulmonary vascular resistance index (IRVP; 194 +/- 11 vs 272 +/- 21 and 206 +/- 32 vs 307 +/- 42 dyn x cm-5m(-2), respectively; p < 0.05). These results show that bupropion alone or in association with nicotine does not markedly affect most hemodynamic parameters of the systemic circulation, although the significant increase in MPAP and IRVP can elevate the pulmonary pressure.

[Vasopressin intravenous infusion causes dose dependent adverse cardiovascular effects in anesthetized dogs].

BACKGROUND: Arginine vasopressin (AVP) has been broadly used in the management of vasodilatory shock. However, there are many concerns regarding its clinical use, especially in high doses, as it can be associated with adverse cardiovascular events. OBJECTIVE: To investigate the cardiovascular effects of AVP in continuous IV infusion on hemodynamic parameters in dogs. METHODS: Sixteen healthy mongrel dogs, anesthetized with pentobarbital were intravascularly catheterized, and randomly assigned to: control (saline-placebo; n=8) and AVP (n=8) groups. The study group was infused with AVP for three consecutive 10-minute periods at logarithmically increasing doses (0.01; 0.1 and 1.0 U/kg/min), at them 20-min intervals. Heart rate (HR) and intravascular pressures were continuously recorded. Cardiac output was measured by the thermodilution method. RESULTS: No significant hemodynamic effects were observed during 0.01 U/kg/min of AVP infusion, but at higher doses (0.1 and 1.0 U/kg/min) a progressive increase in mean arterial pressure (MAP) and systemic vascular resistance index (SVRI) were observed, with a significant decrease in HR and the cardiac index (CI). A significant increase in the pulmonary vascular resistance index (PVRI) was also observed with the 1.0 U/kg/min dose, mainly due to the decrease in the CI. CONCLUSION: AVP, when administered at doses between 0.1 and 1.0 U/kg/min, induced significant increases in MAP and SVRI, with negative inotropic and chronotropic effects in healthy animals. Although these doses are ten to thousand times greater than those routinely used for the management of vasodilatory shock, our data confirm that AVP might be used carefully and under strict hemodynamic monitoring in clinical practice, especially if doses higher than 0.01 U/kg/min are needed.

[Vasopressin intravenous infusion causes dose dependent adverse cardiovascular effects in anesthetized dogs.] / Infusão intravenosa de vasopressina causa efeitos cardiovasculares adversos dose-dependentes em cães anestesiados.

BACKGROUND: Arginine vasopressin (AVP) has been broadly used in the management of vasodilatory shock. However, there are many concerns regarding its clinical use, especially in high doses, as it can be associated with adverse cardiovascular events. OBJECTIVE: To investigate the cardiovascular effects of AVP in continuous IV infusion on hemodynamic parameters in dogs. METHODS: Sixteen healthy mongrel dogs, anesthetized with pentobarbital were intravascularly catheterized, and randomly assigned to: control (saline-placebo; n=8) and AVP (n=8) groups. The study group was infused with AVP for three consecutive 10-minute periods at logarithmically increasing doses (0.01; 0.1 and 1.0U/kg/min), at them 20-min intervals. Heart rate (HR) and intravascular pressures were continuously recorded. Cardiac output was measured by the thermodilution method. RESULTS: No significant hemodynamic effects were observed during 0.01U/kg/min of AVP infusion, but at higher doses (0.1 and 1.0U/kg/min) a progressive increase in mean arterial pressure (MAP) and systemic vascular resistance index (SVRI) were observed, with a significant decrease in HR and the cardiac index (CI). A significant increase in the pulmonary vascular resistance index (PVRI) was also observed with the 1.0U/kg/min dose, mainly due to the decrease in the CI. CONCLUSION: AVP, when administered at doses between 0.1 and 1.0U/kg/min, induced significant increases in MAP and SVRI, with negative inotropic and chronotropic effects in healthy animals. Although these doses are ten to thousand times greater than those routinely used for the management of vasodilatory shock, our data confirm that AVP might be used carefully and under strict hemodynamic monitoring in clinical practice, especially if doses higher than 0.01 U/kg/min are needed. Martins, LC et al.

Estudo da superposição de mecanismos fisiopatológicos como modelo de hipertensão arterial com repercussões cardíacas graves / Study of overlap of pathophysiologicalmechanisms as a model of hypertensionwith severe cardiac effects

Fundamento: Acredita-se que o rato espontaneamente hipertenso (SHR) mimetize a hipertensão arterial (HA) essencial em humanos. Lesões em órgãos-alvo nesses animais não são devidas unicamente ao aumento da pressão arterial. Outros mecanismos fisiopatológicos superajuntados talvez representem melhor o complexo dano cardiovascular observado também em humanos. Objetivo: avaliar, comparativamente, as alterações cardíacas em ratos SHR nos quais mecanismos outros de HA (renovascular, hipervolemia, disfunção endotelial) sejam superpostos. Materiais e Métodos: cinco grupos foram estudados: Controle (C,n=11); SHR (n=11); SHR + L-NAME (SHR + L-NAME, n=11); SHR com estenose cirúrgica de artéria renal (SHR + 2R-1C, n=11); SHR+ deoxicorticosterona e cloreto de sódio 0,9% (SHR+DOCA-SALT, n = 11). Foram avaliados pressão arterial caudal (PAC), hipertrofia do ventrículo esquerdo (VE) e alterações histológicas miocárdicas. Resultados: Após oito semanas, os grupos SHR + L-NAME, SHR + 2R-1C e SHR + DOCA-SALT mantiveram PAC semelhante e mais elevada que os animais SHR (159,9 ± 8,3; 162,7± 16,7 e 166,3 ± 6,7 versus 138±7,8, respectivamente), bem como a espessura relativa da parede do VE (SHR + L-NAME = 0,64 ± 0,06; SHR+DOCA-SALT=0,63 ± 0,07 versus SHR=0,57±0,03) (p < 0,05). Amassa relativa do VE dogrupo SHR+ L-NAME (4,2±1,15) foi maior que nos demais grupos (SHR=2,8±0,5; SHR + 2R-1C=3,2±0,5; SHR + DOCA-SALT = 3,1 ± 0,2) (p <0,05). O desarranjo de fibras, fibrose intersticial, espessura médio-intimal aumentada foram mais frequentes nos ratos SHR + L-NAME. Conclusão: O modelo SHR + L-NAME mostrou repercussões cardíacas mais evidentes que os demais modelos de HA, fato não explicado apenas pelos níveis de PA elevados. Tal modelo pode ser utilizado em estudos futuros como representativo de maior comprometimento cardíaco na HA grave ou em estados avançados da doença.

Background: Spontaneously hypertensive rats (SHR) are believed to mimic arterial hypertension (HA) essential in humans. The injuries on targeted organs on these animals are not due only to increased blood pressure. Other pathophysiological mechanisms may represent better the superimposed complex cardiovascular damage observed on humans as well. Objective: comparatively evaluate the cardiac abnormalities in SHR in which other mechanisms of hypertension (renovascular, fluid overload and endothelial dysfunction) are superimposed. Materials and Methods: 5 groups were studied: Control (C, n=11); SHR (n = 11); SHR + L-NAME (SHR + L-NAME, n= 11), SHR with surgical stenosis of renal artery (SHR+ 2K-1C, n = 11), SHR + deoxycorticosterone and sodium chloride 0.9% (SHR + DOCA-SALT, n = 11). The blood pressure flow (PAC), left ventricular hypertrophy (VE) (echocardiography) and myocardial histological changes were evaluated. Results:After 8 weeks, the SHR + L-NAME, SHR + 2K-1C and SHR + DOCA-SALT groups maintained similar and higher PAC than SHR (159.9 ± 8.3, 162.7 ± 16.7 and 166.3 ± 6.7 versus 138± 7.8, respectively) as well as the relative thickness of the VE wall (SHR + L-NAME = 0.64 ± 0.06, SHR + DOCA-SALT= 0, 63 ± 0.07 versus SHR = 0.57 ±0.03;) (p < 0.05). The relative LV mass (MRVE, mg/g) of the group SHR + L-NAME (4.2 ± 1.15) was higher than in other groups (SHR = 2.8 ± 0.5, SHR + 2K-1C = 3.2±0.5, SHR + DOCA-SALT = 3.1 ± 0.2) (p < 0.05). Fiber disarray, interstitial fibrosis and the increased of intima-media thickness were more frequent in SHR + L-NAME. Conclusion: SHR + L-NAME showed cardiac effects more evident than the other models of hypertension, which was not explained only by high levels of PA. This model can be used in future studies as representative of greater cardiac involvement in hypertension or severe stages of the disease.

Solid dispersions with hydrogenated castor oil increase solubility, dissolution rate and intestinal absorption of praziquantel / Dispersões sólidas com aumento de solubilidade de hidrogenado do óleo de mamona, taxa de dissolução e absorção intestinal de praziquantel

The solubility behavior of drugs remains one of the most challenging aspects in formulation development. Solid Dispersion (SD) has tremendous potential for improving drug solubility. Although praziquantel (PZQ) is the first drug of choice in the treatment of schistosomiasis, its poor solubility has restricted its delivery oral route. In spite of its poor solubility, PZQ is well absorbed in the gastrointestinal tract, but large doses are required to achieve adequate concentration at the target sites. The aim of this study was to improve the solubility and dissolution rate of PZQ and to evaluate its intestinal absorption. SDs were formulated with PEG-60 castor oil hydrogenated (CR-60) using a fusion and evaporation method. Pure PZQ and physical mixtures (PM) and PZQ-CR-60 (2:1; 1:1; 1:2 ratios) were compared as regards their solubility, dissolution and intestinal absorption. The experimental results demonstrated the improvement in the solubility, dissolution rate and intestinal absorption. In addition, the solubility behavior showed pH dependency and that the solubility of PZQ was slower in acidic medium than in neutral and basic mediums. The increase in PZQ solubility of the SD with the CR-60 could be attributed to several factors such as improved wettability, local solubilization, drug particle size reduction and crystalline or, interstitial solid solution reduction.

A solubilidade de fármacos ainda é um dos principais desafios no desenvolvimento de formulações farmacêuticas. As dispersões sólidas (DS) apresentam grande potencial para melhorar a solubilidade de fármacos. O praziquantel é o fármaco de primeira escolha no tratamento da esquistossomose, contudo a baixa solubilidade em água restringe seu uso à administração pela via oral. Apesar da baixa solubilidade, o PZQ é bem absorvido através do trato gastrintestinal, mas doses orais elevadas são requeridas para garantir concentrações suficientes de fármaco para o tecido alvo. O objetivo deste estudo foi melhorar a solubilidade, a dissolução e avaliar a absorção do PZQ. As DS foram formuladas com óleo de castor hidrogenado - PEG 60 (CR-60), pelo uso dos métodos de fusão e evaporação do solvente. PZQ puro, mistura física (MF) e DS de CR-60-PZQ (1:2; 1:1; 2:1) foram comparados quanto à solubilidade, dissolução e absorção intestinal. Os resultados experimentais mostraram aumento na solubilidade, na taxa de dissolução e na absorção intestinal do PZQ nas DS. A solubilidade do PZQ foi maior em meio ácido, mostrando uma dependência do pH. O aumento na solubilidade do PZQ nas DS com CR-60 foi atribuída a fatores como aumento da molhabilidade, solubilização local, redução granulométrica e redução da cristalinidade ou, ainda, a ocorrência de uma solução sólida intersticial.

Infusão intravenosa de vasopressina causa efeitos cardiovasculares adversos dose-dependentes em cães anestesiados / Infusión intravenosa de vasopresina causa efectos cardiovasculares adversos dependientes de la dosis en canes anestesiados / Vasopressin intravenous infusion causes dose dependent adverse cardiovascular effects in anesthetized dogs

FUNDAMENTO: A arginina-vasopressina (AVP) tem sido amplamente utilizada no tratamento do choque vasodilatador. Entretanto, há muitas questões relativas ao seu uso clínico, especialmente em altas doses, pois sua utilização pode estar associada a efeitos cardíacos adversos. OBJETIVO: Investigar os efeitos cardiovasculares da AVP em infusão IV contínua nos parâmetros hemodinâmicos em cães. MÉTODOS: Dezesseis cães saudáveis sem raça definida, anestesiados com pentobarbital, receberam um cateter intravascular e foram aleatoriamente designados para dois grupos: controle (solução salina - placebo; n=8) e AVP (n=8). O grupo do estudo recebeu infusão de AVP por três períodos consecutivos de 10 minutos a doses logaritmicamente progressivas (0,01; 0,1 e 1,0 U/kg/min), a intervalos de 20 minutos. A frequência cardíaca (HR) e as pressões intravasculares foram continuamente registradas. O debito cardíaco foi medido através do método de termodiluição. RESULTADOS: Nenhum efeito hemodinâmico significante foi observado durante a infusão de 0,01 U/kg/min de AVP, mas com as doses mais altas, de 0,1 e 1,0U/kg/min, houve um aumento progressivo na pressão arterial média (PAM) e índice de resistência vascular sistêmica (IRVS), com significante diminuição na frequência cardíaca (FC) e índice cardíaco (IC). Com a dose de 1,0 U/kg/min, também foi observado um aumento significante no índice de resistência vascular pulmonar (IRVP), principalmente devido à diminuição no IC. CONCLUSÃO: A AVP em doses entre 0,1 e 1,0 U/kg/min resultou em significantes aumentos na PAM e no IRVS, com efeitos inotrópicos e cronotrópicos negativos em animais saudáveis. Embora essas doses sejam de 10 a 1.000 vezes maiores do que as rotineiramente utilizadas no tratamento do choque vasodilatador, nossos dados confirmam que a AVP deveria ser usada cuidadosamente e sob rígida monitoração hemodinâmica na prática clínica, especialmente se doses maiores do que 0,01 U/kg/min forem necessárias.

BACKGROUND: Arginine vasopressin (AVP) has been broadly used in the management of vasodilatory shock. However, there are many concerns regarding its clinical use, especially in high doses, as it can be associated with adverse cardiovascular events. OBJECTIVE: To investigate the cardiovascular effects of AVP in continuous IV infusion on hemodynamic parameters in dogs. METHODS: Sixteen healthy mongrel dogs, anesthetized with pentobarbital were intravascularly catheterized, and randomly assigned to: control (saline-placebo; n=8) and AVP (n=8) groups. The study group was infused with AVP for three consecutive 10-minute periods at logarithmically increasing doses (0.01; 0.1 and 1.0U/kg/min), at them 20-min intervals. Heart rate (HR) and intravascular pressures were continuously recorded. Cardiac output was measured by the thermodilution method. RESULTS: No significant hemodynamic effects were observed during 0.01U/kg/min of AVP infusion, but at higher doses (0.1 and 1.0U/kg/min) a progressive increase in mean arterial pressure (MAP) and systemic vascular resistance index (SVRI) were observed, with a significant decrease in HR and the cardiac index (CI). A significant increase in the pulmonary vascular resistance index (PVRI) was also observed with the 1.0U/kg/min dose, mainly due to the decrease in the CI. CONCLUSION: AVP, when administered at doses between 0.1 and 1.0U/kg/min, induced significant increases in MAP and SVRI, with negative inotropic and chronotropic effects in healthy animals. Although these doses are ten to thousand times greater than those routinely used for the management of vasodilatory shock, our data confirm that AVP might be used carefully and under strict hemodynamic monitoring in clinical practice, especially if doses higher than 0.01 U/kg/min are needed.

FUNDAMENTO: La arginina-vasopresina (AVP) ha sido ampliamente utilizada en el tratamiento del choque vasodilatador. No obstante, hay muchos aspectos relativos a su uso clínico, especialmente en altas dosis, pues su utilización puede estar asociada a efectos cardíacos adversos. OBJETIVO: Investigar los efectos cardiovasculares de la AVP en infusión IV continua en los parámetros hemodinámicos en canes. MÉTODOS: Dieciséis canes saludables sin raza definida, anestesiados con pentobarbital, recibieron un catéter intravascular y fueron aleatoriamente designados para dos grupos: control (solución salina - placebo; n=8) y AVP (n=8). El grupo del estudio recibió infusión de AVP por tres períodos consecutivos de 10 minutos a dosis logarítimicamente progresivas (0,01; 0,1 y 1,0 U/kg/min), a intervalos de 20 minutos La frecuencia cardíaca (HR) y las presiones intravasculares fueron registradas continuamente. El débito cardíaco fue medido a través del método de termodilución. RESULTADOS: No se observó ningún efecto hemodinámico significativo durante la infusión de 0,01 U/kg/min de AVP, pero con las dosis más altas, de 0,1 y 1,0 U/kg/min, hubo un aumento progresivo en la presión arterial media (PAM) y en el índice de resistencia vascular sistémica (IRVS), con significativa disminución en la frecuencia cardíaca (FC) e índice cardíaco (IC). Con la dosis 1,0 U/kg/min, también se observó un aumento significativo en el índice de resistencia vascular pulmonar (IRVP), principalmente debido a la disminución en el IC. CONCLUSIÓN: La AVP en dosis entre 0,1 y 1,0 U/kg/min resultó en significativos aumentos en la PAM y en el IRVS, con efectos inotrópicos y cronotrópicos negativos en animales saludables. Aunque estas dosis sean de 10 a 1.000 veces mayores que las rutinariamente utilizadas en el tratamiento del choque vasodilatador, nuestros datos confirman que la AVP debería ser usada cuidadosamente y bajo rígido monitoreo hemodinámico en la práctica clínica, especialmente ...