Dynamic Contrast-Enhanced MRI Using a Macromolecular MR Contrast Agent (P792): Evaluation of Antivascular Drug Effect in a Rabbit VX2 Liver Tumor Model

OBJECTIVE: To evaluate the utility of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) using macromolecular contrast agent (P792) for assessment of vascular disrupting drug effect in rabbit VX2 liver tumor models. MATERIALS AND METHODS: This study was approved by our Institutional Animal Care and Use Committee. DCE-MRI was performed with 3-T scanner in 13 VX2 liver tumor-bearing rabbits, before, 4 hours after, and 24 hours after administration of vascular disrupting agent (VDA), using gadomelitol (P792, n = 7) or low molecular weight contrast agent (gadoterate meglumine [Gd-DOTA], n = 6). P792 was injected at a of dose 0.05 mmol/kg, while that of Gd-DOTA was 0.2 mmol/kg. DCE-MRI parameters including volume transfer coefficient (K(trans)) and initial area under the gadolinium concentration-time curve until 60 seconds (iAUC) of tumors were compared between the 2 groups at each time point. DCE-MRI parameters were correlated with tumor histopathology. Reproducibility in measurement of DCE-MRI parameters and image quality of source MR were compared between groups. RESULTS: P792 group showed a more prominent decrease in K(trans) and iAUC at 4 hours and 24 hours, as compared to the Gd-DOTA group. Changes in DCE-MRI parameters showed a weak correlation with histologic parameters (necrotic fraction and microvessel density) in both groups. Reproducibility of DCE-MRI parameters and overall image quality was not significantly better in the P792 group, as compared to the Gd-DOTA group. CONCLUSION: Dynamic contrast-enhanced magnetic resonance imaging using a macromolecular contrast agent shows changes of hepatic perfusion more clearly after administration of the VDA. Gadolinium was required at smaller doses than a low molecular contrast agent.

Herpes zoster-associated acute urinary retention in immunocompetent patient

Herpes zoster-associated urinary retention is an uncommon event related to virus infection of the S2-S4 dermatome. The possible major reasons are ipsilateral hemicystitis, neuritis-induced or myelitis-associated virus infection. We report a case of a 65-year-old immunocompetent female patient who presented an acute urinary retention after four days under treatment with valacyclovir for gluteal herpes zoster. The patient had to use a vesical catheter, was treated with antibiotics and corticosteroids and fully recovered after eight weeks.

In vitro dissolution and physicochemical characterizations of novel PVP-based solid dispersions containing valsartan prepared by a freeze-drying method

Valsartan [VAL] shows poor oral bioavailability mainly as a result of its low water solubility at low pH. This study is designed to investigate the dissolution properties and physicochemical characteristics of novel PVP-based solid dispersions [SDs] containing VAL. The SDs were prepared with polyvinylpyrrolidone [PVP-K30] as a hydrophilic polymer, sodium hydroxide [NaOH] as an alkalizer, and poloxamer 188 [F68] as a surfactant, without using any organic solvents by a freeze-drying method. The dissolution study was carried out and the physicochemical properties of SDs were also characterized by using differential scanning calorimetry [DSC], fourier transform-infrared [FT-IR] spectroscopy, X-ray diffractometry [XRD] and scanning electron microscopy [SEM]. The dissolution rates of SDs were significantly improved at pH 1.2 and pH 6.8 compared to that of pure drug. The results of physicochemical properties suggested that some interactions between VAL and carriers had occurred in the molecular level and the drug presented in the SDs was amorphous. It was concluded that the novel PVP-based SDs has been successfully prepared by a freeze-drying method, resulting in significant dissolution improvement of VAL

[Separation and assay of some methyl biphenyl derivatives used as angiotensin II antagonists and antihypertensives by using high performance liquid chromatography reversed phase]

Angiotensin II antagonists are major development in hypertension management in over decade, because of their excellent lower side effects and their specific action, as well as their effectiveness. So the research purposed to develop HPLC reserved phase for separation and assay of some angiotensin II antagonists, Valsartan, Losartan and Irbesartan in, raw materials and tablets. Chromatographic separation was achieved on coloun C18 using isocratic elution [at flow rate 1.5 ml/min] by using 10 mM potassium dihydrogen, phosphate buffer [pH=3] and acetonetrile [60: 40 v/v] as the mobile phase and ultraviolet detector set at 254 nm. This method had been validated and accepted, then this method had applied on human serums after using solid-liquid extraction for determination therapeutic concentrations of valsartan in group of patients treated with it

Effects of metronidazole, tinidazole, captopril and valsartan on taste and serum levels of zinc and magnesium

To study the effect of metronidazole, tinidazole, captopril and valsartan on the levels of zinc and magnesium in the serum of rabbits and humans and the histology of taste buds in rabbits. We conducted this study in the College of Medicine and Teaching Hospital, Basrah, Iraq from April 2005 to September 2006. It was in 2 parts: a clinical observational study of 54 patients treated with one of these drugs. The second part involved oral administration of metronidazole [45mg/kg], tinidazole [40mg/kg], captopril [3mg/kg] or valsartan [3mg/kg] or normal saline to 42 rabbits randomly. Serum zinc and magnesium were measured, and histological sections of tongues were examined for taste buds. In rabbits, oral metronidazole [13.6%] or tinidazole [7%] resulted in a significant reduction in serum zinc. Reductions in captopril [6.7%] and valsartan [4.2%] were smaller and insignificant. Body weight increased by 15.5gm [1391 +/- 225.3 gm to 1407 +/- 223.2 gm] in the control group, a lesser increase of approximately 8 gm, was found in the metronidazole group [1452 +/- 222.6 gm to 1460 +/- 221.9 gm]. Rabbit tongues showed moderate degeneration of taste buds caused by tinidazole, severe degeneration of captopril and minimal changes of valsartan. In humans, the drugs did not result in significant changes in serum zinc or magnesium. Approximately 73.3% of patients in the metronidazole group and 11.1% in the valsartan group had taste changes. It is concluded that metronidazole and tinidazole, but not captopril or valsartan resulted in a significant reduction of zinc level in rabbit, but not in human. Captopril and not valsartan caused severe degeneration in taste buds. Serum zinc level seems not to be related to taste buds changes

Varicela: consultas frecuentes acerca de su tratamiento y el manejo de los contactos / Varicella: frequent questions on treatment and recommendations for management of contacts

Dealing with varicella often causes doubts to general practitioners and pediatricians. In this article the author summaries guidelines based on solid evidence to treat varicella and prevent the disease in susceptible contacts in different clinical scenarios and presents his personal point of view in those controversial aspects commonly resolved by the authorized opinión of experts.

El manejo de la varicela despierta, con alta frecuencia, dudas en los médicos generales y pediatras. En este artículo, el autor resume aquellas recomendaciones basadas en sólida evidencia, para tratar la varicela y prevenir la enfermedad en los contactos susceptibles de un caso índice, en diferentes situaciones clínicas. Además emite su personal punto de vista en aquellos aspectos que despiertan controversia y comúnmente son resueltos en base a la opinión de reconocidos expertos.

Infección congénita por citomegalovirus: nuevos aspectos terapéuticos / Congenital cytomegalovirus infection: new therapeutic aspects

La infección por citomegalovirus es la infección congénita más frecuente, presentando morbimortalidad perinatal y secuela neurológica tanto en primoinfección como en reactivación durante el embarazo. Se presenta el caso de una embarazada con lupus eritematoso sistémico, en tratamiento inmunosupresor, que presentó reactivación de infección por citomegalovirus. Se discuten los mecanismos de transmisión y de diagnóstico prenatal, así como nuevas alternativas terapéuticas in útero.

Cytomegalovirus infection is the most common congenital infection, causing perinatal morbidity and neurological sequel in both primary infection and reactivation during pregnancy. A case of a pregnant woman with lupus, in immunosuppressive therapy that suffered reactivation of the cytomegalovirus infection is presented. We discuss the mechanisms of transmission and prenatal diagnosis, as well as new therapeutic alternatives wail in uterus.

Efecto de la n-acetilcisteína, valsartan y lisinopril en la prevención de la disfunción renal precoz secundaria a neumoperitoneo: modelo en ratas / Effect of n-acetylcysteine, valsartan and lisinopril in preventing renal insufficiency secondary to pneumoperitoneum in a rat model

Introducción: El trasplante renal es el tratamiento de elección para los pacientes en insuficiencia renal terminal. A pesar que la nefrectomía clásica del donante vivo ha resultado ser un procedimiento seguro y bien tolerado, existen factores que desincentivan este acto de donación. La nefrectomía laparoscópica del donante vivo ha dado una respuesta a este último punto. Sin embargo, varios investigadores han comunicado mayor disfunción renal precoz en riñones procurados laparoscópicamente en comparación con los procurados en forma clásica abierta. Existe información que la Nacetilcisteina y Valsartán tendrían un efecto protector frente al neumoperitoneo. Con respecto al Lisinopril (inhibidor ECA) existen datos disímiles. El objetivo de este trabajo es evaluar la utilidad dela N-acetilcisteína, Valsartán y Lisinopril en la prevención de la disfunción renal precoz de riñones sometidos a neumoperitoneo en un modelo en ratas. Material y métodos: Se utilizaron 40 ratas Sprague Dawley, macho, de 250 a 300 g, separadas en 4 grupos: Grupo 1: 10 ratas sometidas a hidratación subcutánea con solución salina (control), Grupo 2: 10 ratas sometidas a hidratación subcutánea con solución salina más N-acetilcisteina, Grupo 3: 10ratas sometidas a hidratación subcutánea con solución salina más Valsartán, y Grupo 4: 10 ratas sometidas a hidratación subcutánea con solución salina más Lisinopril. Las ratas fueron anestesiadas y colocadas en neumoperitoneo a 12 mmHg por 90 minutos. Luego las ratas se colocaron en jaula metabólica donde se midió diuresis, presión arterial, función renal, microalbuminuria y enzimas tubulares. Las ratas fueron sacrificadas al séptimo día realizándose estudio histológico. En el análisis estadístico se utilizaron modelos lineales generalizados, análisis de la varianza (Anova) y test exacto de Fisher y Chi-cuadrado...

Introduction: Renal transplant it the treatment of choice for patients with terminal renal insufficiency. Classic open live donor nephrectomy is a safe and well tolerated procedure, however there some factors that may inhibit patients from donating. Laparoscopic live donor nephrectomy has gained wide acceptance, nevertheless several authors have reported early renal insufficiency in these patients compared to those harvested through the classic approach. Apparently n-acetylcysteine and valsartan would have a protective effect against pneumoperitoneum, however there is contradicting data for Lisinopril. We evaluate n-acetylcysteine, valsartan and lisinopril for prevention of early renal insufficiencyin kidneys undergoing pneumoperitoneum in a rat model. Material and methods: A total of 40 male rats (Sprague Dawley) of 250 and 300 grams were divided in4 groups. Group 1 (control): 10 rats with subcutaneous hydration with saline. Group 2: 10 rats with subcutaneous hydration with saline and n-acetylcysteine. Group 3: 10 rats with subcutaneous hydration with saline and Valsartan and Group 4: 10 rats with subcutaneous hydration with saline and Valsartan. All rats underwent general anesthesia with pneumoperitoneum at 12 mmHg for 90 minutes. Rats were placed in a metabolic cage where urine output, blood pressure, renal function, microalbuminuria and tubular enzymes were measured. At postoperative day seven, all animals were put to sleep and histological analysis was performed. Statistics was done using lineal generalized models, Anova, Fisher and Chi-square models were also used. Results: Pneumoperitoneum did not produce early renal insufficiency. Rats with lisinopril presented a decrease in creatinine clearance (0,92 ml/min) p=0,056; higher microalbuminuria (27073,9 mg/dl/creatininuria) p < 0,001 and more histological lesions p=0,017. Urine output, blood pressure, tubular...

Dual renin-angiotensin system blockade plus oral methylprednisone for the treatment of proteinuria in IgA nephropathy / Doble bloqueo del sistema renina-angiotensina más metilprednisona oral para el tratamiento de la proteinuria en la nefropatía por IgA

Renin-angiotensin system inhibition is a widely accepted approach to initially deal with proteinuria in IgA nephropathy, while the role of immunosuppressants remains controversial in many instances. A prospective, uncontrolled, open-label trial was undertaken in patients with biopsy-proven IgA nephropathy with proteinuria more than 0.5 g/day and normal renal function to assess the efficacy of a combination treatment of angiotensin converting enzyme inhibitors plus angiotensin receptor blockers enalapril valsartan coupled with methylprednisone to decrease proteinuria to levels below 0.5 g/day. Twenty patients were included: Age 37.45 more or less 13.26 years (50% male); 7 patients (35%) were hypertensive; proteinuria 2.2 more or less 1.86 g/day; serum creatinine 1.07 more or less 0.29 mg/dl; mean follow-up 60.10 more or less 31.47 months. IgA nephropathy was subclassified according to Haas criteria. Twelve patients (60%) were class II; seven (35%) were class III and one (5%) class V. All patients received dual reninangiotensin system blockade as tolerated. Oral methylprednisone was started at 0.5 mg/kg/day for the initial 8 weeks and subsequently tapered bi-weekly until the maintenance dose of 4 mg was reached. Oral steroids were discontinued after 24 weeks (6 months) of therapy but renin-angiotensin inhibition remained unchanged. At 10 weeks of therapy proteinuria decreased to 0.15 more or less 0.07 g/day (P less than 0.001) while serum creatinine did not vary: 1.07 ± 0.28 mg/dl (P=ns). After a mean follow-up of 42.36 more or less 21.56 months urinary protein excretion (0.12 more or less 0.06 g/day) and renal function (serum creatinine 1.06 more or less 0.27 mg/dl) remained stable. No major side effects were reported during the study. Renin-angiotensin blockade plus oral steroids proved useful to significantly decrease proteinuria to less than 0.5 g/day in patients with IgA nephropathy without changes in renal function.

El doble bloqueo del sistema renina-angiotensina con inhibidores de la enzima convertidora de angiotensina junto a bloqueadores del receptor tipo I de angiotensina II es aceptado como tratamiento en la proteinuria de la nefropatía por IgA, ya que el rol de los inmunosupresores continúa siendo controvertido. Estudio prospectivo, no controlado, abierto para pacientes con nefropatía por IgA con proteinurias major que 0.5 g/día y creatininas séricas menor que 1.4 mg/dl, para evaluar la eficacia de tratamiento de enalapril más valsartán asociado a metilprednisona vía oral para disminuir las proteinurias a menor que 0.5 g/día. Fueron incluidos 20 pacientes: Edad: 37.45 más o menos 13.3 años (50% hombres); 7 pacientes (35%) eran hipertensos; proteinuria inicial 2.2 más o menos 1.86 g/día; creatinina inicial 1.07 más o menos 0.29 mg/dl; seguimiento promedio: 60.10 más o menos 31.47 meses (5 más o menos 2.62 años). La nefropatía por IgA fue subclasificada según Haas: 12 pacientes (60%) clase II; 7 (35%) clase III y 1 (5%) clase V. Todos recibieron enalapril más valsartán según tolerancia más metilprednisona vía oral en dosis de 0.5 mg/kg/día durante las primeras 8 semanas y subsecuentemente se redujo cada dos semanas hasta llegar a 4 mg. Se discontinuaron los esteroides luego de 24 semanas (6 meses). La inhibición del sistema renina angiotensina prosiguió indefinidamente. A las 10 semanas la proteinuria disminuyó de 2.2 más o menos 1.86 g/día a 0.15 más o menos 0.7 g/día (p menor que 0.001); la creatinina no varió significativamente (1.07 más o menos 0.29 mg/dl vs. 1.07 más o menos 0.28 mg/dl) (P=ns). Luego de 10 semanas y con un seguimiento de 42.36 más o menos 21.56 meses la proteinuria (0.12 más o menos 0.006 g/día) y la función renal (creatinina 1.06 más o menos 0.27mg/dl) permanecieron estables. No se informaron efectos adversos durante el estudio. El doble bloqueo del sistema renina angiotensina más bajas dosis de metilprednisona resultó útil para reducir...

Errores en la oportunidad y dosificación de aciclovir o valaciclovir en el tratamiento del herpes zoster / Erroneous prescriptions of aciclovir and valaciclovir in herpes zoster treatment

Medical prescription errors are frequent in community settings and information exploring its magnitude during antiviral treatment of herpes zoster is scarce. A questionnaire was applied to 31 physicians working in hospital- or community-based settings in Santiago, Chile in order to characterize their dosing and timing preferences for aciclovir or valaciclovir prescriptions. Aciclovir was more often prescribed than valaciclovir (71.9 and 28.1 percent, respectively), but less than a third of prescription (27.3 percent) fulfilled the minimal aciclovir dosing and timing criteria for clinical efficacy (4 gr per day and < 72 hours since rash initiaton). The limited size of the simple prevented exploring factors linked to a misleading prescription. Appropriate knowledge on dosing and timing of aciclovir/valaciclovir therapy for herpes zoster was infrequent in a sample of physicians working in various clinical settings in Chile.

Los errores en la prescripción de medicamentos son frecuentes en escenarios ambulatorios y no hay información disponible sobre el uso de antivirales en el tratamiento del herpes zoster. Para conocer la dosis y oportunidad en la prescripción de aciclovir o valaciclovir se aplicó un cuestionario a 31 médicos que trabajan en hospitales o sitios de atención primaria en Santiago y que declararon haber atendido este tipo de pacientes. El compuesto aciclovir fue más indicado que valaciclovir (71,9 vs 28,1 por ciento) pero menos de un tercio de las prescripciones (27,3 por ciento) cumplieron simultáneamente con una dosis mínima (4 g/día) y ventanas de tiempo apropiadas de aciclovir (hasta 72 horas del rash). El reducido tamaño de la muestra impidió efectuar un análisis de los factores ligados a este fenómeno. El conocimiento apropiado sobre dosis y oportunidad de aciclovir o valaciclovir fue infrecuente en un grupo de médicos que declararon atender pacientes con herpes zoster en Santiago.

Antagonistas de los receptores AT1 de la angiotensina II como drogas antiinflamatorias y citoprotectores gástricos / Angiotensin II AT1 receptor antagonists as anti-inflammatory and gastric citoprotections drugs

Objetivo: estudiar en grupos aleatorios de ratas Wistar el efecto antiinflamatorio y citoprotector gástrico de los antagonistas de los receptores AT 1 de la angiotensina II como candesartan, losartan y valsartan. Material y métodos: los animales fueron asignados en forma aleatoria a recibir: 1) etanol al 96% intragástrico 2) indometacina oral, 3) una comida sólida (pellets) durante dos horas e indometacina subcutánea (producción de úlceras del antro gástrico), 4) el edema plantar por carragenina. Resultados: los tres antagonistas de los receptores AT 1 de la angiotensina II dieron citoprotección gástrica ante el etanol 96º, con protección casi total de la mucosa gastrointestinal ante la indometacina oral, impidieron la producción de úlceras del antro gástrico inducidas por indometacina subcutánea, dando marcada respuesta antiinflamatoria ante el infiltrado de neutrófilos en la mucosa gastrointestinal (MPO), y tuvieron efecto antiinflamatorio en el modelo del edema plantar por carragenina. Conclusiones: los antagonistas de los receptores AT 1 de la angiotensinaII tienen un efecto citoprotector gástrico y antiinflamatorio.

Background: The antiinflammatory and gastric cytoprotector effect of angiotensin II AT1 receptor antagonist, such as candesartan, losartan and valsartan was studied. Material and methods: Wistar rats were ramdomly assigned to receive: 1) 96º ethanol; 2) oral indometacin, 3) solid food (pellets) during two hours and subcutaneous indometacin (production of ulcers in the gastric antrum), 4) Carrageen footpad edema. Results: The three AT1 receptor angiotensin antagonists yielded gastric cytoprotection against 96° ethanol, almost total gastrointestinal protection against oral indometacin, prevented gastric ulcers formation in the antrum induced by subcutaneous indometacin, remarkable antiinflammatory response against neutrophil infiltration on the gastrointestinal mucosa, and anti-inflammatory effect in carrageen footpad edema. Conclusions: The AT1 receptor antagonists of angiotensin II are gastric cytiprotectors with a remarkable antiinflammatory effect.

Effect of the combination of angiotensin receptor [AR] inhibitor and statin in patients with diabetic nephropathy

Despite the covencing evidence that antihypertensive treatment particularly with angiotensin converting enzyme [ACE] inhibitor, and angiotensin receptor [AR] blocker intrferes with renal disease progression, progression still cannot be completely halted, and there is a dire need for additional therapeutic intervention. Several studies have revealed the effects of statins in diabetic nephropathy. Therefore we evaluate the short-term effect of the combination of AR blocker [valsartan] and statin [simvastatin] in patients with DN. We included 24 normolipidemic patients with diabetic nephropathy. 9 of them are type I diabetes mellitus [DM], and 15 of them are type 2 DM. Each patient followed up for 3 months on valsartan [160mg /day], then for 6 months with addition of simvastatin [20 mg /day]. In simvastatin treatment' patients, proteinuria was significantly reduced by 56% [from 1242 +/- 524 to 553 +/- 314, p<0.0001] compared with baseline values. The present study demonstrates that statin [simvastatin] administration was associated with further reduction of proteinuria in normolipidemic diabetic patient already on AR blocker [valsartan]

Effects of manipulation of N-methyl-D-aspartate receptors on imipenem/cilastatin-induced seizures in rats.

BACKGROUND & OBJECTIVES: Epileptic seizures have been reported in patients on imipenem/cilastatin (Imi/Cil) therapy. To investigate contribution of N-methyl-D-aspartate (NMDA) receptors in inducing imipenem/cilastatin (Imi/Cil) seizures, the effects of competitive NMDA antagonist, APV [(+/-)-2-amino-5-phosphonovaleric acid], non-competitive NMDA antagonist remacemide [(+/-)-2-amino-N-(1-methyl-1,2-diphenylethyl)-acetamidel, and glycine receptor partial agonist HA-966 [(+/-)-(3-amino-1-hydroxypyrrolid-2-one)] on electroencephalographic (EEG) activity and behaviour were studied in rats. METHODS: Adult male Wistar albino rats were implanted with electrodes and cannulae were placed into the right lateral ventricle. Animals were divided into five groups: (i) saline (icv)+Imi/Cil (ii) APV (0.2 micromol)+Imi/Cil, (iii) APV (0.4 micromol)+Imi/Cil, (iv) remacemide (100 mg/kg, ip)+Imi/Cil, and (v) HA-966 (200 microg, icv)+Imi/Cil. The drugs were administered 30 min before icv injection of Imi/Cil (100/100 microg), and their effects on incidence of seizures, latencies to EEG changes and convulsions, severity, lethality and time to lethal outcome were studied. RESULTS: Imi/Cil provoked complete seizure response in all rats and all animals died within 10-18 min after the injection. EEG epileptiform activity preceded behavioral seizures. Clonic-tonic seizures were characterized by continuous bursts of high frequency high amplitude spikes in the EEG. The dose of 0.2 micromol of APV prolonged only the latency to the first EEG changes, while 0.4 micromol dose significantly influenced all seizure parameters. HA-966 increased only the latency to Imi/Cil-induced convulsions, while remacemide had no significant effect on seizure parameters. INTERPRETATION & CONCLUSION: The results suggested that excitatory neurotransmission contributed to the generation and/or propagation of Imi/Cil-induced seizures in rats, and that the effects of NMDA antagonists depended on a particular binding site within the NMDA receptor complex, and affinity to that site.