Absorption mechanism of three curcumin constituents through in situ intestinal perfusion method

This study aimed to investigate the absorption mechanism of three curcumin constituents in rat small intestines. Self-emulsification was used to solubilize the three curcumin constituents, and the rat in situ intestinal perfusion method was used to study factors on drug absorption, including drug mass concentration, absorption site, and the different types and concentrations of absorption inhibitors. Within the scope of experimental concentrations, three curcumin constituents were absorbed in rat small intestines through the active transport mechanism.

Study on transport mechanism of baicalin in Scutellariae radix extracts and effect of Angelica dahurica extracts on transport of baicalin by Caco-2 cell monolayer model / 中国中药杂志

<p><b>OBJECTIVE</b>To study the transport mechanism of baicalin of Scutellariae Radix extracts and the effect of Angelica dahurica extracts on the intestinal absorption of baicalin by using Caco-2 cell monolayer model, in order to analyze the effect mechanism of Angelica dahurica extracts on the intestinal absorption of baicalin.</p><p><b>METHOD</b>The Caco-2 cell monolayer model was established with human colonic adenocarcinoma cells, and used to study the effect of pH, time, drug concentration and temperature on the transport of baicalin in Scutellariae Radix extracts, the effect of P-gp and MRP protein-dedicated inhibitors on the bidirectional transport of baicalin in Caco-2 cell model, and the effect of angelica root extracts on baicalin absorption and transport.</p><p><b>RESULT</b>Baicalin was absorbed well at 37 degrees C and under pH 7.4 condition and concentration dependent. Its proteins became inactive at 4 degrees C, with a low transport. The bi-drectional transfer PDR was 0. 54. After P-gp inhibitor verapamil and MRP inhibitor probenecid were added, the value of PappBL-AP of baicalin decreased, but without any difference in PDR. The transport of baicalin was improved by 2.34, 3.31 and 3.13 times, after A. dahurica extract coumarin, volatile oil, and mixture of coumarin and volatile oil.</p><p><b>CONCLUSION</b>The transport mechanism of baicalin is mainly passive transfer and supplemented with efflux proteins involved. A. dahurica extracts can enhance the absorption of baicalin, which may be related to the passive transfer merchanism of baicalin. A. dahurica extracts' effect in opening the close junction among cells may be related to its expression or function in inhibiting efflux proteins.</p>

Transport of limonin in rat intestine in situ and Caco-2 cells in vitro / 药学学报

Limonin existed in citrus fruits has been shown to have anti-bacterial, anti-viral, anti-feedant, anti-nociceptive, anti-inflammatory activities and anti-carcinogenic activities. But the clinical use is limited by its low bioavailability. The aim of this study is to observe the absorption and secretion transport mechanisms of limonin in intestine which can pave the way for the further study and clinical use. The transport characteristics and mechanisms of limonin in rat were studied by in situ intestine perfusion and in vitro Caco-2 cells method. The intestinal absorption of limonin was probably via a facilitated diffusion pathway which was poor and without segment-selection. Verapamil and ketoconazole improved the absorption remarkably according to the result of in vitro Caco-2 cells study; however, probenecid had no significant effect on the absorption. The P-gp efflux and CYP3A4 metabolism were involved in the poor intestinal absorption and low bioavailability of limonin. The exploration of the intestinal absorption mechanism is crucial to the design of dosage form and clinical use of limonin.

Rising Gout, Life Threatening Public Enemy

Gout is an inflammatory arthritis characterized by recurrent attacks of inflammation caused by precipitation of monosodium urate crystals (MSU) in the joint and is associated with impaired quality of life. The incidence and prevalence of gout is increasing world wide due to the increasing size of the elderly population, kidney disease, diuretic use, dietary changes, and obesity. Furthermore, emerging evidence suggests that gout is strongly associated with metabolic syndrome and may lead to myocardial infarction, type 2 diabetes mellitus, and premature death. Urate nephropathy is also increasing. Thus, the overall disease and the economic burden of gout is substantial and increasing sharply. Although traditional urate lowering agents including allopurinol, probenecid, and benzbromarone have been available for many years, questions still remain about the optimal dosing regimen. Many patients remain undertreated for this potentially curable disorder. Fortunately, more scientific data and evidence for proper management of gout are available. Renewed interest in gout has led to advances in dietary advice and development of new therapeutic options. The importance of risk factors for gout should be emphasized and patients with gout and hyperuricemia should be educated so that they can achieve a good quality of life and longevity. In this review, the comorbidity, mortality, and economic burdens of gout will be presented. In addition, the importance of proper management and patient education will be stressed.

Functionality of drug efflux pumps in antimonial resistant Leishmania donovani field isolates.

The recent upsurge of antimony (Sb) resistance is a major impediment to successful chemotherapy of visceral leishmaniasis (VL). Mechanisms involved in antimony resistance have demonstrated an upregulation of drug efflux pumps; however, the biological role drug efflux pumps in clinical isolates remains to be substantiated. Thus, in this study, the functionality of drug efflux pumps was measured in promastigotes and axenic amastigotes isolated from VL patients, who were either Sb-sensitive (AG83, 2001 and MC9) or resistant (NS2, 41 and GE1) using rhodamine123 as a substrate for multidrug resistant (MDR) pumps and calcein as a substrate for multidrug resistance-associated proteins (MRP) respectively; their specificity was confirmed using established blockers. Sb-resistant (Sb-R) isolates accumulated higher amounts of R123, as compared to Sb-sensitive (Sb-S) isolates. Verapamil, a MDR inhibitor failed to alter R123 accumulation, suggesting absence of classical MDR activity. In Sb-R isolates, both promastigotes and axenic amastigotes accumulated significantly lower amounts of calcein than Sb-S isolates and probenecid, an established pan MRP blocker, marginally increased calcein accumulation. Depletion of ATP dramatically increased calcein accumulation primarily in Sb-R isolates, indicating existence of a MRP-like pump, which was more active in Sb-R isolates. In conclusion, our data suggested that overfunctioning of a MRP-like pump contributed towards generation of Sb-R phenotype in L. donovani field isolates.

Effect of probenecid on kinetics of enrofloxacin in lactating goats after subcutaneous administration.

A comparative pharmacokinetic study of enrofloxacin (5 mg/kg, sc) was conducted in probenecid-pretreated (70 mg/kg, orally 1.5 h prior to enrofloxacin administration) lactating goats to assess the effect of probenecid on the kinetics of enrofloxacin. Concentration of enrofloxacin in plasma, milk and urine was estimated by microbiological assay using Escherichia coli (ATCC 25922). Minimum detection level of enrofloxacin was 0.01 microg/ml. The plasma log concentration versus time curve showed monophasic pattern and followed one compartment open model. Plasma drug concentration was significantly higher during 1-2 h in probenecid-pretreated group. Significantly higher drug concentration in milk was noted at most of the time points, while significantly lower urine drug concentration (0.083-1 h and 5-12 h) were obtained in probenecid-pretreated group. The kinetic parameters (A, B and 3) were significantly higher, while t(1/2)beta, MRT and Vd(area) were significantly lower in probenecid-pretreated group. Probenecid pretreatment decreased the urinary excretion of enrofloxacin, whereas enhanced excretion in milk which could be useful in cases of affections of udder in goats.

Observation on therapeutic effect of electroacupuncture plus blood-letting puncture and cupping combined with diet intervention for treatment of acute gouty arthritis / 中国针灸

<p><b>OBJECTIVE</b>To explore a more effective therapy for acute gouty arthritis.</p><p><b>METHODS</b>Sixty cases were randomly divided into an observation group and a control group, 30 cases in eachgroup. On the basis of diet intervention, the observation group was treated with electroacupuncture at local points combined with blood-letting puncture and cupping, and the control group with oral administration of Probenecid. Their therapeutic effects were ob served.</p><p><b>RESULTS</b>The effective rate was 96.7% in the observation group which was better than 86.7% in the control group (P < 0.01). After treatment, blood uric acid decreased significantly in the two groups (both P < 0.01), the observed group being lower than the control group (P < 0.01).</p><p><b>CONCLUSION</b>On the basis of diet intervention, electroacupuncture plus blood-letting puncture and cupping is a better therapy for acute gouty arthritis.</p>

Influence of cyclic guanosine 3', 5' monophosphate modulators on muscle contraction of rat aortas

The study examined the influence of probenecid [Pn], sildenafil [Sd] and oxidiazoloquinoxalin [ODQ] on contraction of phenylephrine [PhE] stimulated rat aortas. The study was performed at Peter Holtz Research Center of Pharmacology and Experimental Therapeutics, Ernst-Moritz-Arndt University Greifswald, Greifswald, Germany, from 1st July to 30th September 2005. Thirty-five isolated rat aortas were stimulated with 10 micro M PhE or preincubated for 30 minutes with 10 micro M Pn, or 10 micro M ODQ, or 50 micro M Sd, and then incubated with 10 micro M PhE in the presence or absence of the substances. The phosphorylated myosin light chain 20 was detected by using an antibody against phosphomyosin light chain 2. The ratio of PhE stimulated phosphorylation of aortas [p<0.05] to the untreated was 16.7:1 at 30 seconds and 20.4:1 at 60 seconds. The stimulation decreased significantly at 120 seconds then during the following 10 minutes. Pre-incubation with 50 micro M Sd [p>0.05] or 10 micro M Pn [p<0.05] reduced the phosphorylation induced by PhE that was added to each for 30 seconds. But pre-incubation with 10 micro M ODQ increased the phosphorylation brought about by addition of PhE for 60 seconds, p>0.05. The washout-effect of these modulators was not significant after stimulation with PhE only. The study demonstrates the involvement of cyclic guanosine 3',5' monophosphate and its modulators on muscle contraction of rat aortas. Sildenafil and Pn reduced while oxidiazoloquinoxalin increased the contraction of rat aortas

Effect of Uric Acid (UA) on C-reactive Protein (CRP) Expression in Peripheral Blood Mononuclear Cells (PBMC) / 대한신장학회지

PURPOSE: Systemic inflammatory reaction (SIR) is an important determinant of cardiovascular (CV) mortality in CRF patients. UA is an end-product of purine metabolism, and recent studies have demonstrated that an elevated serum UA level is associated with an increased level of inflammatory mediators. Since hyperuricemia is one of the most prevalent complications in CRF and is linked to CV disease, we hypothesized hyperuricemia in CRF may play an important role in the development of CV disease by inducing SIR. METHODS: PBMCs were isolated by density gradient centrifugation in 21 CRF patients and age and sex-matched 20 healthy adults. CRP expression was evaluated by real time PCR and ELISA in PBMC stimulated with UA (0.3-12 mg/dL). RESULTS: There was no difference in constitutional CRP expression in PBMC from control and CRF patients. UA induced CRP mRNA (RT-PCR) and protein (ELISA) expression in PBMC, which was blocked by the organic anion transport inhibitor, probenecid (1 mM), suggesting entry of uric acid into cells was responsible for CRP expression. PBMC from CRF patients showed a significantly higher CRP production by UA compared to healthy control. There was no correlation between serum UA level and % increase in CRP production by UA. CONCLUSION: The exaggerated CRP expression by UA can be another mechanism of SIR and increased CV morbidity in CRF patients. Prospective studies with uric acid-lowering therapy are necessary to confirm clinical significance of these interesting in-vitro findings.

Polyomavirus-associated Nephropathy after Renal Transplantation / 대한이식학회지

The first clinical infections with polyomavirus (PV) were demonstrated in 1971, when BK virus was isolated from the urine after a kidney transplant recipient and JC virus from the brain of a patient who died of progressive multifocal leukoencephalopathy. Polyomavirus-associated nephropathy (PVAN) has become an important cause of allograft dysfunction and loss in kidney transplantation since first recognized in kidney transplant recipient with PVAN in 1995. Most cases of PVAN are caused by polyomavirus hominis type 1, known as BK virus and arise while the patient in on triple immunosuppressive combinations, often comprising tacrolimus and/or mycophenolate mofetil plus corticosteroids. Significant progress has been made, particularly in the area of diagnostic methods for PV, facilitating diagnosis, screening and monitoring of PV infection. Definitive diagnosis of PVAN requires allograft kidney biopsy. Immunologic control of PV replication can be achieved by reducing, switching, and discontinuing of the immunusuppressive agents. Cidofovir and leflunomide are used empirically in the treatment of PVAN. However, these antiviral agents are not approved for PVAN. Recently, investigational use at low-dose cidofovir (0.25~0.33 mg/kg intravenously biweekly) without probenecid should be considered for the treatment of cases refractory to decreasedmaintenance immunosuppression. PVAN had a serious consequence of kidney transplantation that increasingly cause for chronic allograft kidney loss. Despite reduction in immuo-suppression, allograft kidney loss occurred in 46% of transplant recipients with PVAN. PVAN recurred in 15% of retransplantations compared with 5% of primary kidney transplantations. However, retransplantation is not contraindicated for transplant recipient in whom a first allograft kidney lost due to PVAN. Recently, preemptive retransplantation can be considered in patients with allograft loss due to PVAN.

Expression and Function of ABC Transporters as Multidrug Resistance Mechansims in Gastric Cancer Cells

PURPOSE: Multidrug resistance (MDR) is a phenomenon whereby tumor cell acquire resistance to a broad range of structurally and functionally diverse chemotherapeutic drugs. The most widely implicated mechanism of MDR is that of altered membrane transporter in tumor cells. P-glycoprotein (Pgp), multidrug resistance protein (MRP), and breast cancer-resistance protein (BCRP) are well known membrane transporters, which pump out antitumor agents via an ATP-dependent process, the so called ATP-binding cassette (ABC) superfamily or transporter. This study was undertaken to test the prevalence of each ABC transporter, and which of then exhibit functional activity in various gastric cancer cells. METHODS: The expressions of Pgp, MRP, and BCRP mRNA were determined by RT-PCR assay on 10 gastric cancer cells. The sensitivity to anticancer agents, substrates for each ABC transporter in the gastric cancer cells was determined using the MTT assay. The intracellular accumulation of fluorescent compounds for the functional detection of each ABC transporter was determined using flow cytometry. RESULTS: The Pgp mRNA was expressed at various levels in 9 out of the 10 gastric cancer cells tested, but significantly low. MRP mRNA was constitutively expressed in all the cells. BCRP mRNA was differentially expressed in 5 of the gastric cancer cells. There was no relation between the expressions of Pgp and MRP and the cytotoxicity to each substrate. It was observed that the accumulations of paclitaxel and VP-16 were significantly increased on the additions of PSC833 and probenecid, respectively, in all tested cells. The reversal effect of drug accumulation by each inhibitor was much higher in the MRP than Pgp. With BCRP, the observed cytotoxic effect and amount of mitoxanthrone accumulation were less than in the cells expressing the highest levels of BCRP compared to those that did not. However the mitoxanthrone accumulation was not increased on the addition of FTC in the either cell type. CONCLUSION: This study suggests that of the ABC transporters, MRP has primarily functional activity, whereas that of Pgp is only slight, in the gastric cancer cells. Other possible MDR mechanisms involved will have to be explored in further studies.

Expression and Function of ABC Transporters as Multidrug Resistance Mechansims in Colon Cancer Cells

PURPOSE: Multidrug resistance (MDR) is a phenomenon whereby tumor cells acquire resistance to a broad range of structurally and functionally diverse chemotherapeutic drugs. The most widely implicated mechanism of MDR is that concerned with altered membrane transporters in tumor cells. P-glycoprotein (Pgp), multidrug resistance protein (MRP), and breast-cancer-resistance protein (BCRP) are well-known membrane transporters that pump out antitumor agents by using an ATP-dependent process, the so-called ATP-binding cassette (ABC) superfamily or transporter. This study was undertaken to test the prevalence of each ABC transporter and to determine which transporter has functional acitivity in various colon cancer cells. METHODS: Expressions of Pgp, MRP, and BCRP mRNA were determined in 9 colon-cancer cell lines by using an RT-PCR assay. The sensitivity to anticancer agents substrate for each ABC transporter in the colon cancer cells determined using an MTT assay. The accumulation of fluorescent compounds for functional detection of each ABC transporter was determined by using flow cytometry. RESULTS: Pgp mRNA was variably expressed in 6 of 9 colon cancer cells lines. MRP and BCRP mRNA were expressed in all the 9 cell lines. A smaller cytotoxic effect to paclitaxel and a smaller amount of rhodamine123 accumulation were observed in Colo 320HSR expressing the highest levels of Pgp than in SNU-C5 not expressing Pgp. These effects in Colo320HSR were reversed with the addition of various Pgp inhibitors, but such a reversal did not occur in SNU-C5. The cytotoxic effect to VP-16 was not related to the expression levels of MRP in Colo320HSR and SNU-C, but the amount of calcein-AM accumulation was reversed with addition of probenecid, MRP inhibitor. The cytotoxic effect and the drug accumulation of mitoxantrone were not related to the expression levels of BCRP. CONCLUSIONS: This study suggests that of the ABC transporters, primarily Pgp and MRP have functional activity in colon cancer cell lines.

Neonatal jaundice and glucose-6- phosphate dehydrogenase deficiency

One hundred new born males babies aged 7 days and above were included in this study. These were divided into two groups - Group I included G6PD normal subjects and Group II included G6PD deficient subjects. Total bilirubin and G6PD enzyme levels were done by commercially available kits. Results were analysed by using students t test and level of significance was done. A significant increase in total bilirubin level was observed in infants of G6PD deficiency, Erythrocyte G6PD level is significantly decreased in 06% of infants born with neonatal jaundice

A Case of Type I Glycogen Storage Disease with Decreased Growth Hormone Secretion / 대한소아내분비학회지

Glycogen storage diseases(GSD) are inherited disorders affecting glycogen metabolism and type I GSD is due to the absence or deficiency of glucose-6-phosphatase(G6Pase) enzyme in the liver, kidney, and intestinal mucosa. The defect leads to inadequate hepatic conversion of G6P to glucose and thus make affected individuals susceptible to fasting hypoglycemia, and the accumulation of glycogen occurs in the liver and other organs. Type Ia is the most common form of GSD and clinically growth retardation may manifest of GSD itself rather than growth hormone deficiency(GHD), but we experienced a case of type I GSD with GHD in a 14-year-o1d male. The height was 125 cm, compatible with 50 th percentile of height of 8 years of age. He has doll-like face with fat cheek, relatively thin extremities, and metabolic acidosis, hyperuricemia, hypoglycemia, hyperlipidemia. GH stimulation test with clonidine and L-dopa revealed that the patient had decreased GH secretion. After laboratory work up including liver biopsy, he was diagnosed as type I GSD. Hypoglycemia was managed with frequent feeding with high starch diet(uncooked cornstarch). Metabolic acidosis and hyperuricemia were treated with sodium bicarbonate, allopurinol and probenecid. The patient is being followed at out-patient clinic with clinical improvement after of diet therapy and GH administration.

A Case of Renal Hypouricemia and Hypercalciuria / 대한신장학회잡지

We encountered a case of renal hypouricemia and absorptive hypercalciuria. Although renal hypouricemia is asymptomatic as usual, it is rarely complicated with acute renal failure and urolithiasis. A 43-year-old man had hypouricemia (serum uric acid, 0.6-1.0mg/dl) with an increased renal uric acid clearance (69.4ml/min), hypercalciuria (367.2mg/day). In present case, there was no response of uric acid excretion to either pyrazinamide or probenecid and hypercalciuria disappeared after calcium restriction diet. These results suggest that the present case had the defect of both pre-and postsecretory reabsorption of uric acid and absorptive hypercalciuria.

Abdome agudo em ginecologia / Acute abdomen in gyncology

O objetivo deste trabalho é revisar as três principais causas do abdome agudo em ginecologia que säo a doença inflamatória pélvica, prenhez ectópica e a torçäo anexial, abordando aspectos epidemiológicos, diagnósticos e terapêuticos

Cambios en los niveles estriatales de glutamato y aspartato en un modelo de la corea de Huntington: prevención de la neurotoxicidad del ácido quinolínico por kinurenina y probenecid / Changes in the striatal levels of glutamate and aspartante in a Huntington chorea model: prevention of quinolinic acid induced neurotoxicity by kynurenine and probenecid

La kinurenina (KYN) es el metabolito precursor del antagonista de los receptores glutamatérgicos para N-metil-D-as-partato (NMDA), el ácido kinurénico (KYNA). Por su pate, el probenecid (PROB) bloquea la excreción del KYNA desde el fluido extracelular. El KYNA antagoniza la neurotoxicidad ácido quinolínico (QUIN), en el cerebro de mamíferos. En este trabajo evaluamos el efecto de la administración sistémica de KYN y del PROB por separado o en combinación, sobre el contenido estriatal de dos aminoácidos excitadores del sistema nervioso, los ácidos glutámico (Glu) y aspártico (Asp), después de la administración intraestriatal unilateral de QUIN (240 nmol/ml) a las ratas. Los contenidos estriales de Glu y Asp. Analizados por cromatografía de líquidos, se encontraron disminuidos en ratas lesionadas por QUIN al compararse contra valores control (-44 por ciento y -43 por ciento, respectivamente). Los cambios en las concentraciones de estos aminoácidos fueron parcial o totalmente prevenidos por la administración de los pretratamientos con KYN (150, 300 ó 450 mg/kg, i.p.) o PROB (100, 200 ó 300 mg/kg, i.p.) a las ratas 2 horas antes de la inyección del QUIN. La coadministración de ambos fármacos previno la pérdida estriatal de Glu y Asp mediada por QUIN. Por su parte, la administración de un conocido antagonista de los receptores para NMDA, la dizocilpina (MK-80 1, 10 mg/kg, i.p.) previno totalmente la disminución estriatal de ambos aminoácidos. Estos hallazgos sugieren un papel farmacológico de la KYN y del PROB como inductores del antagonismo del KYNA sobre los receptores para NMDA

Estudo prospectivo controlado comparando lomefloxacina e ampicilina mais probenecide em dose única oral no tratamento de uretrite gonocócica aguda no homem / Controlled prospective study comparing lomefloxacin and ampicilin more probenecid in a single dose in the treatment of acute gonococcal urethritis in the man

As infecçöes gonocócicas há muito constituem um fator de importância para a saúde pública, devido à sua alta prevalência na populaçäo. Torna-se, portanto, imperioso a obtençäo de tratamentos eficazes e práticos, visando a observância completa do paciente ao tratamento, a cura clínica e a interrupçäo do ciclo de transmissäo. Neste estudo comparou-se lomefloxacina e ampicilina, quanto a sua eficácia clínica, laboratorial e seus efeitos colaterais, administradas em dose única. A lomefloxacina mostrou-se superior quanto à eficácia e apresentou menos efeitos adversos em relaçäo à ampicilina.