Liver uptake of Biguanides in rats

Metformin is an oral antihyperglycaemic agent widely used in the management of non-insulin-dependent diabetes mellitus. The liver is the primary target, metformin being taken up into human and rat hepatocytes via an active transport mechanism. The present study was designed to compare hepatic uptake of two biguanides, metformin and phenformin, in vitro and in vivo. In in vitro experiments, performed using rat cryopreserved hepatocytes, phenformin exhibited a much higher affinity and transport than metformin, with marked differences in kinetics. The K_m values for metformin and phenformin were 404 and 5.17 μM, respectively, with CLint (V_max/K_m) values 1.58 μl/min per 10⁶ cells and 34.7 μl/min per 10⁶ cells. In in vivo experiments, when ¹⁴C-metformin and ¹⁴C-phenformin were given orally to male rats at a dose of 50 mg/kg, the liver concentrations of radioactivity at 0.5 hour after dosing were 21.5 μg eq./g with metformin but 147.1 μg eq./g for phenformin, ratios of liver to plasma concentrations being 4.2 and 61.3, respectively. In conclusion, the results suggest that uptake of biguanides by rat hepatocytes is in line with the liver distribution found in vivo, phenformin being more efficiently taken up by liver than metformin after oral administration.     

浅麻醉下犬脑组织对异丙酚的摄取及其分布

目的:研究异丙酚浅麻醉时在犬脑不同区域的摄取及分布。方法:6条成年雄犬,静脉注射异丙酚4.5mg/kg,达到有效麻醉深度后3min,取颈内动脉和颈内静脉血并断头法将犬处死,解剖犬脑,分别取额叶、顶叶、颞叶、海马、扣带回、丘脑、中脑、桥脑、小脑组织。高效液相色谱-紫外线法测定血浆浓度及组织浓度。结果:各个脑区药物浓度分布呈桥脑>中脑>丘脑>小脑>扣带回>额叶>颞叶>顶叶>海马的趋势,动脉血药浓度明显高于静脉血药浓度。结论:异丙酚浅麻醉时在犬脑不同区域分布不同,其中以脑干和丘脑最高,可能在异丙酚静脉麻醉中发挥着重要作用。     

Experimental and clinical tests of the oxyconsumeter: A new oxygen uptake monitor

Summary The prototype of a microprocessor controlled oxygen uptake monitor oxyconsumeter developed by Draeger-werk AG, Luebeck, FRG, has been tested. The measuring accuracy of this device was assessed with laboratory bench experiments utilizing both the nitrogen dilution technique and the hydrogen combustion technique to simulate oxygen uptake ( O2). The correlation coefficient between the simulated and the measured O2 values was 0.9989 (p<0.05, n=115). The average relative error of the O2 values was –3.32%±3.88% when breathing 21 vol% oxygen and –5.58%±4.53% for 70 vol% oxygen (percent of reading). This was within the range given by the manufacturer (±5% for 21 vol% to <40 vol%, ±10% for 40 vol% to <70 vol%) with few exceptions. Furthermore the oxyconsumeter was used in clinical experiments to determine oxygen uptake during general anaesthesia. Oxygen uptake was monitored using a non-rebreathing system with an externally triggered expiratory valve. The difference between preanaesthetic reference values and values determined during anaesthesia averaged –24.8±20.1 ml/min/m2 oxygen. This average relative change of –16.0±11.5% was statistically significant in 11 of 15 cases (p<0.05).     

Market uptake of orphan drugs – a European analysis

What is known and Objective: Variations in market uptake of an orphan drug have important implications with respect to access to care and inequality of treatment. Therefore, the aim of this study was to quantify both the sales and volume uptake of orphan drugs in Europe and to assess whether a country’s gross domestic product (GDP) and/or health technology assessment (HTA) influences the orphan drugs’ market uptake. Methods: We analysed the numbers of orphan drugs launched and the sales and volume uptake for 17 orphan drugs in 23 European countries from 2001 until the beginning of 2010 using the IMS Health database. Countries were clustered based on GDP and the availability of a formal HTA‐organization. Results and Discussion: The uptake of orphan drugs varied across European countries. The highest volumes and contributions of orphan drugs in the first year occurred in countries with a high GDP (and implicitly, a higher budget for healthcare), independently of the existence of an HTA‐organization. In contrast, in countries with a low GDP, orphan drugs were less available when there was a formal HTA‐organization. There, budgetary restrictions can cause the exclusion of less cost‐effective orphan drugs. What is new and Conclusion: We observed substantial variation in the market uptake of orphan drugs. Such variation may have important implications with respect to access to care and inequality of treatment. The uptake of orphan drugs could be promoted through the clinical added value of orphan drugs (CAVOD) project and various conditional pricing and reimbursement mechanisms.     

同步实时测峰值摄氧量与6min步行试验

目的：评价健康受试者6min步行试验（6MWT）中峰值摄氧量（peak VO2，PVO2）与步行距离的关系。方法：对51例健康受试者进行6min步行试验，同时采用无线遥测便携式K4B^2气体分析仪实时测量每次呼吸的VO2、VCO2等气体交换参数。结果：6MWT的步行距离与PVO2呈线性相关（r=0．619，P〈0．001），回归方程VO2/kg=0．05D-6．331（P〈0．001）。PVO2〉PVCO2，R〈1，提示6MWT为无氧阈以下的运动试验。结论：6MWT步行距离与PVO2密切相关，此方法安全简便，对于评价心肺功能以及评估心肺康复治疗疗效有很好的应用价值。     

Kinetics of platelet 5-hydroxytryptamine uptake in headache patients

Platelet 5-hydroxytryptamine (5-HT) uptake was measured in asymptomatic headache patients attending a specialist migraine clinic, and in hospital staff who did not suffer from regular or severe headache. Current levels of anxiety and depression were assessed in all subjects using the Hospital Anxiety and Depression (HAD) scale and their possible influence on the uptake kinetics taken into account during the analysis of results. The Michaelis-Menten constant (Km) was significantly raised in common migraine and tension headache compared with controls (p less than 0.001 and p less than 0.01, respectively), but not in classical migraine or cluster headache. The increase remained significant after adjusting for differences in age, sex, presence of anxiety or depression (HAD sub-scale score greater than or equal to 8), drug intake during the week before testing, time elapsed since last attack and time of assay (am or pm). No differences were observed between patients and controls in the maximal rate of uptake (Vmax) or platelet count, and previous reports of a reduction in Vmax in patients experiencing attack within 5 days prior to testing could not be confirmed. The cause and significance of an increased Km are not clear, but plasma factors acting as competitive inhibitors for the uptake site or an alteration in the configuration of the uptake site are possible explanations. If confirmed, the shared biochemical abnormality may suggest that common migraine and tension headache have a common pathogenesis.     

肾动态显像中肾外摄取99Tcm-DTPA原因探讨

⁹⁹Tc^m-DTPA是常用的肾动态显像放射性示踪剂,经静脉注射后快速经肾小球滤过到尿液而不被肾小管重吸收和分泌。正常情况下肾外脏器及组织不摄取⁹⁹Tc^m-DTPA,但一些疾病如良恶性肿瘤、骨转移癌、浆膜腔积液、炎性脓肿等可导致⁹⁹Tc^m-DTPA的摄取。现对肾动态显像中肾外摄取⁹⁹Tc^m-DTPA的原因进行综述。     

Platelet glutamate uptake and release in migraine with and without aura

Glutamate may play an important role in the pathogenesis of migraine: glutamate release in the brain may be involved in the development of spreading depression and increased concentrations of this amino acid have been reported in plasma and platelets from migraine patients. Here we assessed platelet glutamate uptake and release in 25 patients affected by migraine with aura (MA) and 25 patients affected by migraine without aura (MoA), comparing the results with a group of 20 healthy matched controls. Both glutamate release from stimulated platelets and plasma concentrations of the amino acid were assessed by high-performance liquid chromatography, and were increased in both types of migraine, although more markedly in MA. Platelet glutamate uptake, assessed as 3H-glutamate intake, was increased in MA, while it was reduced in MoA with respect to the control group. These results support the view that MA might involve different pathophysiological mechanisms from MoA and, specifically, up-regulation of the glutamatergic metabolism. Understanding these dysfunctional pathways could lead to new, possibly more successful therapeutic approaches to the management of migraine.     

Hepatic uptake and intestinal absorption of bile acids in the rabbit

Abstract The existence of transporters for bile acids (BA) in liver and intestine has been well documented, but information is still needed as to their respective transport capacity. In the present investigation, we compared the hepatic and intestinal transport rates for BA, using perfused livers and intestines. The livers and intestines were separately perfused and dose-response curves (0·25–10 mM) for tauroursodeoxycholate, taurocholate and taurodeoxycholate were obtained. The intestinal and mesenteric concentration and bile acid pattern were also evaluated in six non-fasting rabbits. Taurocholic, tauroursodeoxy-cholic and taurodeoxycholic acid ileal absorption showed saturation kinetics in the intestine as in the liver; the maximal uptake velocity for each bile acid in the liver was tenfold higher than the respective maximal transport velocity in the intestine; the Km values obtained in the liver were of the same order of magnitude, i.e. in the millimolar range. Taurocholic, tauroursodeoxycholic and taurodeoxycholic acid transport differences in the liver paralleled those in the intestine. Although the intestine was not homogeneously filled, the bile acid concentration in the ileal content fell into the range of the Km for the three studied bile acids, while the portal blood total bile acid concentration was inferior to the observed Kms of liver uptake. Therefore, both the hepatic and intestinal systems do not operate at their maximal transport rates at the prevailing concentrations in portal blood and luminal content, and the hepatic transport occurs at its highest efficiency (below the Km values) in physiological conditions.     

The relationship between oxygen demand, oxygen uptake, and oxygen supply

Results of the relationships between oxygen supply, demand, and uptake can be used to interpret cardiac output values, identify types of acute circulatory failure, guide attempts to improve cellular function, and thus prevent the development of multiple organ failure and death. Five steps in the interpretation of cardiac output values are recommended: (1) relate cardiac output to the patient's size; (2) determine the presence of anemia or hypoxemia; (3) measure mixed venous O₂ saturation and (4) blood lactate levels; and (5) evaluate O₂ uptake before and after a transient increase in cardiac output.     

Oxygen uptake and carbon dioxide elimination after acetazolamide in the critically ill

Acetazolamide, which reversibly inhibits carbonic anhydrase, is a useful diuretic in alkalotic and over-hydrated patients. In two earlier investigations we have consistently found increases in the arterial and venous oxygen saturation and tension when patients were treated with acetazolamide 15 mg·kg^-1. A plausible explanation of this phenomenon is that acetazolamide diminishes oxygen consumption. In the present study we measured oxygen uptake in 10 critically ill patients. We found a minor and statistically insignificant decrease in oxygen consumption. Nevertheless SvO₂ increased from 0.77 to 0.83 and PvO₂ from 5.9 kPa to 6.8 kPa. It is still not possible from this investigation to determine the origin of the improvement in blood oxygenation. The inhibition of carbonic anhydrase caused a CO₂ retention of 5.8% of the total CO₂ production. An increase in body stores of CO₂ of this magnitude is without clinical significance.     

Decreased leg glucose uptake during exercise contributes to the hyperglycaemic effect of octreotide

Aim: During prolonged infusion of somatostatin, there is an increase in arterial glucose concentration, and this increase persists even during prolonged exercise. The aim of the study was to measure glucose uptake in the leg muscles during infusion of the somatostatin analogue octreotide before and during leg exercise. Material and methods: Eight healthy male subjects were investigated twice in the fasting state: during 3 h infusion of octreotide [30 ng (kg min)^?1] or sodium chloride with exercise at 50% of maximal VO₂ in the last hour. Glucose uptake and oxygen uptake in the leg were measured using Fick’s principle by blood sampling from an artery and a femoral vein. Blood flow in the leg was measured using the indicator (indocyanine green) dilution technique. Results: After an initial decrease during rest, octreotide infusion resulted in a significant increase in arterial glucose concentrations compared to control conditions during exercise (mean ± SEM: 7·6 ± 0·6 versus 5·6 ± 0·1 mmol l^?1, P<0·01). During rest, octreotide did not change the leg glucose uptake (59 ± 10 versus 55 ± 11 μmol min^?1). In contrast, leg glucose uptake was significantly lower during exercise compared to control conditions (208 ± 79 versus 423 ± 87 μmol min^?1, P<0·05). During exercise, leg oxygen uptake was not different in the two experiments (20·4 ± 1·3 versus 19·5 ± 1·1 μmol min^?1). Conclusion: In conclusion, infusion of octreotide reduced leg glucose uptake during exercise, despite the same leg oxygen consumption and blood flow compared to control conditions. The hyperglycaemic effect of octreotide can partly be explained by the reduction in leg glucose uptake. Furthermore, the results suggest that a certain level of circulating insulin is necessary to obtain sufficient stimulation of glucose uptake in the exercising muscles.     

Reproducibility and sensitivity of muscle reoxygenation and oxygen uptake recovery kinetics following running exercise in the field

The purpose of this study was to assess the reliability of postexercise near‐infrared spectroscopy (NIRS)‐derived measurements and their sensitivity to different exercise intensities in the field. Seventeen athletes (24·1 ± 5·6 year) repeated, on three occasions, two 2‐min submaximal shuttle‐runs at 40% and 60% of V_IFT (final speed of the 30–15 intermittent fitness test) and a 50‐m shuttle‐run sprint (Sprint), with (OCC) or without (CON) repeated transient arterial occlusions of the medial gastrocnemius during the postexercise period. NIRS variables (i.e. oxyhaemoglobin [HbO₂], deoxyhaemoglobin [HHb] and their difference [Hb_diff]) were measured continuously for 3 min after each exercise. Half‐recovery (½Rec) and mean response (MRT; monoexponential curve fitting) times of muscle reoxygenation and muscle oxygen uptake () recovery were calculated. Reliability was assessed using the typical error of measurement, expressed as a coefficient of variation (CV). Postexercise recovery of muscle reoxygenation revealed CVs ranging from 16·8% to 37·3%; CV for recovery ranged from 6·2% to 20·9%, with no substantial differences shown between NIRS variables and exercise intensities. While running, intensity did not affect MRT or ½Rec for muscle reoxygenation, and differences were found for recovery (e.g. [Hb_diff]‐ MRT = 28·7 ± 5·2, 34·2 ± 5·1 and 37·3 ± 6·2 s for 40%, 60% and Sprint, respectively, P<0·01). To conclude, the kinetics of postexercise NIRS measurements showed CV values ranging from 6% to 37%, with no substantial differences between exercise intensities or NIRS‐derived variables. However, exercise intensity did influence recovery kinetics, but not that of muscle reoxygenation in an occlusion‐free condition.     

First-pass uptake of methotrexate after intra-arterial bolus injection in human head and neck cancers

The aim of this study was to quantify first-pass uptake of methotrexate into tumour and healthy tissue after intra-arterial (i.a.) injection in patients with head and neck cancers. Twenty-one patients were studied; during surgery, a bolus injection of 10 mg of ³H-labelled methotrexate was administered into the tumour-supplying artery. At 15–20 s after injection, and again 2–3 h later, a biopsy of the tumour and of surrounding healthy tissue was taken and radioactivity was measured. In 8 of 17 pretreated patients the biopsy specimens contained no tumour cells. In tumour-bearing patients, radioactivity in tumour was three times higher than in healthy tissue ( P  = 0.006). In tumour-negative patients there was no difference in activity between the two biopsy sites ( P  = 0.889). However, after 2–3 h the concentration of methotrexate in all surgical specimens returned to near background level and the initial difference between tumour-positive and tumour-negative samples was lost. Our results show that i.a. injection of methotrexate does not necessarily lead to high tumour cell exposure.     

Preferential cellular uptake of amphiphilic macromolecule-lipid complexes with enhanced stability and biocompatibility

Amphiphilic macromolecules (AM) were electrostatically complexed with a 1:1 ratio of 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) to form AM-lipid complexes with drug delivery applications. The complexes exist as AM-coated liposomes and their drug delivery properties can be tuned by altering the AM-lipid weight ratio. The complexation and tuning are achieved in a simple, efficient, and scalable manner. The gradual increase in lipid ratios concurrently increased the zeta potential of the complexes, which directly correlates to increased cell uptake of the complexes in vitro with preferential uptake noted in BT-20 carcinoma cells versus normal fibroblasts. Increasing AM content increased complex steric stability in the presence of serum proteins and reduced the inherent cytotoxicity towards fibroblasts in vitro. AM-lipid complexes solubilized paclitaxel and showed drug-mediated, dose-dependent cytotoxicity towards target BT-20 cells in vitro. AM-lipid complexes make good candidates as drug delivery systems due to their tunable zeta potential, steric stability, inherently low cytotoxicity, and ability to load and deliver insoluble chemotherapeutic agents. Significantly, their preferential uptake in a carcinoma cell line over normal cells in vitro demonstrates a unique, passive targeting approach to delivery anti-cancer therapeutics.     

The uptake, storage, and efflux of serotonin in platelets from migraine patients

A recently developed method for analysing 5-hydroxytryptamine (5-HT) efflux from platelets preloaded with a small amount of 14C-5-HT enables the assessment of the relative size of the granular and the cytoplasmatic pools of 5-HT within the platelets and of the rate of spontaneous efflux from these two compartments. This method, together with conventional assessment of the 5-HT uptake measures Km and Vmax, was applied in this study, comparing platelets from 14 patients with common migraine and 10 patients with classic migraine with platelets from 25 healthy controls. All patients were unmedicated and in an attack-free period. Neither the total patient group nor either of the two subgroups differed significantly from the control group on any measure of 5-HT uptake or efflux. However, two differences approached the conventional significance level: the relative size of the granular compartment (Compartment III) was larger for classic than for common migraine, and the efflux rate from Compartment III was shorter for classic migraine than for the healthy controls (P approximately 0.10 in both cases). Further studies are required to show whether these differences are real and, if so, whether they have any relevance for the pathogenesis of migraine attacks.