Infusion Of Analogue Research Articles

Intrinsic mechanisms of right ventricular autoregulation

To elucidate the adaptation of the right ventricle to acute and intermittently sustained afterload elevation, targeted preload reductions and afterload increases were implemented in a porcine model involving 12 pigs. Preload reduction was achieved via balloon occlusion of the inferior vena cava before, immediately and 5 min after acute afterload elevation induced by pulmonary artery occlusion or thromboxane A2 analog (U46619) infusion. Ventricular response was monitored by registration of pressure–volume (PV) loops using a conductance catheter. The end-systolic pressure–volume relationship (ESPVR) during pure preload reduction was adequately described by linear regression (mean and SEM slope of ESPVR (Ees) 0.414 ± 0.064 mmHg/ml), reflecting the classical Frank-Starling mechanism (FSM). The ESPVR during acute afterload elevation exhibited a biphasic trajectory with significantly distinct slopes (mean and SEM Ees bilin1: 1.256 ± 0.066 mmHg ml; Ees bilin2: 0.733 ± 0.063 mmHg ml, p < 0.001). The higher slope during the first phase in the absence of ventricular dilation could be explained by a reduced amount of shortening deactivation (SDA). The changes in PV-loops during the second phase were similar to those observed with a preload intervention. The persistent increase in afterload resulted in an increase in the slopes of ESPVR and preload recruitable stroke work (PRSW) with a slight decrease in filling state, indicating a relevant Anrep effect. This effect became more pronounced after 5 min or TXA infusion. This study demonstrates, for the first time, the relevance of intrinsic mechanisms of cardiac autoregulation in the right ventricle during the adaptation to load. The SDA, FSM, and Anrep effect could be differentiated and occurred successively, potentially with some overlap. Notably, the Anrep effect serves to prevent ventricular dilation.

Synthetic Analogue of Leu-Enkephalin in COVID-19 (a Prospective Clinical Study)

One of the main problems facing intensivists when treating patients with COVID-19 is severe and critical acute respiratory distress syndrome (ARDS) with the underlying viral pneumonia. The current guidelines of the Russian Ministry of Health (Version 15 of 22.02.22) do not include drugs with a lung protective effect. This issue could be solved by administration of a synthetic analogue of leu-enkephalin.Aim. Study the efficacy of a synthetic analogue of leu-enkephalin in ARDS in patients with COVID-19.Materials and methods. The study included 35 patients divided into 2 groups. Group 1 (main) patients (n=15) in addition to standard therapy received a continuous infusion of synthetic analogue of leu-enkephalin at a rate of 5 µg/kg/hour for 5 days. Patients from group 2 (control, n=20) were treated according to the Temporary Guidelines of the Ministry of Health (V.15), but without the synthetic analogue of leu-enkephalin. The radiological data, frequency, severity and evolution of respiratory complications, changes in P/F (PaO2/FiO2) ratio, as well as changes in the scores of prognostic APACHE II, SOFA, and NEWS scales were evaluated.Results. In patients taking the studied drug, the percentage of lung damage did not change with the median (IQR) of 0 [–8; 0], while in the control group it increased by approximately 10% with the median (IQR) of +10,0 [+2; +20] (P=0.001). The proportion of patients in group 1 with positive disease evolution within 5–9 days after treatment initiation was significantly higher and reached 46.7 [24.8; 69.9]%, whereas in group 2 it was 15.0 [5.2; 36.0]% (P=0.04). Also, in group 1, starting from day 4, the median P/F ratio was significantly higher than in group 2 reaching 220 [185;245] versus 127 [111;158], respectively (P=0.014). The need for non-invasive lung ventilation in group 1 on day 7 averaged 7%, while in group 2 it was as high as 45.0%, which was significantly higher than in the main group (P=0.013).Conclusions. The use of synthetic analogue of leu-enkephalin according to the specified regimen had a significant impact on the main parameters of the viral pneumonia severity. The results serve as a rationale for the development of a novel effective treatment strategy to supplement the current standard COVID-19 management.

Konjenital nefrotik sendromlu bir infantta periton diyalizine bağlı olarak görülen nadir bir komplikasyon olarak şiloz asit

Chylous ascites is a rare but important non-infectious complication in patients undergoing peritoneal dialysis. A male infant of 1.5-month-old with congenital nephrotic syndrome admitted to our pediatric intensive care unit becasue of deterioration in general appearence, diffuse edematous appearance and respiratory distress. Peritoneal catheter insertion and peritoneal dialysis was performed in the 3rd day of hospitalization. Five days after peritoneal dialysis catheter insertion (on the 8th day of hospitalization) the peritoneal dialysis effluent had a milky appearance. The chemical analysis of the milky effluent showed characteristics of chylous ascites: triglycerides 468 mg/dl. The chylous ascites resolved at the 5th day of our treatment with a low fat diet with medium chain triglycerides and intravenous infusion of somatostatin analogue (octreotide) and the patient was transferred to the pediatric service for maintenance of the treatment.

Insulin Plays a Permissive Role for the Vasoactive Effect of GIP Regulating Adipose Tissue Metabolism in Humans.

Glucose-dependent insulinotropic polypeptide (GIP) in combination with hyperinsulinemia increases blood flow and triglyceride (TAG) clearance in subcutaneous (sc) abdominal adipose tissue in lean humans. The present experiments were performed to further investigate the role of insulin for the vasoactive effect of GIP in adipose tissue metabolism and whether the vasodilatory effect of GIP is dependent on C-peptide. Six lean healthy subjects were studied. The sc abdominal adipose tissue metabolism was assessed by Fick's principle during GIP infusion (1.5 pmol/kg/min) in combination with 1) euglycemic-high insulinemic clamp (Eugluc-Hiinsu), raising plasma insulin concentrations to postprandial levels, 2) hyperglycemic-euinsulinemic clamp (Hygluc-Euinsu), and 3) hyperglycemic-hyperinsulinemic clamp, raising plasma insulin concentrations to supraphysiological levels. During the hyperglycemic clamps, endogenous insulin and C-peptide secretion were inhibited by infusion of the somatostatin analogue octreotide. During GIP infusion, Eugluc-Hiinsu, and hyperglycemic-hyperinsulinemic clamps, sc abdominal adipose tissue blood flow (ATBF) was similar and increased from 2.1 ± 0.2 and 2.2 ± 0.4 ml min(-1) (100 g tissue)(-1) to 7.1 ± 0.6 and 7.6 ± 0.1 ml min(-1) (100 g tissue)(-1), respectively (P < .01). ATBF remained virtually constant (2.7 ± 0.4 ml min(-1) [100 g tissue](-1)) during Hygluc-Euinsu and GIP infusion. In addition, adipose tissue TAG clearance increased significantly (P = .03), whereas free fatty acid output (P = .01), glycerol output (P = .02) and free fatty acid/glycerol release ratio (P = .04) decreased during the Eugluc-Hiinsu clamp compared to Hygluc-Euinsu clamp with GIP. In healthy lean humans, insulin is permissive for GIP to induce an increase in blood flow and TAG clearance in sc abdominal adipose tissue. This effect is independent of C-peptide.

Two Birds with One Stone: Possible Dual-Role of Oxytocin in the Treatment of Diabetes and Osteoporosis.

Oxytocin (OT), a hormone most commonly associated with labor and lactation, may have a wide variety of physiological and pathological functions, which makes OT and its receptor potential targets for drug therapy. In this review, we highlight the newly discovered metabolic role of OT in diabetes and its complication, such as diabetic osteopathy. OT may have positive metabolic effects; this is based on the change in glucose metabolism, lipid profile, and insulin sensitivity. It may modify glucose uptake and insulin sensitivity both through direct and indirect effects. It may also cause regenerative changes in diabetic pancreatic islet cells. Moreover, it has an anabolic effect on the bone biology. So, the activation of the OT receptor pathway by infusion of OT, OT analogs, or OT agonists may represent a promising approach for the treatment of diabetes and some of its complications, including diabetic osteopathy.

Salsolinol: a potential modulator of the activity of the hypothalamic–pituitary–adrenal axis in nursing and postweaning sheep

The most well-known physiological action of salsolinol (1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline) is the stimulation of prolactin secretion, especially during lactation. In addition, our recent work demonstrated that salsolinol inhibits the stress-induced activity of the hypothalamic–pituitary–adrenal (HPA) axis in lactating sheep. Here, we investigated whether salsolinol regulates the basal activity of the HPA axis in lactating sheep and whether its inhibitory action on the stress-induced activity of the HPA axis is present during the postweaning period. The first experiment was performed during the fifth week of lactation, in which unstressed sheep received an intracerebroventricular infusion of an antagonistic analogue of salsolinol, 1-MeDIQ (1-methyl-3,4-dihydroisoquinoline). Simultaneously, the infundibular nucleus and/or median eminence was perfused using the push–pull method. Sheep that received 1-MeDIQ infusion showed significantly higher concentration of plasma ACTH during the second, third, and fourth hour (P < 0.001, P < 0.01, and P < 0.001, respectively) and cortisol during the third and fourth hour (P < 0.001 and P < 0.01, respectively) than did sheep that received control infusion. There was no significant difference in the mean perfusate corticotropin-releasing hormone concentration between the 1-MeDIQ and control treatments. In the second experiment, sheep received an intracerebroventricular infusion of salsolinol during the ninth week of lactation and 48 h after lamb weaning. A comparison between the control groups in the first and second experiments revealed that sheep after weaning (ninth week of lactation) had significantly higher mean ACTH (P < 0.001) and cortisol (P < 0.001) concentrations during the first 2 h of the experiment than the nursing females (fifth week of lactation) had. Salsolinol significantly reduced the increased concentrations of ACTH and cortisol (P < 0.01) in sheep after lamb weaning. However, there was no difference in the expression of proopiomelanocortin messenger RNA within the anterior pituitary between the control and salsolinol-treated groups. In conclusion, salsolinol regulates the basal activity of the HPA axis in lactating sheep. In addition, the HPA axis of postweaning females is more sensitive to stressors associated with the experimental procedures, and salsolinol attenuates ACTH and cortisol release in this phenomenon.

Intrauterine Growth Restriction Disrupts Nucleosome Positioning at a Growth Hormone Response Element in the Insulin‐like Growth Factor 1 Gene

Intrauterine growth restriction (IUGR) increases the risk of adult onset diseases such as obesity and type II diabetes. Persistent downregulation of insulin‐like growth factor 1 (IGF1) has been implicated in these diseases. IUGR downregulates liver IGF1 expression in newborn and in day 21 (d21) mice. IGF1 expression at d21 is dependent on growth hormone (GH)‐mediated upregulation at multiple GH response elements (GHRE) including one containing tandem STAT5b binding sites within intron 2 (i2). We hypothesized that IUGR would disrupt prenatal epigenetic programming of the i2 GHRE and prevent postnatal i2 GHRE activation. IUGR mice were generated by thromboxane A2 analog infusion from gestation day 12.5 to term to elicit maternal hypertension. The GHRE chromatin state at the i2 GHRE was assessed by Na‐bisulfite sequencing for DNA methylation and GpC methyltransferase mapping for nucleosome positioning. In normal mice, the GHRE remains hypermethylated throughout gestation and begins to demethylate at d17. By d21 a single nucleosome is displaced. IUGR animals undergo similar DNA demethylation. However, we found two distinct nucleosome patterns at the d21 hepatic i2 GHRE. Some IUGR animals showed no nucleosome displacement, while in others, the nucleosome free region (NFR) was expanded on the 3′ side suggesting the NFR was misaligned. Evidence suggests different GHRE in IGF1 have unique functions and when tandem STAT5b sites are used, both must be functional for the enhancer to work. We speculate the altered NFR spacing could disrupt proper enhanceosome assembly and result in loss/altered GHRE activity.

Measurement of regional cerebral glucose uptake by magnetic resonance spin-lock imaging

PurposeThe regional uptake of glucose in rat brain in vivo was measured at high resolution using spin-lock magnetic resonance imaging after infusion of the glucose analogue 2-deoxy-d-glucose (2DG). Previous studies of glucose metabolism have used 13C-labeled 2DG and NMR spectroscopy, 18F-labeled fluorodeoxyglucose (FDG) and PET, or chemical exchange saturation transfer (CEST) MRI, all of which have practical limitations. Our goal was to explore the ability of spin-lock sequences to detect specific chemically-exchanging species in vivo and to compare the effects of 2DG in brain tissue on CEST images. MethodsNumerical simulations of R1p and CEST contrasts for a variety of sample parameters were performed to evaluate the potential specificity of each method for detecting the exchange contributions of 2DG. Experimental measurements were made in tissue phantoms and in rat brain in vivo which demonstrated the ability of spin-lock sequences for detecting 2DG. ResultsR1p contrast acquired with appropriate spin-lock sequences can isolate the contribution of exchanging protons in 2DG in vivo and appears to have better sensitivity and more specificity to 2DG–water exchange effects than CEST. ConclusionSpin-lock imaging provides a novel approach to the detection and measurement of glucose uptake in brain in vivo.

The effects of cardiac output and pulmonary arterial hypertension on volumetric capnography derived-variables during normoxia and hypoxia.

The aim of this study was to test the effect of cardiac output (CO) and pulmonary artery hypertension (PHT) on volumetric capnography (VCap) derived-variables. Nine pigs were mechanically ventilated using fixed ventilatory settings. Two steps of PHT were induced by IV infusion of a thromboxane analogue: PHT25 [mean pulmonary arterial pressure (MPAP) of 25 mmHg] and PHT40 (MPAP of 40 mmHg). CO was increased by 50% from baseline (COup) with an infusion of dobutamine≥5 μg kg(-1) min(-1) and decreased by 40% from baseline (COdown) infusing sodium nitroglycerine≥30 μg kg(-1) min(-1) plus esmolol 500 μg kg(-1) min(-1). Another state of PHT and COdown was induced by severe hypoxemia (FiO2 0.07). Invasive hemodynamic data and VCap were recorded and compared before and after each step using a mixed random effects model. Compared to baseline, the normalized slope of phase III (SnIII) increased by 32% in PHT25 and by 22% in PHT40. SnIII decreased non-significantly by 4% with COdown. A combination of PHT and COdown associated with severe hypoxemia increased SnIII by 28% compared to baseline. The elimination of CO2 per breath decreased by 7% in PHT40 and by 12% in COdown but increased only slightly with COup. Dead space variables did not change significantly along the protocol. At constant ventilation and body metabolism, pulmonary artery hypertension and decreases in CO had the biggest effects on the SnIII of the volumetric capnogram and on the elimination of CO2.

Oxytocin as a novel therapeutic option for type I diabetes and diabetic osteopathy.

The aim of the present study was to highlight the newly discovered metabolic role of oxytocin (OT) in the type I diabetic rats. Previous studies have demonstrated that OT has a beneficial role on bone physiology and therefore, the OT effect on the diabetic osteopathy will be assessed as well. Induction of the type I diabetes was carried out by an intraperitoneal injection of 60 mg/kg body weight of streptozotocin. The metabolic role of OT on diabetic rats after OT treatment with intramuscular injection of 40 µIU/kg body weight for 6 weeks was assessed. Histological and ultrastructural studies of rat pancreas samples, before and after the OT injection, were performed and compared with the obtained physiological results. Oxytocin treatment had positive metabolic effects in diabetic rats. This is based on the change in glucose metabolism, lipid profile, and insulin sensitivity in experimental animals. In addition, OT treatment showed histological regenerative changes of pancreatic islet cells of diabetic rats. Moreover, OT administration showed that it has an anabolic effect on the bone biology. The results suggest that activation of the oxytocin receptor (OTR) pathway by infusion of OT, OT analogs, or OT agonists may represent a promising approach for the treatment of diabetes and some of its complications, including diabetic osteopathy.

Transition from prostacyclin analogue infusion to oral therapy in patients with pulmonary arterial hypertension: a 5-year follow-up.

Transition from prostacyclin analogue infusion to oral therapy in patients with pulmonary arterial hypertension (PAH) is possible with acceptable short- and midterm results. However, there is a paucity of data on long-term outcomes after successful transition. Using a predefined protocol, transition to oral therapy was attempted in 22 patients with clinically stable PAH. Clinical and hemodynamic data were retrospectively collected at baseline as well as during and after transition. Parameters for successful versus nonsuccessful transition were also evaluated. All patients had severe PAH at baseline and showed clinical and hemodynamic improvement with prostacyclin analogue infusion. Initial oral agents used for transition were bosentan (63.6%), sildenafil (31.8%), and tadalafil (4.5%). Combination therapy was used in 68% of the patients. Successful transition was achieved in 11 patients (50%) with a mean transition duration of 16 months. After successful transition, clinical and hemodynamic parameters remained stable at midterm (mean, 18 months) and long-term (mean, 60 months) follow-up. Compared with the successful transition group, patients who experienced failure were older, had a higher frequency of idiopathic PAH, and had worse hemodynamic parameters during treatment with prostacyclin analogue alone, as well as during the transition period. In conclusion, successful transition from prostacyclin analogue infusion to oral therapy can be achieved in a significant proportion of patients with clinically stable PAH. After an initial successful transition, patients were able to maintain clinical and hemodynamic stability at the mid- and long-term follow-up.

Novel and Emerging Therapies: Thrombus-Targeted Fibrinolysis

Thrombolytic therapy by infusion of analogs of tissue plasminogen activator (tPA), other recombinant-based plasminogen activators (e.g., alteplase, reteplase, and tenecteplase), streptokinase, and urokinase (uPA) aims to clear blood clots and restore blood flow in occluded blood vessels. Thrombolytic therapy is thereby frequently used in patients with myocardial infarction, stroke, peripheral arterial disease, and massive pulmonary embolism. The leading drawbacks of thrombolysis and associated therapy are represented by a significant burden of inefficacy combined with a high risk of bleeding complications. Recent advances in understanding the complex pathophysiology of vascular occlusions, combined with important technological innovations, are notably improving the therapeutic armamentarium against thrombotic and occlusive disorders. Most of the past and ongoing research in this area have entailed thrombus-targeted fibrinolytic therapy with either tissue- and fibrin-specific immunoconjugates, fibrinolytic-bearing erythrocytes, or fibrinolytic-bearing nanoparticles. The greatest advantages of thrombus-targeted fibrinolysis, especially with biocompatible nanoparticles, are represented by their preferential localization within developing clots, effectual thrombolysis and enhanced safety due to substantial reduction of the dosage of fibrinolytic agents, and reduced onstream adverse effects. These positive biological features, coupled with minimal extravasation and favorable clearance from the circulation, appear advantageous for obtaining more efficacious and durable thrombolytic effects while concomitantly lowering or even eliminating the risk of systemic bleeding complications that typically accompany the injection of free or soluble plasminogen activators. Although an ideal technique has not been definitely established so far, tPA-bearing nanoparticles exhibiting affinity for clot-specific cells and biomolecules coupled with low-frequency ultrasound seem to bear the greatest advantages for prevention and therapy of acute thrombosis, with the possibility to specifically guide and concentrate the thrombolytic agent at the site of pathologic thrombi and clear preexisting clots by a series of mechanisms combining mechanical stress and increased penetration and effectiveness of the drugs employed.

Noninvasive Assessment of Murine Pulmonary Arterial Pressure

Background— Genetically modified mice offer the unique opportunity to gain insight into the pathophysiology of pulmonary arterial hypertension. In mice, right heart catheterization is the only available technique to measure right ventricular systolic pressure (RVSP). However, it is a terminal procedure and does not allow for serial measurements. Our objective was to validate a noninvasive technique to assess RVSP in mice. Methods and Results— Right ventricle catheterization and echocardiography (30-MHz transducer) were simultaneously performed in mice with pulmonary hypertension induced acutely by infusion of a thromboxane analogue, U-46619, or chronically by lung-specific overexpression of interleukin-6. Pulmonary acceleration time (PAT) and ejection time (ET) were measured in the parasternal short-axis view by pulsed-wave Doppler of pulmonary artery flow. Infusion of U-46619 acutely increased RVSP, shortened PAT, and decreased PAT/ET. The pulmonary flow pattern changed from symmetrical at baseline to asymmetrical at higher RVSPs. In wild-type and interleukin-6–overexpressing mice, the PAT correlated linearly with RVSP ( r 2 =−0.67, P &lt;0.0001), as did PAT/ET ( r 2 =−0.76, P &lt;0.0001). Sensitivity and specificity for detecting high RVSP (&gt;32 mm Hg) were 100% (7/7) and 86% (6/7), respectively, for both indices (cutoff values: PAT, &lt;21 ms; PAT/ET, &lt;39%). Intraobserver and interobserver variability of PAT and PAT/ET were &lt;6%. Conclusions— Right ventricular systolic pressure can be estimated noninvasively in mice. Echocardiography is able to detect acute and chronic increases in RVSP with high sensitivity and specificity as well as to assess the effects of treatment on RVSP. This noninvasive technique may permit the characterization of the evolution of pulmonary arterial hypertension in genetically modified mice.

251 Non-invasive assessment of murine pulmonary arterial pressure: validation and application to models of pulmonary hypertension

Genetically modified mice offer the unique opportunity to gain insights into the pathophysiology of pulmonary arterial hypertension (PAH). In mice, right heart catheterization is the only available technique to measure right ventricular systolic pressure (RVSP). However, it is a terminal procedure and does not allow serial follow-up. Our objective was to validate a non-invasive technique to assess RVSP in mice. Right ventricle catheterization and echocardiography were simultaneously performed in mice with pulmonary hypertension induced acutely by infusion of a thromboxane analogue, U-46619 or chronically by lung-specific over-expression of interleukin 6 (IL-6). In a subgroup of mice, echocardiography was performed using light anesthesia before catheterization. Pulsed-Doppler of pulmonary artery flow was recorded in the parasternal short axis view. Pulmonary acceleration time (PAT), and ejection time (ET) were measured. Infusion of U-46619 acutely increased RVSP, shortened PAT and decreased PAT/ET. The pulmonary flow pattern changed from symmetric at baseline to asymmetric at higher RVSPs. Transgenic IL-6 mice had high RVSP measured by catheter (39±7 mmHg), short PAT (17±4 ms) and low PAT/ET ratio (31±8%). The PAT correlated linearly with RVSP (r2=–0.67; p<0.0001), as did PAT/ET (r2=–0.76, p<0.0001). Sensitivity and specificity for detecting high RVSP (>32 mmHg) were 100% (7/7) and 86% (6/7), respectively, for both indexes (cutoff values: PAT <21 ms and PAT/ET <39%). PAT/ET measured during light anesthesia correlated with PAT/ET obtained during invasive catheterization (r2=0.87, p<0.0001). Intra-observer and inter-observer variability of PAT and PAT/ET were less than 6%. Pulmonary artery systolic pressure can be estimated noninvasively in mice. Echocardiography allows to monitor acute changes of RVSP and to detect pulmonary hypertension. This technique enables to follow PAH evolution easily and repeatedly in mice.Download : Download full-size image

Effect of a somatostatin analogue on trophic hormone levels in acromegalic patients with elevated hGH after adenomectomy and treatment with bromocriptine.

Five female acromegalic patients who had undergone surgical adenomectomy, but still had elevated hGH serum levels, were treated with bromocriptine, 5-15 mg daily, for at least 4 months without a satisfactory response. In an attempt to lower serum hGH levels, p-NH2-Phe4-D-Trp8-somatostatin was administered, 100 micrograms as an i.v. bolus, followed by infusion of 250 micrograms over a 4 hour period. The analogue decreased hGH levels by about 50% in 3 out of 5 patients, both during bromocriptine treatment and also in its absence. Of the remaining two patients, one showed a decrease in hGH levels in response to the analogue only during bromocriptine treatment and the other only without it. Saline infusion after bromocriptine administration did not induce a decrease in hGH levels in three of these patients. Somatostatin analogue caused a fall in serum insulin levels in all but one patient, who had diabetes mellitus and in whom serum insulin was undetectable. Both hGH and insulin levels showed a significant rebound after infusion of the analogue, but returned to basal levels within 24 hours. Prolactin did not change during the analogue infusion in 4 patients with normal PRL levels. However, in one patient in whom prolactin and hGH levels were elevated during bromocriptine treatment, the infusion of somatostatin analogue decreased both hormones. The analogue induced no changes in serum TSH, FSH and LH levels of any of the patients.

Impaired glycocalyx barrier properties and increased capillary tube haematocrit

Impaired glycocalyx barrier properties and increased capillary tube haematocrit

Changes in glycemic control and quality of life in pediatric type 1 diabetics with continuous subcutaneous insulin infusion of insulin aspart following multiple daily injection therapy.

The efficacy of continuous subcutaneous insulin infusion (CSII) of the rapid-acting insulin analogue, insulin aspart, was evaluated in 26 patients with childhood-onset type 1 diabetes aged between 6 and 18 yr who had been on basal-bolus therapy (multiple daily injection (MDI) of regular human insulin or rapid-acting insulin and intermediate/long-acting insulin). The glycemic control in the patients was evaluated based on changes in the clinical parameters and the patient quality of life (QOL) was evaluated by using the insulin therapy-related QOL questionnaire. Twenty two patients continued CSII during the 6-mo study period. The mean HbA1c was 7.8 ± 1.8% at baseline and it decreased to 7.4 ± 0.8% at 6 mo after the start of the CSII. Overall, no decrease of the QOL post-CSII initiation was noted. The possible superiority of CSII as compared to MDI was suggested for patients who “eat out” or “have to look for an appropriate place for insulin injection.” Aside from an inadequate indwelling needle placement detected after the initiation of CSII in several patients, no adverse event associated with NovoRapid® was seen. In conclusion, CSII of rapid-acting insulin appears to be a useful therapy for patients with childhood-onset type 1 diabetes.

Differential anti-inflammatory properties of peroxisome proliferator-activated receptors (PPAR) α and γ in experimental pancreatitis

Perfluorooctanoic acid (PFOA) has anti-inflammatory effects in models of cutaneous inflammation, possibly via activation of PPAR-α and PPAR-γ. We have therefore investigated whether PFOA has similar effects in a model of acute oedematous pancreatitis and whether such effects could be explained by agonism at PPAR-α or PPAR-γ. Acute pancreatitis was induced in anesthetized rats by i.v. infusion of the cholecystokinin analogue, caerulein. The PPAR-α agonist clofibrate or the PPAR-γ agonist rosiglitazone were injected s.c. before the experiments. Pancreatic oedema, neutrophil activation and production of prostaglandin (PG) E2 and prostacyclin (via 6-keto-PGF1α) were assessed in the pancreas. Acute pancreatitis caused significant oedema formation, neutrophil activation as assessed by myeloperoxidase activity in the tissue, and increased synthesis of pro-inflammatory prostanoids. Neutrophil activation was unaffected by clofibrate but was abolished by rosiglitazone. In contrast, prostanoid synthesis was unaffected by rosiglitazone but was inhibited by clofibrate. In conclusion, our data demonstrate that activation of PPAR-α and PPAR-γ has differential anti-inflammatory effects in acute interstitial-oedematous pancreatitis. Neutrophil activation is sensitive to inhibition by PPAR-γ activation while the production of pro-inflammatory prostanoids can be attenuated by activation of PPAR-α. Thus, the anti-inflammatory potential of PPAR-α and PPAR-γ ligands should be further investigated. from 13th Scientific Symposium of the Austrian Pharmacological Society (APHAR). Joint Meeting with the Austrian Society of Toxicology (ASTOX) and the Hungarian Society for Experimental and Clinical Pharmacology (MFT) Vienna, Austria. 22–24 November 2007

Functional Gallbladder and Sphincter of Oddi Disorders

The functional disorder of the gallbladder (GB) is a motility disorder caused initially either by metabolic abnormalities or by a primary motility alteration. The functional disorders of the sphincter of Oddi (SO) encompass motor abnormalities of either the biliary or the pancreatic SO. Dysfunction of the GB and/or biliary SO produce similar patterns of pain. The pain caused by a dysfunction of the pancreatic SO can be similar to that of acute pancreatitis. The symptom-based diagnostic criteria of motility dysfunction of the GB and biliary SO are episodes of moderate to severe steady pain located in the epigastrium and right upper abdominal quadrant that last at least 30 minutes. GB motility disorder is suspected after gallstones and other structural abnormalities have been excluded. This diagnosis should then be confirmed by a decreased GB ejection fraction induced by cholecystokinin at cholescintigraphy and after disappearance of the recurrent biliary pain after cholecystectomy. Symptoms of biliary SO dysfunction may be accompanied by features of transient biliary obstruction, and those of pancreatic SO dysfunction are associated with elevation of pancreatic enzymes and even pancreatitis. Biliary-type SO dysfunction is more frequently recognized in postcholecystectomy patients. SO manometry is valuable to select patients with sphincter dysfunction; however, because of the high incidence of complications, these patients should be referred to an expert unit for such assessment. Thus invasive tests should be performed only in the presence of compelling clinical evidence and after noninvasive testing has yielded negative findings. The committee recommends that division of the biliary or pancreatic sphincters only be considered when the patient has severe symptoms, meets the required criteria, and other diagnoses are excluded.

Treatment with phosphodiesterase inhibitors type III and V: milrinone and sildenafil is an effective combination during thromboxane-induced acute pulmonary hypertension

To evaluate the effects of phosphodiesterase type III and V (PDEIII and PDEV) inhibition on pulmonary and systemic haemodynamics in a porcine model of acute pulmonary hypertension. Twenty-four adult swine were anaesthetized with 1 MAC isoflurane and mechanically ventilated with an FI(O(2)) of 100%. Micromanometer-tipped catheters were placed in the ascending aorta, pulmonary artery and right ventricle. Pulmonary flow was measured with a perivascular probe using transit time ultrasound. Pulmonary hypertension was induced with a continuous infusion of the thromboxane analogue, U46619. The animals were then randomized to four groups: Group 1 (n=6) received 50 mg of sildenafil (PDEV inhibitor) diluted in water via an orogastric tube; Group 2 (n=6) received 50 microg kg(-1) of i.v. milrinone (PDEIII inhibitor); Group 3 (n=6) received sildenafil followed by milrinone; and Group 4 (n=6) received placebo via an orogastric tube. Pulmonary hypertension was achieved in all animals. Calculated pulmonary vascular resistance decreased by an average of 36% after sildenafil (P<0.05), 41% after milrinone (P<0.05), and 61% with both drugs combined (P<0.05). Systemic vascular resistance decreased by 37% (P<0.05) with milrinone alone, and 36% (P<0.05) with milrinone and sildenafil combined but it was preserved in the sildenafil group. Cardiac output and right ventricular dP/dT were significantly improved after milrinone or both drugs combined, but not with sildenafil. Milrinone and sildenafil are effective pulmonary vasodilators, with independent action and additive effect. Both drugs combined achieved a better haemodynamic profile, with greater pulmonary vasodilatation and increased contractility but without additional systemic vasodilatation. The systemic haemodynamic profile (systemic vasodilation, cardiac output, right ventricular dP/dT) is improved with milrinone but not with sildenafil.