No generation of bradykinin with a new polyacrylonitrile membrane (SPAN) in haemodialysis patients treated with ACE inhibitors

BACKGROUND: Anaphylactoid reactions occurring in uraemic patients haemodialysedwith polyacrylonitrile haemodialysis (HD) membranes and beingtreated with ACE inhibitors have been attributed to an excessivegeneration of bradykinin. METHODS: Here we tested in a prospective trial a new type of polyacrylonitrilemembrane (SPAN) with respect to bradykinin generation in nineHD patients receiving either captopril or enalapril. Each patienthad three consecutive HD sessions with each of the three testedmembranes, high-flux SPAN, high-flux polysulphone (F60) andlow-flux Hemophan (GFS Plus 16). RESULTS: No clinical signs of anaphylactoid reactions were observed inany of these patients but the number of patients was relativelysmall and the duration of exposure to different membranes relativelyshort. At 5 min after the start of HD session, plasma bradykininlevels were significantly higher in the venous than in the arterialline for all three HD membranes: SPAN, 18.5±11.9 versus12.4±5.3 fmol/ml (p<0.05); F60, 19.0±13.8 versus11.5±6.5 fmol/ml (P<0.01); and GFS Plus 16, 39.1±22.9versus 15.8±12.4 fmol/ml (P<0.005), mean±SDrespectively. Higher venous line levels were still observedat the 15 and 60 min time points for F60 and GFS Plus 16, butnot for SPAN. However, these levels were still insignificantcompared to levels measured during episodes of anaphylacticshock from the literature. Plasma histamine and C5a anaphylatoxinlevels did not show any increase during HD with SPAN. CONCLUSIONS: The SPAN membrane did not induce significant bradykinin releasein dialysis patients on ACE-inhibitor therapy. It may thereforebe used for high-flux dialysis in such patients.     

Oxalate elimination via hemodialysis or peritoneal dialysis in children with chronic renal failure

. Oxalate elimination and oxalate dialysance via hemodialysis (HD) or peritoneal dialysis (CAPD) has not been studied in detail in pediatric patients. We studied plasma oxalate, oxalate elimination, and oxalate dialysance in 15 infants and children undergoing CAPD (9 female, 6 male, aged 9 months to 18 years) and in 10 children on HD (4 female, 6 male, aged 7 – 18 years). Two children in each group had primary hyperoxaluria (PH). The mean duration of dialysis prior to examination was 12±11 months in CAPD and 31±23 months in HD patients. Bicarbonate HD was performed 5 h three times a week, CAPD consisted of five daily exchanges in 5 patients and four changes in the remaining 10 children (dwell volume 40 ml/kg body weight, 2.3 g/l glucose). Although oxalate dialysance was significantly higher in HD (mean 115.6 ml/min per 1.73 m² in HD versus 7.14 ml/min in CAPD), mean oxalate elimination per week was not different between both renal replacement therapies (3,478 μmol/1.73 m² surface area/week in CAPD versus 3,915 μmol/1.73 m² per week in HD). Oxalate elimination in patients with PH was between 6,650 and 9,900 μmol/week. Plasma oxalate remained elevated in both procedures [28 – 84 μmol/l in CAPD (92/148 in PH) and 33 – 101 μmol/l in HD (70/93 in PH)]. Oxalate elimination can be increased by a more frequent hemodialysis regimen. Received May 24, 1995; received in revised form and accepted October 31, 1995     

Human pharmacokinetics of orally administered strontium

Summary Pharmacokinetics of orally administered SrCl₂ (2.5 mmol), were studied in six healthy male volunteers. In the overall plasma concentration time (C-t) curves, two absorption phases were observed due to two dominant intestinal absorption loci. A method was devised to obtain separately the plasma C-t curves associated with each of the two absorption loci (curve 1 and curve 2). These curves and the overall plasma C-t curve were analyzed with a nonlinear estimation program (PCNONLIN). Pharmacokinetic parameters (mean±SD, n=6) calculated from the overall curve were as follows: peak plasma concentration (C_max) 3.55±1.22 μg/ml and area under the plasma C-t curve (AUC^∞) 9138±1930 μg·min/ml. The pharmacokinetic parameters calculated from curve 1 were as follows: terminal plasma elimination half-life time 47.3±7.9 hour, the plasma elimination half-life time of the preceding phase 5.2±3.3 hour, C_max,1 3.09±0.95 μg/ml, the first-order absorption rate constant for absorption locus 1 (k_a,1) 5.7±1.2×10⁻² minute⁻¹ and the time lag (t_{lag, 1}) 11.7±7.9 minute. In three of the subjects the pharmacokinetic parameters of absorption locus 2 could be evaluated: k_a,2=4.6±0.4×10⁻² minute⁻¹, t_lag,2=77.3±4.0 minute, t_max,2=153±16 minute, C_max,2=0.9±0.4μg/ml and AUC ₂ ^∞ =1204±565 μg·minute/ml. AUC ₂ ^∞ /AUC^∞=0.14, indicating that 14% of the absorbed dose was absorbed via the second locus. The half-life time for the urinary strontium (Sr):creatinine ratio was 39.5±9.5 hour and the cumulative urinary excretion (day 0–6) was 34.0±13.8 mg, representing 15.5±6.3% of the administered dose and 84% of the estimated absorbed dose, respectively. The estimated bioavailability was 20% and the renal clearance (day 0–6) was lower than 4 ml/minute, indicating tubular reabsorption of Sr.     

Procalcitonin serum levels in children undergoing chronic haemodialysis

Infections account for considerable morbidity and mortality in patients requiring haemodialysis (HD). Procalcitonin (PCT)—a low molecular weight protein of 13 kDa—helps one to distinguish viral from bacterial infections and to evaluate the severity of bacterial infections. We investigated (1) PCT baseline levels in eight children undergoing chronic HD with high-flux membranes and (2) changes in the serum levels of PCT, C-reactive protein (CRP) and beta-2-microglobulin (β2-MG)—a peptide with biochemical characteristics similar to those of PCT—before and after haemodialysis sessions. Blood sampling was performed three times in the mid-week session. Serum PCT of the seven uninfected children before HD sessions was increased (0.75±0.07 ng/ml), whereas CRP levels were normal. PCT after dialysis decreased significantly by 40% (P<0.0001) compared with initial values, whereas CRP levels before and after HD were not different. β2-MG decreased by 70%, probably due to different biochemical proprieties of both proteins. PCT serum levels 15 min and 60 min after the HD session remained unchanged in comparison with those at the end of the HD session, suggesting accumulation of PCT between HD sessions rather than HD-induced production to be responsible for the increased baseline PCT serum levels. We concluded that CRP serum levels were not affected by HD in our group. Moderately elevated baseline PCT serum levels that are presumably due to reduced renal clearance and uraemia and dialysability of PCT should be taken into consideration. However, increase of serum PCT in patients with severe bacterial infections is generally massive (10-fold to 1,000-fold), suggesting a low risk for false negative results in such cases.     

The PTH-Calcium Relationship During a Range of Infused PTH Doses in the Parathyroidectomized Rat

To establish the PTH dosage that maintains normal mineral homeostasis in the PTX rat, a series of doses of rat 1-34 PTH were infused via a subcutaneously implanted miniosmotic pump. The doses were 0, 0.011, 0.022, 0.044, and 0.11 μg/100 g/hour. After 48 hours, serum calcium ranged from 5.56 ± 0.02 to 16.29 ± 0.25 mg/dl, ANOVA P < 0.001, and serum phosphorus from 12.49 ± 0.03 to 5.33 ± 0.34 mg/dl, ANOVA P < 0.001. By post hoc test, the serum calcium level was different (P < 0.05) at every PTH dose; the serum phosphorus level was different (P < 0.05) at every PTH dose except between the two highest doses. The PTH dosage that produced a normal serum calcium (10.09 ± 0.10 mg/dl) and phosphorus (6.90 ± 0.18 mg/dl) was 0.022 μg/100 g/hour. The relationship between increasing doses of PTH and both serum calcium and phosphorus was curvilinear and the calcium-phosphorus product was remarkably constant from a serum calcium of 7–13 mg/dl. The increase in serum calcium and the decrease in serum phosphorus were more rapid at lower than at higher PTH doses so that for both, an asymptote was reached. At the highest serum calcium values, the calcium-phosphorus product increased and in individual rats, an increase in serum phosphorus was associated with a decrease in serum calcium. In summary, this study shows that (1) for rat 1-34 PTH, the normal replacement dose in the PTX rat with normal renal function on a normal diet is 0.022 μg/100 g/hour; (2) the relationship between PTH and both serum calcium and phosphorus is curvilinear, and an asymptote is reached for both; and (3) the calcium-phosphorus product is remarkably constant as the serum calcium increases from 7 to 13 mg/dl and only increased during marked hypercalcemia when serum phosphorus did not decrease further or even tended to increase. Received: 30 May 1997 / Accepted: 15 October 1997     

Enhancement of t-PA Induced Fibrinolysis with Laser Energy: In-Vitro Observations

The solid-state, pulsed-wave, holmium:YAG laser operates within strong water absorption peaks at the mid-infrared optical wavelength. This laser has been shown to be capable of inducing a mechanical, photoacoustic dissolution of fibrin, a major constituent of thrombi. It is not known whether this laser's energy combined with pharmacologic therapy can enhance the rate of fibrinolysis. The aims of this study were (1) to test the hypothesis that mid-infrared laser emission can enhance tissue-type plasminogen-activator (t-PA) mediated fibrinolysis and (2) to test the combined effect of these two methods of fibrinolysis on fibrin clots varying in age. Three in vitro experimental protocols were used. (1) Fibrin clots were treated with 116 000 IU t-PA for 1, 6 and 12 h, respectively, and then exposed to mid-infrared laser energy (solid-state, pulsed-wave, holmium:YAG, 2.1 μm wavelength 250 ms pulse length, 5 Hz repetition rate, 500 mJ/pulse (33 J/cm²)). (2) Fibrin gels layered with t-PA were exposed to either 25, 50, 75 or 100 J laser energy. t-PA was then allowed to interact with the lased gels for an additional 4 h. (3) The effects of varying clot age (1, 4 or 8 h) on laser (75 J) augmentation of t-PA induced fibrinolysis were tested. Each experimental protocol had control gels and following each experimental manoeuvre, 20 μl of the plasmin inhibitor ε-amino-n caproic acid was added and fibrin degradation products (FDPs), an indicator of fibrinolysis, were measured by latex agglutination. In fibrin clots exposed to t-PA for 6 h, the addition of laser energy significantly increased FDPs released (t-PA alone 40±0 μg/ml, laser plus t-PA 160±0 μg/ml, p<0.001). For gels exposed to t-PA for 12 h, addition of laser energy resulted in complete dissolution of the clot (FDPs with t-PA alone 160±0 μg/ml vs. laser plus t-PA>300 μg/ml, p=0.001). The rise in FDPs was significantly greater with 75 J of laser energy compared to 25 J (160±0 μg/ml vs. 80±0 μg/ml, p=0.0001), however, energy levels greater than 75 J did not further increase the amount of FDPs indicating a plateau phenomenon in dose–response relationship. t-PA had a decreased fibrinolytic effect on 4 and 8 h-old clots (FDPs of 60±20 μg/ml and 30±10 μg/ml, respectively). Laser energy reversed this trend and enhanced fibrinolysis in both 4 and 8 h-old clots. In 4 h-old clots, laser plus t-PA resulted in FDP release of 160±0 μg/ml compared to 60±20 μg/ml for t-PA alone (p=0.007). In 8 h-old clots, FDP release with laser plus t-PA was 160±0 μg/ml compared to 30±10 μg/ml with t-PA alone (p=0.0004). It was concluded that in vitro application of mid-infrared laser energy significantly enhances fibrinolysis in fibrin clots initially treated by t-PA. The in vitro interaction between mid-infrared laser and t-PA is energy dependent, however, at energy levels exceeding 75 J there is a plateau phenomenon in dose–response relationship. This wavelength photoacoustic energy also augments the decreased response of ageing clots to t-PA.     

Measurements of blood DMSO and DMSO2 in a healthy person and a hemodialysis patient

Background. The aim of the present study was twofold: (1) to confirm gas chromatography/mass spectrometry (GS/MS) as a means of measuring blood and urine concentrations of dimethyl sulfoxide (DMSO) and its metabolite, dimethyl sulfone (DMSO₂), and (2) to measure blood concentrations of DMSO and DMSO₂ in a hemodialysis (HD) patient receiving DMSO. Methods. Measurements were made after deprotenization, using 450 μl of plasma or urine, then using 2 μl of supernatant for GC/MS. DMSO-d ₆ was used as the internal standard. The two subjects were a healthy 43-year-old man, weighing 82 kg, who received a single dose of 5 ml DMSO, and a 48-year-old man, an HD patient, weighing 56 kg, with a 3-year history of HD. The etiology of chronic renal failure was primary amyloidosis. The HD patient had been receiving 5 ml DMSO/day for 3 years and 10 months. Results. A good calibration curve for trace amounts of DMSO and DMSO₂, in the range of 0.25 ng to 50 ng, was obtained from GC/MS. The recovery rate and repeatability from plasma were also good. In the healthy subject, the maximum drug concentration time (Tmax) for DMSO was 2.0 h, the maximum drug concentration (Cmax), 74.92 μg/ml whole blood, and T1/2, 6.8 h. Tmax for DMSO₂ was 24.0 h, Cmax, 58.32 μg/ml whole blood, and T1/2 was greatly extended, to 56.8 h. Blood concentrations of DMSO and DMSO₂ in the HD patient before HD were remarkably high, at 171.32 and 814.22 μg/ml whole blood, respectively. After HD, these values decreased to 66.48 and 405.05 μg/ml whole blood, respectively, but were still higher than the value in the healthy subject. Conclusions. Because the effective drug concentration of DMSO has not been established, the dose level for HD patients must be investigated from the standpoint of therapeutic drug monitoring. Furthermore, as the blood concentration of the metabolite DMSO₂ is higher than that of DMSO, attention must be directed to the pharmacokinetics of DMSO₂. Received: March 1, 2000 / Accepted: May 16, 2001     

Is there a role for endothelin-1 in the hemodynamic changes during hemodialysis?

Background  The etiology of hemodialysis (HD)-induced hypotension and hypertension remains speculative. There is mounting evidence that endothelin-1 (ET-1) may play a vital role in these hemodynamic changes. We examined the possible role of intradialytic changes of ET-1 in the pathogenesis of hypotension and rebound hypertension during HD. Methods  The present study included 45 patients with end-stage renal disease (ESRD) on regular HD. They were divided according to their hemodynamic status during HD into three groups (group I had stable intradialytic hemodynamics, group II had dialysis-induced hypotension, and group III had rebound hypertension during HD). In addition, 15 healthy volunteers were included as a control group. Pulse and blood pressure were monitored before, during (every half hour), and after HD session. ET-1 level was measured at the beginning, middle, and end of HD. ET-1 was measured in the control group for comparison. Results  Pre-dialysis levels of ET-1 were significantly higher in dialysis patients compared to the controls (P < 0.001); however, they were comparable in the three HD groups. The post-dialysis ET-1 level was not changed significantly in group I compared with predialysis values (14.49 ± 2.04 vs. 14.33 ± 2.23 pg/ml; P = NS), while the ET-1 concentration decreased significantly in group II and increased in group III in comparison to predialysis values (8.56 ± 1.44 vs. 11.75 ± 2.51; 16.39 ± 3.12 vs. 11.93 ± 2.11 pg/ml, respectively; P < 0.001). Conclusion  Altered ET-1 levels may be involved in the pathogenesis of rebound hypertension and hypotension during HD.     

Augmentation of coronary bypass graft flow induced by dipyridamole and its relation to bypass graft patency

To evaluate the effect of dipyridamole on coronary bypass graft flow, 10 mg of dipyridamole was injected intravenously, during the measurement of graft flow, at the time of surgery. Its concentration in serum was measured and compared with that after oral administration. In 50 individual vein grafts performed on 35 patients, graft flow increased from 65 ±37 to 96±55 ml/min (p<0.001) after the dipyridamole injection and the arterial pressure decreased slightly. In 40 grafts whose graft flow was increased by more than 10 ml/min by dipyridamole, the patency rate (at 5 weeks) was 98 per cent, whereas that of the 10 other grafts, which responded poorly, was only 50 per cent (p<0.01). The serum concentration of dipyridamole, 3 minutes after intravenous injection, was 1.46±0.68 μg/ml, while the level of orally administrated dipyridamole, in 3 groups of patients who were given 50 mg, 75 mg and 100 mg, three times a day, respectively, was steady, being 0.68±0.20 μg/ml, 1.43±0.41 μg/ml and 1.73±0.50 μg/ml, 2 hours following ingestion. We concluded that intravenous dipyridamole increases the graft flow and that a better patency is obtained in those grafts in which the graft flow is increased by more than 10 ml/min. It is also expected that routine doses of oral dipyridamole possibly increase the graft flow after coronary bypass surgery. This paper was presented at the Xth World Congress of Cardiology held in Washington DC, USA, September 14–19, 1986     

The Effect of PTH Antagonist BIM-44002 on Serum Calcium and PTH Levels in Hypercalcemic Hyperparathyroid Patients

BIM-44002, a pure competitive antagonist of parathyroid hormone (PTH), has a high affinity for the PTH/PTHrP receptor in vitro, and can completely inhibit the actions of a PTH agonist in rats in vivo. Toxicology studies in rats and dogs showed BIM-44002 to be devoid of any adverse effects. Therefore we undertook an investigation to evaluate the potential utility of BIM-44002 in lowering elevated serum calcium in three patients with primary hyperparathyroidism. BIM-44002 was administered by continuous intravenous infusion at dosages of 100 μg/hour (370 nmol/hour) for 12 hours, followed by 200 μg/hour for 12 hours, followed by 400 μg/hour for 12 hours. Vital signs and serum ionized and total calcium were monitored hourly and for 3 hours after cessation of the infusion. Blood for PTH determinations was obtained at the same time points. Serum calcium and PTH did not change during and after the infusion of the antagonist. No subject experienced any adverse reactions to the infusion of the antagonist. We conclude that although the PTH antagonist BIM-44002 was effective both in vitro and in vivo in animals, and it was safe in humans, it was not able to lower serum calcium in patients with hyperparathyroidism. Possible reasons for lack of clinical efficacy are discussed.     

The effect of two different doses comprising the simultaneous administration of intravenous B-complex vitamins and oral folic acid on serum homocysteine levels in hemodialysis patients

Background: Several regimens using different doses of folic acid (FA) alone or supplemented with B-complex vitamins (BCVs) have been tested for their ability to reduce total homocysteine (tHcy) serum levels in hemodialysis (HD) patients. In the present study, we assessed the effect of two different doses comprising the simultaneous administration of intravenous (IV) BCVs and an oral FA supplementation on serum tHCy levels in HD patients. Patients–methods: In a cohort of 49 patients (31 male, 18 female) undergoing chronic HD treatment for a mean of 40.0±40.7 months, serum concentrations of tHcy, folate and vitamin-B12 (vB12) were determined at the end of three sequential periods as follows: 20 weeks without any BCV and/or FA supplementation (period A), 20 weeks with a dose comprising the simultaneous administration of IV BCVs and an oral supplementation of 5 mg of FA once a week (period B), and 20 weeks with a dose comprising the simultaneous administration of IV BCVs and an oral supplementation of 5 mg of FA thrice a week (period C). An IV dose of BCVs consisting of a 5 mL solution containing vitamin B₁ (250 mg), vitamin B₆ (250 mg) and vitamin B₁₂ (1.5 mg) was administered at the end of hemodialysis. Results: Mean serum tHcy levels were significantly higher at the end of period A relative to levels at the end of periods B and C (35.8±23 μmol/L vs. 22.0±17.6 and 15.0±4.5 μmol/L, respectively; p < 0.000001). Mean serum folate levels and mean serum vB12 levels were significantly lower at the end of period A relative to levels at the end of periods B and C (p < 0.000001). Mean serum tHcy levels were lowest at the end of period C (p < 0.000001 in comparison to periods A and B), and 26 of the 49 HD patients (67.3%) possessed tHcy levels below 16 μmol/L. Conclusions: In HD patients, high doses consisting of the simultaneous administration of IV BCVs and an oral FA supplementation resulted in the efficient reduction of serum tHcy levels.     

Continuous EPO receptor activator therapy of anemia in children under peritoneal dialysis

The short half-life of erythropoietin (rHuEPO) leads to repeated fluctuations in hemoglobin levels and the need for frequent administration. Continuous erythropoietin receptor activator (CERA) therapy has been approved for once or twice a month in adult dialysis patients. To evaluate the efficacy and safety of CERA therapy in the management of anemia in pediatric peritoneal dialysis (PD) stable PD children under twice-a-week EPO were converted to a subcutaneous CERA, scheduled every 2 weeks. The follow-up was 6 months. The primary efficacy parameter was hemoglobin > 11 g/dL. The exclusion criteria were ferritin <100 ng/ml and Hb saturation <20%. Sixteen children, aged 9.75 ± 3.6 years, including 11 boys, participated in the study. Mean Hb level at month 0 was 10.8 ± 1.9 g/dL. A decrease in hemoglobin to 10.38 ± 1 g/dL at month 2 was observed. The CERA dose was increased from 0.86 ± 0.33 to 1.67 ± 0.4 μg/kg at month 3. The target Hb level was reached by the 3rd month. The Hb level and CERA dose were 12.2 ± 1.2 and 1.6 ± 0.67 μg/kg respectively at the end of the study. No adverse events were observed during the protocol. CERA is an effective and safe therapy for maintaining hemoglobin levels when administered twice, up to once a month, in PD children. Doses required to reach target Hb were higher than published experiences in adult populations.     

Can intravenous atropine prevent bradycardia and hypotension during induction of total intravenous anesthesia with propofol and remifentanil?

This study was conducted to examine whether pretreatment with intravenous atropine could prevent bradycardia and hypotension during induction of total intravenous anesthesia with propofol and remifentanil in a prospective randomized placebo-controlled manner. Seventy patients, aged 24–78 years, were randomly divided into two groups, and received 0.5 mg atropine or placebo saline 1 min before induction of intravenous anesthesia with remifentanil at 0.4 μg/kg/min, propofol at a target blood concentration of 3 μg/ml, and vecuronium 1.5 mg/kg. Immediately after tracheal intubation, the infusion rate of remfentanil and the target concentration of propofol were reduced to and kept at 0.1 μg/kg/min and 2 μg/ml, respectively, for 10 min. Noninvasive blood pressure (BP) and heartrate (HR) were measured and recorded every minute. Intravenous atropine could prevent a fall in HR, but not a fall in BP, during induction of intravenous anesthesia with propofol and remifentanil of our dosing regimen. Our data suggested that a fall in HR induced by propofol–remifentanil anesthesia was mainly caused by centrally mediated sympatholytic and/or vagotonic actions of propofol and remifentanil, whereas a fall in BP was mainly the result of their direct vasodilating actions.     

Adrenomedullin Reduces Ischemic Brain Injury after Transient Middle Cerebral Artery Occlusion in Rats

Summary  Background. The effect of adrenomedullin, a vasodilatory peptide on transient middle cerebral artery (MCA) occlusion was investigated in rats.  Methods. Transient MCA occlusion for 2 hours was made by using the intra-arterial suture method, followed by reperfusion.  Findings. An intravenous infusion of adrenomedullin (1 μ g/kg/min) from one hour before ischemia to one hour after ischemia significantly reduced the infarct size and improved neurological deficits (p<0.05), without affecting systemic blood pressure or other physiological parameters. The infarct size was reduced with adrenomedullin by 25.4±12.7%, 31.3±5.8%, 31.6±6.1% respectively at the coronal level 6, 8 and 10 mm posterior from the frontal pole. Adrenomedullin also significantly inhibited the increase in myeloperoxidase (MPO) activity in the MCA area of the ischemic hemisphere after 22-hour reperfusion (control: 0.205±0.054 unit/g wet tissue, adrenomedullin group: 0.047±0.009 unit/g wet tissue, p<0.0001).  Interpretation. These data suggest that adrenomedullin reduces acute ischemic brain injury and one of is neuroprotective mechanisms may be derived from inhibition of the infiltration of neutrophils into the ischemic tissue.     

Prevention of acute cyclosporin nephrotoxicity by verapamil and atrial natriuretic factor in the rat

Nephrotexicity is the most common and important side-effectof cyclosporin (CsA) therapy. CsA alters renal haemodynamicswith a reduction in renal blood flow (RBF) and glomerular filtrationrate (GFR) and a significant increase in renal vascular resistances(RVR). The present experimental study investigates whether verapamilor atrial natriuretic factor (ANF) are able to prevent the nephrotoxicityof CsA. All studies were conducted in an in-situ autoperfused rat kidneymodel which allows continuous measurement of renal blood flowwithout dissection of the renal artery. CsA as a 40 mg/kg bolus dose significantly decreased RBF (from2.15±0.1 and 2.19±0.1 before CsA, to 1.29±0.16ml/min/100 g BW, 60 mm after CsA administration) (P<0.05),and GFR (from 0.14±0.1 and 0.13±0.01 before CsA,to 0.08±0.01 ml/min/100 g BW, 60 min after CsA administration)(P<0.05). CsA significantly increased RVR (from 9.5±0.73and 9.8±0.78 before CsA, to 16.7±2.9 mmHgxmin/ml60 min after CsA administration) (P<0.05). Verapamil pretreatment(as continuous intrarenal infusion at the rate of 1.25 µg/kg/min)attenuated the fall in GFR (from 0.16±0.01 and 0.19±0.03ml/min/100 g before CsA to 0.20±0.05 ml/min/100 g BW,60 mm after CsA administration) (NS) and in RBF (from 2.42±0.2and 2.6±0.22 ml/min/100 g before CsA to 1.79±0.17ml/min/100 g BW, 60 min after CsA administration (P<0.05).Pretreatment with ANF (as continuous intrarenal infusion atthe rate of 2.5 µg/kg/min) protected GFR (from 0.11±0.02and 0.18±0.03 ml/min/100 g before CsA, to 0.11±0.03ml/min/100 g BW, 60 min after CsA administration) (NS) and RVR(from 9.53±0.6 and 8.95±0.74 mmHgxmin/ml beforeCsA to 11.93±1.19 minHgxmin/ml, 60 min after CsA administration)(NS)and attenuated the fall in RBF (from 2.17±0.11 and 2.2±0.14ml/min/100g before CsA to 1.56±0.25 ml/min/100 g BW 60mm after CsA administiation)(P<0.05) when compared with initialvalues. These studies suggest that verapamil and ANF can prevent CsA-inducedrenal toxicity. Further studies should evaluate their usefulnessin clinical practice.     

氨甲环酸不同用药途径对女性股骨颈骨折全髋关节置换术失血的疗效分析

目的：研究氨甲环酸不同应用方式治疗老年女性股骨颈骨折行全髋关节置换术围手术期失血的疗效。方法：将2015年12月至2018年1月老年女性股骨颈骨折行全髋关节置换术患者77例分成4组：A组（静脉用药组）21例,年龄（77.10±7.02）岁,于手术切皮前5 min使用15 mg/kg氨甲环酸静脉滴注并且术中生理盐水灌注关节腔;B组（局部用药组）18例,年龄（73.83±6.56）岁,于手术切皮前5 min生理盐水静脉滴注并且术中使用总剂量为3 g的氨甲环酸灌注关节腔;C组（联合用药组）19例,年龄（74.26±6.04）岁,术前使用15 mg/kg氨甲环酸静滴并且术中使用总剂量为1.5 g的氨甲环酸灌注关节腔;D组（对照研究组）19例,年龄（76.69±9.27）岁,于手术切皮前5 min生理盐水静脉滴注并且术中生理盐水灌注关节腔。记录术后伤口引流量、血红蛋白变化,根据身高体重和手术前后的红细胞压积（HCT）计算所有患者的总失血量等。结果：A组术后引流量为（111.91±35.02） ml,血红蛋白改变量为（26.86±12.99） g/L,总失血量为（628.6±306.78） ml;B组术后引流量为（108.89±36.61） ml,血红蛋白改变量为（26.28±8.59） g/L,总失血量为（584.41±250.86） ml;C组术后引流量为（102.63±47.36） ml,血红蛋白改变量为（26.89±12.47） g/L,总失血量为（634.78±384.89） ml;D组术后引流量为（107.37±40.53） ml,血红蛋白改变量为（40.95±12.48） g/L,总失血量为（1 005.24±483.37） ml。4组术后引流量比较差异无统计学意义（P>0.05）;A、B、C组术后血红蛋白改变量、总失血量少于对照组D组（P<0.05）,但是3组组间比较差异无统计学意义（P>0.05）。结论：应用氨甲环酸能有效减少老年女性股骨颈骨折行全髋关节置换术围手术期失血,但是最佳给药方式及给药剂量需要进一步的研究。     

Effects of intraventricular infusion of vascular endothelial growth factor on cerebral blood flow,edema, and infarct volume

Summary.  Background: Therapeutic cerebral angiogenesis, utilizing angiogenic factors to enhance collateral vessel formation within the central nervous system, is a potential method for cerebral revascularization. A prior dose-response study determined that intracerebroventricular infusion of vascular endothelial growth factor (VEGF) increases vascular density with minimal associated brain edema at a concentration of 5 μg/ml. The purpose of this study was to assess effects of intracerebroventricular infusion of VEGF (5 μg/ml) on cerebral blood flow, infarct volume, and brain edema after ischemia.  Methods: Recombinant human VEGF₁₆₅ was infused into the right lateral ventricle of rats with an osmotic minipump at a rate of 1 μl/hr for 7 days. Control animals received vehicle only. Ischemia was produced by transient (2 hours) middle cerebral artery occlusion (MCAO). After MCAO, cerebral blood flow was determined with the indicator fractionation technique: infarct volume was assessed with 2,3,5-triphenlytetrazolium chloride staining, and brain edema was determined by measuring brain water content.  Findings: Cerebral blood flow was not significantly different in animals treated with VEGF compared to controls. There was a significant reduction in total infarct volume after temporary MCAO in VEGF-treated animals compared to controls (163±37 mm³ vs. 309±54 mm³, P<0.05). Brain water content after transient MCAO was also significantly reduced in VEGF-treated animals compared to controls (80.9±0.7% vs. 83.3±0.6%, P<0.05).  Interpretation: Intracerebroventricular infusion of VEGF₁₆₅ (5 μg/ml) decreases infarct volume and brain edema after temporary MCAO without a significant increase in cerebral blood flow. These results indicate that VEGF may have a direct neuroprotective effect in cerebral ischemia. Published online January 14, 2003 RID="*" ID="*"  This work was funded by a Pharmacia Upjohn Cerebrovascular Fellowship Award to Dr. Harrigan and an internal grant from the Department of Surgery, University of Michigan Health System.  Correspondence: M. R. Harrigan, M.D., Department of Neurosurgery, University of Michigan Health System, 1500 E. Medical Center Drive, Room 2128 Taubman Center, Campus Box 0338, Ann Arbor, MI 48109-0338.     

Zinc concentration in human prostatic fluid: Normal,chronic prostatitis,adenoma and cancer

Radionuclide induced energy dispersive X-ray fluorescence was used to estimate zinc content in prostatic fluid in normal, chronic prostatitis, adenoma and cancer cases. Groups of patients suffering from chronic prostatitis, adenoma and malignant tumours consisting of 28, 28 and 13 men, respectively, were examined. The control group included 22 healthy volunteers. Expressed prostatic fluid was obtained by digital rectal massage. The zinc concentration of intact prostatic fluid was 590±45 (SE) μg/ml. Almost no difference was found between the zinc concentration for chronic prostatitis and for adenoma, and those for normal levels being 455±60 (SE) and 540±50 (SE) μg/ml, respectively. Prostatic neoplasm resulted in a significant decrease of zinc secretion, with the concentration averaging 34.7±9.6 μg/ml, p<0.000001.     

Response of plasma 1,25-dihydroxyvitamin D in the human PTH(1–34) infusion test: An improved index for the diagnosis of idiopathic hypoparathyroidism and pseudohypoparathyroidism

Summary Synthetic human parathyroid hormone (1–34) (hPTH(1–34) infusion test has been utilized in the differential diagnosis of hypoparathyroidism by examining the incremental response of urinary phosphate and cyclic adenosine monophosphate (AMP). The response of plasma levels of 1,25-dihydroxyvitamin D (1,25(OH)₂D) in parathyroid hormone (PTH) infusion test was studied as a new criterion for the differential diagnosis of idiopathic hypoparathyroidism (IHP) and pseudohypoparathyroidism (PHP). Fourteen patients with IHP, 4 patients with PHP, and five control subjects were studied. All subjects received an intravenous infusion of 30 μg hPTH(1–34) over 5 minutes. The basal levels of plasma 1,25(OH)₂D in patients with IHP and PHP were significantly lower than those in control subjects, but there was no significant difference between the levels in patients with IHP and in patients with PHP. The plasma levels of 1,25(OH)₂D increased after the infusion of hPTH(1–34) and reached a peak 6 to 24 hours afterward. The 1,25(OH)₂D increase at 24 hours after the infusion (Δ1,25(OH)₂D) in control subjects and in patients with IHP were 18.1±3.91 (mean±SEM) and 24.1±2.80 pg/ml, respectively. There was no significant increase in patients with PHP (Δ1,25(OH)₂D=4.9±1.97 pg/ml). From these results, the measurement of Δ1,25(OH)₂D in hPTH(1–34) infusion test is useful as a criterion for the differential diagnosis of hypoparathyroidism.     

Removal of clodronate by haemodialysis in end-stage renal disease patients

BACKGROUND: Clodronate is a potent calcium-lowering drug. The effect ofhaemodialysis on clodronate pharm-acokinetics is unknown. METHODS: The removal of clodronate by haemodialysis was determined in10 end-stage renal disease patients (ESRD). A 2-h infusion of300 mg of clodronate was followed immediately by a 4-h haemodialysis.Vascular access was by AV fistula. A 1.5-m² cuprophane hollow-fibredialyser was applied. Blood flow was 205±15ml/min, dialysateflow 523±29 ml/min. Clodronate was determined by high-performanceliquid chromatography in total collected dialysate, and in bloodbefore and after the dialyser at initiation, 2 h, and 4 h ofHD. RESULTS: The initial predialyser serum concentration of clodronate was13.6 ± 4 ug/ml. It decreased to 4.9 ± 0.5 ug/mland 2.6 ± 0.5 ug/ml at 2h and 4h respectively. The clearanceof clodronate (86 ± 10 ml/min) remained unchanged duringHD. Clodronate in total collected dialysate per single 4-h HDwas 105 ± 16 mg (35% of injected dose). CONCLUSIONS: We conclude that clodronate is effectively removed from plasmaby HD. The present data together with information provided byprevious studies suggest that 300 mg of clodronate given asan 2-h infusion immediately prior to haemodialysis is an adequatedosage for ESRD patients.