Effect of propranolol on nitrogen and energy metabolism in sepsis

Pharmacologic therapy designed to block adrenergic activity or alter hormonal milieu may modulate energy and protein metabolism in stress. The metabolic effects of propranolol (beta adrenergic receptor blocker) in sepsis was investigated in 22 well-nourished rats that underwent superior vena caval cannulation, cecal ligation, and puncture. Animals were randomly assigned to receive either a continuous infusion of 0.7 mg/day of propranolol combined with parenteral nutrition (n = 11) or parenteral nutrition alone (n = 11). Both groups received isocaloric, isonitrogenous, isovolemic, parenteral nutrition post-operatively for 24 hr. Nitrogen balance was better for the propranolol group than for the control group (+743 +/- 84 mg/kg/day versus +300 +/- 63 mg/kg/day, respectively, P less than 0.05). A significant difference between the pharmacologic therapy and control groups was noted for urinary 3-methylhistidine excretion versus control (0.99 +/- 0.08 micrograms/kg/day versus 7.5 +/- 0.37 micrograms/kg/day, respectively, P less than 0.01). Measured energy expenditure was similar for both pharmacologic therapy and control groups (149 +/- 20 kcal/kg/day versus 134 +/- 11 kcal/kg/day, respectively, P = N.S.). No statistically significant difference was demonstrated for 24-hr survival between propranolol and control groups (73 and 64%, respectively). Continuous, low-dose propranolol promotes nitrogen retention and decreases 3-methylhistidine excretion without altering energy expenditure in parenterally fed septic rats.     

石杉碱甲类似物的研究II.N-甲基吡啶酮石杉碱甲类似物的合成

石杉碱甲(1)是从中草药石杉属植物千层塔(Lycopodium serratum Thunb.)中分得的一种高效可逆的乙酰胆碱酯酶抑制剂,临床试验证实它对早老性痴呆症有显著疗效。本文报道N-甲基吡啶酮石杉碱甲类似物2和3的合成。2-甲氧基-5-甲氧羰基-11-亚甲基-5,9-甲撑环辛-7-烯并吡啶(9)在乙腈中用三甲基氯硅烷和碘化钠选择性脱保护以定量的产率得吡啶酮10,再用甲醇钠和碘甲烷甲基化得N-甲基吡啶酮11,11经碱性水解,Curtius重排和氨基的脱保护得N-甲基吡啶酮石杉碱甲类似物2。通过类似的途径从中间体2-甲氧基-5-甲氧羰基-7-甲基-11-酮-5,9-甲撑环辛-7-烯并吡啶(14)合成了类似物3。类似物2和3的乙酰胆碱酯酶抑制活性均低于天然石杉碱甲。     

Analysis of Various Creatinine Clearance Formulas in Predicting Gentamicin Elimination in Patients With Low Serum Creatinine

Predicted gentamicin elimination rate constants (k_els) using creatinine clearance (C1_cr) estimates from seven equations were compared with k_els calculated from steady-state serum gentamicin concentrations in 186 hospitalized patients. In predicting k_el, the equations varied significantly in precision (mean absolute percentage error), and were particularly imprecise among patients with serum creatinine values of 71 μmol/L or less. Significant differences in bias (mean prediction error) were also observed. All equations using serum creatinine as an element showed improved precision, and most showed reduced bias when a minimum value of 71 μmol/L was used. The Cockcroft-Gault normalized to 72 kg and the Hull equations are among the simplest to calculate and, when using a minimum serum creatinine of 71 μmol/L, had significantly greater precision and less bias than several of the equations. We recommend one of these two methods for predicting gentamicin k_el in patients with low serum creatinine values.     

Effect of inhaled fluticasone propionate on BAL TGF-beta(1) and bFGF concentrations in clinically stable lung transplant recipients.

BACKGROUND: Inhaled fluticasone propionate (FP) therapy decreases inflammation and sub-basement membrane thickness in asthmatic airways. Bronchiolitis obliterans syndrome (BOS) in lung transplant recipients (LTRs) involves progressive airway fibrosis and obliteration. Therefore, augmented immunosuppression may be of some benefit in treating BOS. In this study, we examined the effect of 3 months of treatment with high-dose inhaled FP on the concentrations of 2 fibrogenic factors, transforming growth factor (TGF)-beta(1) and beta fibrogenic growth factor (bFGF) in bronchoalveolar lavage (BAL) fluid from clinically stable LTRs. METHODS: We conducted a randomized, double-blind, placebo-controlled, parallel group study with inhaled FP (750 microg, twice/day for 3 months) in 28 LTRs (15 FP and 13 placebo). We recruited 23 healthy controls. We performed spirometry, bronchoscopy, and bronchoalveolar lavage procedures before treatment and after 3 months of treatment. We used commercially available enzyme-linked immunosorbent assay kits to measure BAL fluid TGF-beta(1) and bFGF concentrations. RESULTS: In LTRs before treatment, BAL TGF-beta(1) concentrations (but not bFGF concentrations), total cell counts, and neutrophil percentage increased compared with controls (p < 0.05). We found no significant differences between FP and placebo groups at baseline measurements. After treatment, BAL TGF-beta(1) concentrations significantly increased in the FP group (p = 0.03), but we found no difference between FP and placebo groups; BAL bFGF concentrations increased during treatment in both groups compared with controls (p < 0.05), but not significantly within either patient group (p > 0.05). We found a reverse correlation between forced expiratory volume in 1 second (FEV(1)) and BAL TGF-beta(1) concentration in the FP group (r = -0.53, p = 0.04), and between FEV(1) and BAL TGF-beta(1) concentration in the placebo group (r = -0.74, p = 0.004). Multivariable analysis indicated no significant independent effects of inhaled FP in either BAL TGF-beta(1) or bFGF concentrations. CONCLUSIONS: Bronchoalveolar fluid TGF-beta(1) concentrations increased in LTRs after transplantation and may correlate with the decrease in lung function. Inhaled FP added to conventional immunosuppression had no effect on TGF-beta(1) or bFGF production in BAL fluid.     

Continuous arteriovenous haemofiltration in the treatment of tumour lysis syndrome

The management of tumour lysis syndrome remains problematic despite the rigorous use of preventative measures. Continuous arteriovenous haemofiltration (CAVH) is well suited to its use in both the prevention and treatment of metabolic abnormalities and renal insufficiency associated with tumour lysis. We report the successful use of CAVH in the treatment of a patient with tumour lysis syndrome.     

Effects of adenosine 5’-triphosphate, uridine 5’-triphosphate, adenosine 5’-tetraphosphate and diadenosine polyphosphates in guinea-pig taenia caeci and rat colon muscularis mucosae

The functional effects of adenosine 5’-triphosphate (ATP), uridine 5’-triphosphate (UTP), adenosine 5’-tetraphosphate (AP₄) and the diadenosine polyphosphates P₁,P₃-diadenosine triphosphate (Ap₃A), P₁,P₄-diadenosine tetraphosphate (Ap₄A) and P₁,P₅-diadenosine pentaphosphate (Ap₅A) were studied in two isolated smooth muscle preparations thought to contain P_2Y (P2Y₁) receptors, the guinea-pig taenia caeci (which relaxes to ATP) and the rat colon muscularis mucosae (which contracts to ATP). In addition, the breakdown of these compounds by the rat colon muscularis mucosae was investigated by high pressure liquid chromatography. In the guinea-pig taenia caeci all the purine nucleotides caused relaxation with a potency order of Ap₃A=Ap₄A> ATP>AP₄=Ap₅A, and these relaxations were antagonised by suramin with apparent pA₂ values in the region of 5, consistent with activation of a P2Y₁ receptor. In the rat colon muscularis mucosae the nucleotides caused contraction with a potency order of Ap₃A = Ap₄A>ATP=AP₄ =Ap₅A >UTP. However, while suramin (100 μM) inhibited responses to ATP and UTP at all concentrations of agonist, it only inhibited contractions induced by the higher concentrations of AP₄, Ap₃A and Ap₄A and had little effect on contractions induced by Ap₅A. A higher concentration of suramin (1 mM) enhanced contractions induced by ATP but greatly inhibited those induced by UTP and had no effect on responses to the other agonists. The A₁ adenosine receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX; 10 nM) had no effect on responses to ATP or UTP but inhibited responses to Ap₃A, Ap₄A, Ap₅A and AP₄. A combination of suramin (1 mM) and DPCPX (10 nM) almost abolished responses to all the agonists. ATP and UTP were rapidly degraded by the rat colon muscularis mucosae while AP₄, Ap₃A, Ap₄A and Ap₅A were degraded more slowly, and the major product detected after breakdown of the purine nucleotides was inosine rather than adenosine. The breakdown of all the nucleotides was inhibited by suramin (1 mM), although this inhibition did not achieve statistical significance in the case of ATP. These results show that while the diadenosine polyphosphates appear to act as P2 agonists in the taenia caeci, in the rat colon muscularis mucosae their major action is via adenosine A₁ receptors rather than via P2 receptors. In addition, although they are more stable than ATP or UTP, their action in this tissue is clearly affected by their degradation which complicates the effects of suramin. Received: 23 March 1998 / Accepted: 29 June 1998     

Endocrinology: Immunohistochemical sex steroid receptor distribution in endometrium from long-term subdermal levonorgestrel users and during the normal menstrual cycle

The bleeding problems experienced by users of subdermal levonorgestrelimplants (Norplant) remain unexplained. The aim of the presentstudy was to investigate the oestrogen (ER) and progesteronereceptor (PR) distribution in levonorgestrel-treated endometrialbiopsies from 31 subjects recruited in Jakarta, Indonesia, andto compare the sex steroid receptor immunostaining with thatof endometrium from 58 normally cycling women from Melbourne,Australia. Sex steroid receptor immunoreactivity was additionallycompared with days of exposure to subdermal levonorgestrel,serum oestradiol and progesterone levels and days of bleedingduring a 90-day reference period. An immunohistochemical techniquewith an alkaline phosphatase anti-alkaline phosphatase (APAAP)detection system for use in formalin-fixed paraffin wax embeddedendometrial tissue was employed. Significantly greater meanimmunostaining scores of stromal PR were observed in Norplantcompared with control endometrium at all stages across the cycle.No significant correlations were demonstrated between sex steroidreceptor immunostaining and days of exposure to subdermal levonorgestrel,serum oestradiol or progesterone concentrations or days of bleedingduring a 90-day reference period. Whether the elevated stromalPR immunostaining in Norplant-treated endometrium is a consequenceof increased synthesis or reduced turnover of receptor remainsunclear. As yet it is undetermined whether increased PR immunoreactivitycorresponds to an increase in number of functional PR.     

A model of sterile vesicoureteric reflux in the sheep

Eighteen Coopworth ewe lambs were divided into three groups based on the initial cystourethrogram and cystometry findings at 5 – 7 weeks of age: group 1, 6 lambs with spontaneous low-pressure bilateral vesicoureteric reflux (VUR) on bladder filling were used to study the natural history of reflux; group 2, 5 lambs with no VUR detected were used to establish an experimental model of bilateral VUR using an unroofing surgical procedure; group 3, 7 lambs with spontaneous VUR detected during micturition had the same surgical procedure to increase the degree of VUR. All three animal groups were followed for 4 – 10 months. Spontaneous VUR was demonstrated in 13 of 18 lambs (25/36 ureters). The presence and severity of spontaneously occurring reflux in group 1 lambs diminished with increasing age. VUR was created successfully in group 2 and increased in degree in group 3 animals. The only significant histological finding in all three animal groups with grades II and III VUR was distal renal tubular dilatation. The sheep is a useful and readily available animal for studying VUR. During 4 – 10 months of follow-up, sterile reflux without bladder outflow obstruction resulted in distal renal tubular dilatation, but no renal parenchymal damage. Received April 17, 1997; received in revised form August 5, 1997; accepted August 21, 1997