Preoperative dextromethorphan reduces intraoperative but not postoperative morphine requirements after laparotomy.

UNLABELLED: N-methyl-D-aspartate (NMDA) antagonists combined with opioids are thought to be effective in the control of pain states. We evaluated morphine use and analgesia in 37 patients postlaparotomy. Patients received 60 mg of oral dextromethorphan or placebo the night before and again 1 h before surgery. Morphine was titrated intraoperatively to maintain blood pressure and heart rate within 20% of baseline and postoperatively via patient-controlled analgesia (PCA). The dextromethorphan and placebo groups were compared for morphine use intraoperatively, in recovery, via PCA in the first 4 and 24 h, and total use over the study period. Pain scores at rest and on activity for the first 4 and 24 h were also compared. Intraoperatively, the dextromethorphan group required less morphine: 13.1+/-4.3 vs 17.6+/-6.0 mg (P = 0.012). Postoperatively, there was no significant difference between the dextromethorphan and placebo groups for morphine use: in the recovery room 10.9+/-7.7 vs 12.1+/-7.7 mg; the first 4 h of PCA 15.9+/-9.3 vs 12.7+/-5.1 mg; the first 24 h of PCA 76.4+/-44.7 vs 61.8+/-27.5 mg; or in total morphine use 100.4+/-49.5 vs 91.5+/-3.1 mg. Pain scores for the two groups were not statistically different throughout the study period. We conclude that 60 mg of oral dextromethorphan given the night before and repeated an hour before surgery does not provide a postoperative morphine-sparing effect or improve analgesia after laparotomy. IMPLICATIONS: Patients given dextromethorphan before surgery had significantly reduced intraoperative morphine requirements. However, postoperative morphine requirements were unaltered. Dextromethorphan may need to be continued postoperatively to improve postoperative analgesia.

Fibrinogen inhibits the heparin cofactor II-mediated antithrombin activity of dermatan sulfate.

Dermatan sulfate is a naturally occurring antithrombotic glycosaminoglycan. The antithrombin activity of several dermatan sulfate preparations has been measured in whole human plasma and found to be -55% of that in purified systems. Kinetic studies under pseudo-first-order conditions indicated that the reduction in antithrombin activity of dermatan sulfate in plasma compared with that in buffer was due to noncompetitive inhibition with respect to dermatan sulfate. Analysis of the protein profile bound to immobilized dermatan sulphate showed that on a molar basis, histidine-rich glycoprotein and apolipoprotein E were the most abundant proteins specifically bound, together with significant amounts of fibrinogen and vitronectin. Addition of these proteins to the purified system showed that only fibrinogen inhibited the antithrombin activity of dermatan sulfate and that it did so in a concentration-dependent manner over the physiologic range of plasma fibrinogen levels. These results indicate that the anticoagulant activity of dermatan sulfate may be modulated in human plasma by fibrinogen.

Kinetic properties of NAD-dependent glyceraldehyde-3-phosphate dehydrogenase from the host fraction of soybean root nodules.

The kinetic mechanism of NAD-dependent glyceraldehyde-3-phosphate dehydrogenase [D-glyceraldehyde-3-phosphate:NAD+ oxidoreductase (phosphorylating), EC 1.2.1.12] from the host cytosolic fraction of soybean (Glycine max L. Merr. cv. Williams) root nodules has been investigated by steady-state initial velocity studies and inhibition studies with products and product analogs. The results were consistent with the enzyme having a bi-uni-uni-uni ping-pong mechanism in which NAD+ and phosphate interacted sequentially with the enzyme, followed in turn by the release of 1,3-bisphosphoglycerate, the addition of D-glyceraldehyde-3-phosphate, and the release of NADH. At pH 7.2, NAD+ bound to the enzyme in a rapid-equilibrium fashion, whereas at pH 8.8 there was rapid-equilibrium addition of both NAD+ and phosphate to the enzyme. NADH was a strong competitive inhibitor with respect to NAD+ and phosphate. The enzyme was very labile, especially above pH 8, but the rate of loss of activity was considerably reduced in the presence of NAD+ and phosphate. The possible role of these properties in the regulation of NAD-dependent glyceraldehyde-3-phosphate dehydrogenase in the host cytosol of soybean nodules is discussed.

Low-affinity material does not contribute to the antithrombotic activity of Orgaran (Org 10172) in human plasma.

Orgaran is a LMW heparinoid composed of heparan sulphate (83% w/w) of which 4-5% has high affinity for antithrombin, dermatan sulphate (12% w/w) and chondroitin sulphate (5% w/w). To examine the contribution of the low-affinity fraction to Orgaran's antithrombotic activity we have quantitated the binding of plasma proteins to Orgaran and its component fractions in whole, hirudin-anticoagulated human plasma. Antithrombin, largely bound to the high-affinity fraction, and histidine-rich glycoprotein, interacting with low-affinity components, were the dominant proteins bound to Orgaran. Vitronectin, fibrinogen, fibronectin, heparin cofactor II, and apolipoprotein B were also detected in small amounts. The ratio of bound antithrombin, histidine-rich glycoprotein and vitronectin to GAG was negatively correlated with the Orgaran concentration in plasma, implying that the efficacy of Orgaran may not be linearly related to dose. Binding of antithrombin to the high-affinity fraction was not decreased by other plasma proteins or affected by addition of low-affinity material. Moreover, the antithrombin and anti-factor Xa activities of the high-affinity material were unaltered by low-affinity GAGs. On the basis of our results we conclude that the low-affinity material does not contribute to the antithrombotic activity of Orgaran by binding non-anticoagulant plasma proteins and releasing the high-affinity chains to interact with antithrombin and its target proteinases.

Interaction of immobilised unfractionated and LMW heparins with proteins in whole human plasma.

The profile of proteins bound to immobilised heparins in hirudin-anticoagulated human plasma was analysed. In molar terms, antithrombin III was the most abundant protein bound to therapeutic doses of unfractionated heparin (M(r) = 12,000), whereas heparin cofactor II constituted < 1% of the protein bound. Histidine-rich glycoprotein was the only plasma protein likely to influence anticoagulant activity by direct competition with antithrombin III, though significant quantities of complement Factor H, fibrinogen, fibronectin, vitronectin and apolipoprotein B were also detected. Only traces of von Willebrand factor, complement factor I, inter-alpha-trypsin inhibitor, alpha 2-macroglobulin, serum amyloid P and transferrin were identified, and neither thrombospondin nor platelet factor 4 were measurable. Binding of both antithrombin III and histidine-rich glycoprotein varied with the ratio of heparin to plasma. Clexane (M(r) = 4,500) also bound antithrombin III, but both histidine-rich glycoprotein and vitronectin were quantitatively significant neutralising proteins. Neutralising proteins dominated the binding profile for Oligo H (M(r) = 2,200).

Small deep cerebral infarcts: Is there synergism between hypertension and diabetes?

Diabetics have a stroke risk similar to that of nondiabetic hypertensives. The prevalence of hypertension is greater in diabetics than in nondiabetics, and hypertension is probably the principal cause of the increased stroke risk in diabetics. Diabetes itself, however, also contributes independently to the risk for stroke. It has recently been suggested that a synergistic interaction between diabetes and hypertension is a major contributor to the risk of stroke in diabetics. In order to look for synergistic interaction between diabetes and hypertension, we compared the frequency of small deep infarcts seen on computed tomography [small deep infarcts (SDIs)] between a group of diabetics and a group of nondiabetics individually matched for age, hypertension, and sex. There were no significant differences between diabetics and nondiabetics in the number or size of SDIs, the ventricular size, or the severity of paraventricular white matter lesions. This study is against the presence of a synergistic effect between diabetes and hypertension on small cerebral arteries and suggests that the majority of the risk for SDIs in diabetics is due to hypertension.