Loperamide (Imodium, Janssen-Ortho Inc, North York, Ontario/McNeil Consumer Products, Guelph, Ontario) is a synthetic piperidine derivative used for the treatment of both acute and chronic diarrhea. It exerts its action via cholinergic, noncholinergic, opiate and nonopiate recep­tor-mediated mechanisms. After oral administration, little systemic absorption takes place. About 40% ofa2 mg dose is excreted in the feces, with about 30% being unchanged drug. Reproductive studies performed in the rat and rabbit re­vealed no evidence of impaired fertility or harm to the fetus at dose levels up to 30-fold the therapeutic dose for humans. This drug is commonly used for both acute and chronic con­ditions, such as travellers’ diarrhea and inflammatory bowel disease. There are limited human data available on the use of this drug in pregnancy.

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D-GalN administration is a model of hepatotoxicity used ex­tensively in experimental studies. D-GalN depletes the intra- cellular uracil nucleotides in hepatocytes that lead to inhibition of RNA and protein synthesis. D-GalN increases serum transaminase levels, hepatic necrosis and coma. In the present study and in another, D-GalN induced liver injury and increased TNF-a concentration in rat serum. TNF-a is essential to induce cell death in unviable hepatocytes and exacerbates D-GalN-induced damage. In this sense, TNF-a treatment induces apoptosis in vivo and in vitro when D-GalN is also administered. Under our conditions, a short time after D-GalN portal infu­sion, a significant increase in serum ALT (Figure 1) and TNF-a (Figure 2) was observed compared with the control group. Nevertheless, the serum concentrations of IL-1a (Fig­ure 3) and NOx (Figure 4) did not change with D-GalN ad­ministration. Such inability of D-GalN to stimulate IL-1 a release has also been pointed out using IL-1 receptor antago­nist to prevent the lethal combination of TNF-a and D-GalN treatment. Because the manufacturer indicated that the D-GalN had no trace amount of endotoxin, our re­sults indicate that D-GalN is able to stimulate inflammatory cells to release inflammatory mediators. In our experimental conditions, the toxicity induced by D-GalN was low, and ALT levels (Figure 1) decreased 15 mins after infusion. This may be due to the low dose of D-GalN used or some other extrahepatic changes induced by D-GalN.

Effect of PGE₁ and D-GalN on serum ALT activity: Thenormal range of ALT activity in rat serum is 18 to 20 U/L (20). In the present study, D-GalN infusion induced a signifi­cant increase 5 and 10 mins after treatment in ALT (29+1.5 and 43±1.2 U/L, respectively) activity compared with the control group (23+0.3 and 27±2.7 U/L, respectively) (P<0.05) (Figure 1). PGE1 did not significantly change ALT activity. Preadministration of PGE₁ to D-GalN-treated rats significantly reduced ALT levels to values below those ob­tained in the control group (P<0.05) (Figure 1). Effect of PGE1 and D-GalN on serum TNF-a concentra­tion: The normal range of TNF-a concentration in rat serum is 11 to 18 pg/mL (20). TNF-a release increased significantly 5 to 15 mins after D-GalN infusion compared with the con­trol group (P<0.05) (Figure 2). PGE1 resulted in a significant increase in TNF-a (56±4.7 pg/mL) 15 mins after 0.9% so­dium chloride infusion compared with the control group (33±6.9 pg/mL) (P<0.05) (Figure 2). Preadministration of PGE1 to D-GalN-treated rats caused an additional signifi­cant increase in TNF-a concentration from 1 to 10 mins after D-GalN infusion compared with the D-GalN group (P<0.05) (Figure 2).

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Reagents: All chemicals were obtained from Sigma Chemi­cal Co (St Louis, Missouri). D-GalN was obtained from Sigma Chemical Co. PGE₁ (alprostadil) was purchased from The Upjohn Co (Kalamazoo, Michigan). Antigen and polyclonal antibody obtained from Genzyme Diagnostics (Cambridge, Massachusetts) were used for quantification of TNF-a and IL-1a by ELISA. Nitrate reductase and lactate dehydrogenase (LDH) were obtained from Boehringer Mannheim (Mannheim, Germany). Animals and treatments: Male Wistar rats (175 to 225 g) were housed in a climate-controlled (21°C) room under a 12 h light-dark cycle and were given tap water and standard laboratory rat chow ad libitum. Animal care standards and experimental protocols were according to the Guide for the Care and Use of Laboratory Animals. Rats were divided into four groups of 30 according to treatment: control, D-GalN, PGEj, and PGE^+D-GalN. Each group was further divided into another six groups according to the time point of the kinetics (0, 1, 2.5, 5, 10 and 15 mins) in relation to the last treatment. All operations were performed under general (pentobarbital) anesthesia. The abdomen was entered through a midline incision to observe clearly the hepatic lob­ules and portal vein. To restrain and accelerate liver re­sponse, treatments (in a volume of 500 pL) were infused as a bolus through the cannulated portal vein instead of intraperitoneally. Control and PGE₁-treated animals re­ceived the corresponding volume of 0.9% sodium chloride or PGEj (250 pg/kg) dissolved in 20% ethanol. D-GalN was also dissolved in 0.9% sodium chloride, and the dose (200 mg/kg) administered was adjusted according to the mode of administration compared with higher doses used in intraperitoneal administration. In the PGEj+D-GalN group, PGE₁ was infused 10 mins before D-GalN infusion.

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TNF-a but not IL-1a is correlated with PGE₁-dependent protection against acute D-galactosamine-induced liver injury

Experimental studies have shown that prostaglandins have protective properties against different models of liver injury. Prostaglandin E (PGE) reduces liver toxicity in­duced by D-galactosamine (D-GalN), thioacetamide, aflatoxin B1, carbon tetrachloride, bile duct ligature, fat-enriched and choline-deficient diet, viral hepati­tis and complement-mediated hepatic necrosis. Fur­thermore, PGE has a beneficial effect on fulminant viral hepatitis in humans, reducing serum transaminase levels and improving encephalopathy and coagulation factors. Prostacyclin also reduces transaminase levels during D-GalN-induced hepatic necrosis.

Different hypotheses have been suggested to explain the protective effect of prostaglandins in liver injury according to the different experimental models used. Among those cited are increased vascularization, reduced plasma membrane microviscosity, modification of the arachidonic acid cascade profile, antifibrotic activity and immunomodulatory activity.

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Novelties in measurement programs

Speed of measurement by densitometric techniques in children is of great importance, because it is hard to keep children mo­tionless during the performance. However, utilization of speed­ing up measurement as fan beam technique has still some dis­advantages enforcing the needs of its further evaluation and cross-calibration. For accurate determination of bone mineral accrual in growing subjects with the use of DXA correction of all magnification errors is needed. Children with growth abnor­malities often show deficient BMD for chronological age. That might be a reflection of growth irregularities rather than poor bone mineralization. Taking on account body size deficit, im­proves significantly the assessment of bone status in children. In the newest software for DXA appeared the possibility of ad­justing body size using three-step assessment: height for age, BMC for height and bone area for height. Moreover, incor­poration of the variable standard deviations in DXA pediatric reference data results in more accurate assessment of pedi- atric skeletal health; what is especially ortant during pubertal growth spurt. The other prospective technical improvements are related to incorporation of reference ranges for subcranial BMD and normalization of skeletal status with the use of mus­cle mass adjustment.

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The first generation of QUS systems characterized the bone tis­sue with the use of two relevant parameters: the speed of sound (SOS) and the attenuation of the signal [broadband ultra­sound attenuation (BUA)]. The amount of attenuation de­pends on the structure, the specific acoustic properties of the medium, and the wavelength the ultrasound signal used. In performed in vivo ultrasound measurements, it is not possible to separate absorption from scattering what is resulting measure­ment of total attenuation. Generally, QUS devices provide a combined measurement nominated “stiffness” or “quantitative ultrasound index”. These parameters are calculated from both SOS and BUA values indirectly reflected information of strength as bone quality. Amplitude of the ultrasound signal decreas­es with the increase in bone porosity and lead to the identifica­tion of an amplitude-related measurement of SOS (AD-SOS).

Expressed in meters per seconds parameter is able to magnify the differences in SOS as measured in diverse bone status. SOS measured along cortical bone with little interference of soft tissue could also provide some relevant information about the biomechanical behavior of that kind of tissue as a whole, regarding all the matrix mineralization and the mi- crostructural factors of bone material quality together. Even when this approach is used it still needs to be validated. In sum up, QUS can be regarded as promising technique for improving noninvasively the resources of bone strength.

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