Α1-acid Glycoprotein Concentrations Research Articles

Prepartum milking effects on parlour behaviour, endocrine and immune responses in Holstein heifers

Transition of primiparous heifers to the milking herd is a period with multiple stressors. The objective of these studies was to determine effects of parlour experience and prepartum milking (pre-milking) on behavioural and physiological indicators of stress after calving. Two experiments were conducted, one was in a free-stall housing confinement system and the second was in a modified grazing system. Forty-eight first-calf heifers were assigned to three treatments: control; experienced heifers taken through the parlour without milking; or pre-milk heifers milked for 3 weeks prior to estimated parturition. Blood was collected within 24 h of parturition and on days 3, 5, 7, 10 and 14 following parturition for cortisol and acute phase protein determination. In the grazing system, 20 heifers were assigned to a prepartum milked or control group as in the confinement system and behaviour observations included days -21, -14, -7, -5, -3 and -1 relative to calving and days 1, 3, 7, 9, 14, and 16 post-calving. Milk production was greatest for prepartum milked heifers in both housing systems. However, somatic cell score was reduced by prepartum milking only in the confinement system. Balking occurred least in parlour-experienced heifers. In confinement housing, shifting while in the parlour was the only behaviour that was greater at first milking in control heifers. Kicking was most frequent for parlour experienced heifers on day 2. Grazing system pre-milked heifers shifted more at their first milking (day -21) than did the controls at their first milking (day 1). Shifting within cow was greatest on day -21 compared with day -5 (P<0.05). Pre-milked heifers shifted more on day 1 post-calving than did the control heifers (P<0.05). These results showed that shifting was the most indicative behaviour of restlessness, was transient, and decreased by day 5 prior to calving. Cortisol and alpha1-acid glycoprotein concentrations were not different; however, haptoglobin increased for all treatments up to and including day 3 and haptoglobin concentrations of pre-milked heifers began to decrease by day 5 post-calving. Pre-milked heifers had lower haptoglobin concentrations than the control heifers and tended to have lower concentrations than experienced heifers on day 10 post partum. By day 14 post partum, all haptoglobin concentrations were <200 microg/ml, but the haptoglobin concentration of control heifers was greater than that of pre-milked and experienced heifers. These results showed that prepartum milking and parlour experience shorten some acute phase protein responses, but minimally affect early parlour behaviours.

Using pharmacokinetics to predict the effects of pregnancy and maternal–infant transfer of drugs during lactation

Knowledge of pharmacokinetics and the use of a mechanistic-based approach can improve our ability to predict the effects of pregnancy for medications when data are limited. Despite the many physiological changes that occur during pregnancy that could theoretically affect absorption, bioavailability does not appear to be altered. Decreased albumin and α1-acid glycoprotein concentrations during pregnancy will result in decreased protein binding for highly bound drugs. For drugs metabolised by the liver, this can result in misinterpretation of total plasma concentrations of low extraction ratio drugs and overdosing of high extraction ratio drugs administered by non-oral routes. Renal clearance and the activity of the CYP isozymes, CYP3A4, 2D6 and 2C9, and uridine 5′-diphosphate glucuronosyltransferase are increased during pregnancy. In contrast, CYP1A2 and 2C19 activity is decreased. The dose of a drug an infant receives during breastfeeding is dependent on the amount excreted into the breast milk, the daily volume of milk ingested and the average plasma concentration of the mother. The lipophilicity, protein binding and ionisation properties of a drug will determine how much is excreted into the breast milk. The milk to plasma concentration ratio has large inter- and intrasubject variability and is often not known. In contrast, protein binding is usually known. An extensive literature review was done to identify case reports including infant concentrations from breast-fed infants exposed to maternal drugs. For drugs that were at least 85% protein bound, measurable concentrations of drug in the infant did not occur if there was no placental exposure immediately prior to or during delivery. Knowledge of the protein binding properties of a drug can provide a quick and easy tool to estimate exposure of an infant to medication from breastfeeding.

Synthesis of acute phase proteins in rats with cirrhosis exposed to lipopolysaccharide

BackgroundIn patients with cirrhosis, infection is frequent and a leading cause of death. This is secondary to various immunologic abnormalities in both the innate and the adaptive immune system. However, it remains unclear whether cirrhosis affects the inflammatory systemic component of the innate immunity, 'the acute phase response', mostly effectuated by the liver itself. We hypothesized that rats with cirrhosis raise a reduced acute phase response induced by lipopolysaccharide (LPS).ResultsWe examined the acute phase response induced by intraperitoneal injection of a low dose of LPS, in sham operated control animals and in rats with liver cirrhosis induced by bile duct ligation (BDL). We measured the serum concentrations of the most important acute phase proteins and their liver tissue gene expressions, assessed by mRNA levels. The BDL-model itself increased the serum concentration of α1-acid glycoprotein (α1AGP) and haptoglobin. LPS was lethal to 25% of the cirrhotic animals and to none of the controls. Twenty-four hours after LPS, the serum concentration of α1AGP and haptoglobin, the mRNA level of these acute phase proteins and of α2-macroglobulin and thiostatin rose to the same level in the animals with cirrhosis and in controls.ConclusionIn rats with experimental cirrhosis LPS caused high mortality. In the survivors, the cirrhotic liver still synthesized acute phase proteins as the normal liver, indicating a normal hepatic contribution to this part of the acute phase response.

Hepatic pharmacokinetics of propranolol in rats with adjuvant-induced systemic inflammation

Systemic inflammation is known to affect drug disposition in the liver. This study sought to relate and quantitate changes in hepatic pharmacokinetics of propranolol with changes in hepatic architecture and physiology in adjuvant-treated rats. Transmission electron microscopy was used to assess morphological changes in mitochondria and lysosomes of adjuvant-treated rat livers. The disposition of propranolol was assessed in the perfused rat liver using the multiple indicator dilution technique. Hepatic extraction and mean transit time were determined from outflow-concentration profiles using a nonparametric method. Kinetic parameters were derived from a two-phase physiologically based organ pharmacokinetic model. Possible relationships were then explored between the changes in hepatic drug disposition and cytochrome P-450 activity and iron concentration. Adjuvant treatment induced the appearance of mitochondrial inclusions/tubularization and irregularly shaped lysosomes in rat livers. Livers from adjuvant-treated rats had (relative to normal) significantly higher alpha(1)-acid glycoprotein (orosomucoid) and iron tissue concentrations but lower cytochrome P-450 content. The hepatic extraction, metabolism, and ion trapping of propranolol were significantly impaired in adjuvant-treated rats and could be correlated with altered iron store and cytochrome P-450 activity. It is concluded that adjuvant-induced systemic inflammation alters hepatocellular morphology and biochemistry and consequently influences hepatic disposition of propranolol.

Continuous extrapleural infusion of ropivcicciine in children: is it safe?

To the Editor: In contrast to bupivacaine, ropivacaine has not yet been shown to be suitable in the clinical context of continuous intercostal nerve blockade using an extrapleural catheter in children and young infants.1,2 After approval of the hospital’s Ethical Committee and obtaining parental consent, the pharmacokinetics of an extrapleural bolus of 0.5 mL·kg–1 ropivacaine 0.2% followed by a continuous extrapleural infusion at two different rates (0.2 mL·kg–1·hr–1 and 0.3 mL·kg–1·hr–1, resp.) for 48 hr were evaluated in two children undergoing cardiac surgery via a lateral thoracotomy (patient 1: male, four years old; patient 2: female, six years old). Anesthesia was performed according to our standard protocol and at the end of the operation an extrapleural catheter (20-gauge, multi-orifice, SIMS Portex Ltd., Hythe, UK) was placed as described earlier.3 The bolus of ropivacaine 0.2% was administered when the patients recovered from anesthesia (adequate reactions to verbal command) and the infusion was maintained for 48 hr. Total plasma concentrations of ropivacaine and plasma concentration of α1-acid glycoprotein were assessed at the hours t = 1/6, 1/3, 0.5, 1, 3, 6, 18, 30, 48, 50, 52 and 54. Total ropivacaine plasma concentration showed a first peak 30 min after the initial bolus. Its highest value was measured at the end of the continuous infusion (Figure) and exceeded the limit of 2.2 mg·L–1 that is accepted to be safe in terms of toxicity as described by Knudsen et al.4 The measured concentrations of α1-acid glycoprotein remained within the normal range. The capacity of α1-acid glycoprotein to buffer the free fraction of ropivacaine which, mainly, is responsible for toxic reactions in the context of a continuous infusion of local anesthetics was, therefore, not increasing. Thus, we may not assume a subsequent decrease in the unbound fraction of ropivacaine. Clinically, no pathological findings in terms of toxicity were found. Our preliminary results suggest that intercostal nerve block with an initial bolus of 0.5 mL·kg–1, followed by a continuous infusion through an extrapleural catheter of 2 mg·mL–1 ropivacaine at 0.2 mL·hr–1 and 0.3 mL·hr–1 over 48 hr is at the edge of being considered a safe technique for analgesia after lateral thoracotomy. More investigations also in terms of pharmacodynamics are needed to determine the optimal rate and concentration of ropivacaine administered through an extrapleural catheter in children.

Akupunktur und Moxibustion als ergänzende Therapie bei M. Crohn

BackgroundAcupuncture has traditionally been used in the treatment of inflammatory bowel disease in China and is increasingly applied in Western countries. The aim of the study was to investigate the efficacy of acupuncture in the treatment of active Crohn's disease. MethodsProspective, randomized, controlled, single-blind clinical trial. Change in Crohn's Disease Activity Index (CDAI) was used after treatment as main outcome measure, changes in quality of life and general well-being, serum markers of inflammation (α1-acid glycoprotein, C-reactive protein) as secondary outcome measures. 51 patients with mild to moderately active Crohn's disease were treated in a single center for complementary medicine by three trained acupuncterists and randomly assigned to receive either traditional acupuncture (TCM group, n = 27) or control treatment at non-acupuncture points (control group, n = 24). Patients were treated in 10 sessions over a period of 4 weeks and followed up for 12 weeks. ResultsIn the TCM group CDAI decreased from 250 (±51) to 163 (±56) points as compared with a mean decrease from 220 (±42) to 181 (±46) points in the control group (TCM vs. control group: p = 0.003). In both groups these changes were associated with improvements in general well-being and quality of life. α1-acid glycoprotein concentration fell significantly only in the TCM group (p = 0.046). ConclusionsApart from a marked placebo-effect traditional acupuncture offers an additional therapeutic benefit in patients with mild to moderately active Crohn's disease.

Drug development and use in the elderly: search for the right dose and dosing regimen

Across the globe over the last few decades, there has been a remarkable increase in the proportion of the population which is elderly, and this trend is set to continue. Data from 10 countries that accounted for about 55% of the world population of 6079 million in the year 2000 provide an overview of this significant shift in demography. Table 1 summarizes the projections for the next 25 years. Hitherto, increases in life expectancy have been most obvious in the affluent countries; however, improvements in public health and disease control are also leading to increases in life expectancy in the less affluent countries. As a result of relatively larger increases in life expectancy at birth, significant shifts in demography are also expected in countries that are at present economically less affluent. The number of elderly people in the world is therefore expected to continue to increase for some considerable time. Interestingly, the most dramatic increases in the proportion of the population who are elderly are anticipated in countries where total populations are projected to decrease (such as Japan, Germany and Italy). Table 1 Age-related demography in 2000 and projected changes in 10 major countries The 2001 population census of the UK revealed that since the census of 1951, the proportion of elderly population above 65 years and 85 years has increased from 16% and 0.4% respectively to 21% and 1.9%, respectively. These changes in demography will have significant effects on the economics generally as well as on the provisions for healthcare. Cardiovascular and neurological diseases and cancers are the most prevalent in the elderly. These three groups of diseases account for about 54% of the total burden of disease in Europe in terms of disability adjusted life years. Of the total gross Hospital and Community Health Services expenditure of £31.9 billion in the year 2001–2002 in the UK, 13% was expended on people aged 65–74 years, 16% on those aged 75–84 years and 10% for people aged 85 years or more. Furthermore, about 55% of the community prescriptions during 2001 in the UK were dispensed for the elderly. Cardiovascular and psychoactive drugs accounted for more than 40% of these prescriptions. In view of many age-related changes in the pharmacokinetics and pharmacodynamics of a drug, the safe and effective prescribing of medicines in the elderly will continue to present a major challenge. This review provides an overview of the issues relevant to development and clinical use of drugs in the elderly population, with particular reference to determining the right dosage and dose regimen and the regulatory requirements that facilitate this process. It also examines whether, as a result of advancing age per se, the dosing regimens in the elderly and the frail elderly might be different from those in the non-elderly.

Uterine Involution and Fertility of Holstein Cows Subsequent to Early Postpartum PGF2α Treatment for Acute Puerperal Metritis

The objective was to evaluate the effect of 2 doses of PGF2α injected early postpartum on uterine involution, serum concentration of acute phase proteins at 12 d postpartum, and fertility in Holstein cows with acute puerperal metritis. Only cows diagnosed with retained fetal membranes and metritis and treated with ceftiofur hydrochloride for 5 d were used in the study. Two hundred cows were assigned randomly to be treated (n=100) or to serve as controls (n=100). Treatment consisted of 2 i.m. injections of PGF2α 8h apart on d 8 postpartum. A subsample of 90 cows was selected randomly (45 treated cows; 45 controls) to evaluate uterine diameter using ultrasonography, uterine score, and serum concentrations of acute phase proteins at 12 d postpartum. The outcome variable for all cows was conception rate at first service. Postpartum, primiparous, treated cows had smaller uterine diameters and lower uterine scores than controls. Cows with a uterine diameter <5.1cm at 12 d postpartum were 5.5 times more likely to conceive at first service than cows with larger uterine horn diameter. Treatment significantly reduced the concentrations of serum α1-acid glycoprotein. Within primiparous cows, treatment also increased conception at first service by 17%. It was concluded that 2 doses of PGF2α 8h apart at 8 d postpartum in primiparous cows with acute puerperal metritis decreased the diameter of uterine horns and serum concentration of α1-acid glycoprotein at 12 d postpartum and increased the conception rate at first service.

Prospective evaluation of the pharmacokinetic (PK) and toxicity profile of docetaxel in the elderly

8043 Background: The PK of anticancer drugs may be altered with aging due, in part, to differences in body composition and decreased end organ function. Despite the increasing number of elderly patients presenting with cancer, few pharmacological studies have been conducted in this subgroup of patients treated with anticancer drugs, including docetaxel. Methods: The PK and toxicity of docetaxel were studied during cycle 1 of therapy in a cohort of 20 elderly cancer patients (median age [range], 71 years [y] [65–80]) and a group of 20 cancer patients aged <65y (median age [range], 53 years [26–64]). Docetaxel 75 mg/m2 was given once every 3 weeks. Docetaxel concentrations were determined in serial samples obtained up to one week after drug administration using LC/MS/MS. Docetaxel PK parameters were calculated using a 3-compartment model. Cytochrome P4503A (CYP3A), was phenotyped using the erythromycin breath test (ERMBT) prior to drug administration. The sample size was based on a power analysis to detect an effect size of 1.5, assuming a coefficient of variation of 50% with α=0.05 and β=0.12. Results: Patient characteristics, including BSA, liver function, and PS were not significantly different between the 2 cohorts (P>.18), although pre-treatment serum α1-acid glycoprotein concentrations were 20% lower in the elderly (mean, 126mg/dL [≥65y] vs 154mg/dL [<65y]; P=.036). The ERMBT parameter, percentage 14C-exhaled/h, was not altered in elderly patients (mean, 2.32%[≥65y] vs 2.45%[<65y]; P=.35) suggesting similar CYP3A4 activity. Docetaxel PK parameters were not different between the 2 cohorts (P>.15), and the mean(SD) clearance of docetaxel was 30.1(18.3) L/h (≥65y) vs 30.0(14.8) L/h (<65y) (P=.98). Although the younger cohort of patients were more heavily pretreated (P=.024), the percentage of patients with grade 4/febrile neutropenia was greater in the elderly (65%/20% [≥65y] vs 25%/0% [<65y]; P>.12). Conclusions: CYP3A activity and docetaxel PK are unaltered in elderly patients. In the population studied, the incidence of neutropenia appeared to be greater in the elderly, which was unrelated to differences in drug clearance between the 2 groups. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Pharmaceuticals

Impact of elements containing glycopeptide resistance genes on expression of virulence in Enterococcus faecalis peritonitis: a pilot study with rats.

The relationship between virulence and chromosomal elements containing glycopeptide resistance genes was experimentally assessed for two transconjugant strains of Enterococcus faecalis (VanA and VanB phenotypes) and compared to that for a susceptible wild-type strain. Microbiologic and inflammatory effects were assessed in a polymicrobial rat model of peritonitis. Mean peritoneal enterococcus concentrations +/- standard deviations at day 1 were 2.1 +/- 1.9, 1.3 +/- 1.1, and 1.7 +/- 2.0 log(10) CFU/ml for susceptible, VanA, and VanB strains, respectively (P < 0.05). At day 3 also there were lower concentrations of glycopeptide-resistant enterococcal strains in peritoneal fluid (3.2 +/- 3.4, 1.8 +/- 1.8, and 2.1 +/- 2.4 log(10) CFU/ml for susceptible, VanA, and VanB strains, respectively [P < 0.05]). Transconjugant glycopeptide-resistant strains were associated with increased peritoneal cell counts at the different evaluation times of the experiment (P < 0.001). Plasma alpha1-acid glycoprotein concentrations were lower in the presence of the susceptible strain (667 +/- 189 mg/liter) than in the presence of the VanA or VanB strain (1,193 +/- 419 or 1,210 +/- 404 mg/liter, respectively [P < 0.05]), while concentrations of tumor necrosis factor alpha and interleukin-6 in peritoneal fluid remained similar for the strains. These results suggest a trend toward variation of virulence of transconjugant strains compared to the wild-type strain in this peritonitis model.

個別薬物療法のための血しょう中蛋白非結合型Ｄｉｓｏｐｙｒａｍｉｄｅ濃度測定の有用性

The unbound concentration of disopyramide (DP) in plasma was studied to determine whether or not it is a useful index to assess the effectiveness of DP in anti-arrhythmic therapy. In 20 arrhythmic patients administered DP (Rythmodan®, 100-600 mg/day), there was no correlation between the dose and total or unbound plasma concentration of DP. The values of unbound fraction (fp) of DP in plasma widely varied from 0.25 to 0.57. The fp values were not correlated with the albumin concentration in plasma, but did correlate with the concentration of α1-acid glycoprotein. We further examined the relationship between the total or unbound plasma concentrations of DP and it's effectiveness in 16 of the 20 patients (4 patients had side effects). There was significant difference in the plasma concentrations of DP between the effective group and the ineffective group.However, as the range of the concentration for the two groups overlapped in 75%. the total concentration cannot be used to define the effectiveness. On the other hand, the unbound concentration of DP was greater than 0.8μg/mL in the effective group, whereas it was lower than 0.8μg/mL in the ineffective group.There was no correlation between the unbound concentration of mono-N-dealkyldisopyramide (MND) and the effectiveness. The range of the unbound plasma concentration of MND was 0.1-1.0μg/mL, and no patient developed side effects such as tachycardia or constipation due to the anticholinergic effect. In conciusion, an unbound concentration of DP in plasma of over 0.8μg/mL can be used as an index of the effectiveness of anti-arrhythmic therapy in therapeutic drug monitoring.

Anemia and interleukin-10, tumor necrosis factor alpha, and erythropoietin levels among children with acute, uncomplicated Plasmodium falciparum malaria.

Anemia is an important complication of malaria, and its pathogenesis is not well understood. To gain insight into potential age-related relationships between tumor necrosis factor alpha (TNF-alpha), interleukin 10 (IL-10), erythropoietin, and anemia during acute malaria, 273 children of ages 12 to 120 months presenting with acute, uncomplicated malaria in Kampala, Uganda, were monitored at enrollment and 3 and 7 days later. Younger children had higher geometric mean erythropoietin, TNF-alpha, and alpha(1)-acid glycoprotein (AGP) concentrations than older children. Univariate regression analysis revealed that age, log(10) erythropoietin levels, IL-10/TNF-alpha ratio, and AGP levels were each significantly associated with hemoglobin levels at baseline. Hemoglobin concentrations were inversely correlated with the log(10) erythropoietin level at all three visits. For the older age groups, higher levels of TNF-alpha were significantly associated with higher IL-10 levels at all three visits, but this relationship was significant only at baseline for younger children. These data suggest that younger children do not maintain IL-10 production in response to the inflammatory process, and this mechanism may contribute to the more severe anemia found in younger children. Acute malaria is an illness whose incidence and severity are largely age dependent. Further studies are needed to understand the relationships between age-related immune responses to malaria and their role in the pathogenesis of malarial anemia.

Relation of serum retinol to acute phase proteins and malarial morbidity in Papua New Guinea children

Acute phase proteins (APPs) are associated with malaria-induced hyporetinemia (serum retinol <0.70 micromol/L); however, the degree of the association is not well documented. The association between malaria-induced hyporetinemia and APPs was assessed. In a cross-sectional study, 90 children with serum retinol concentrations from <0.35 to >1.05 micromol/L were selected from children in a clinical trial of vitamin A supplementation. Serum was collected before treatment allocation. Retinol binding protein (RBP) concentrations were determined by radioimmunoassays, and transthyretin, alpha(1)-acid glycoprotein (AGP), alpha(1)-antichymotrypsin, C-reactive protein (CRP), haptoglobin, and albumin concentrations by radial immunodiffusion assays. Children in the subsample had high rates of splenomegaly and Plasmodium-positive blood-smear slides (P < 0.01); AGP (Pearson's r = -0.40, P < 0.001) and CRP (r = -0.21, P = 0.04) were inversely correlated with retinol. The negative APPs RBP, transthyretin, and albumin were positively and significantly associated with retinol. All APPs, except alpha(1)-antichymotrypsin, were significantly correlated with splenomegaly. Of the positive APPs, AGP correlated with CRP (r = 0.37, P < 0.001), indicating chronic inflammation. In a stepwise regression analysis, 73% of retinol's variability was explained by RBP and transthyretin. The model predicted that a 1-SD increase in RBP or transthyretin increases retinol by approximately 0.38 or 0.47 micromol/L, respectively, whereas an equivalent increase in AGP decreases retinol by 0.12 micromol/L. The RBP-transthyretin transport complex of retinol is not altered by inflammation. Positive APPs are useful markers of type and severity of inflammation; however, except for AGP, it is unlikely that they can correct for malaria-induced hyporetinemia.

Serum α1-acid glycoprotein concentrations before and after relapse in dogs with lymphoma treated with doxorubicin

Objective To determine whether serum α1-acid glycoprotein (AGP) concentration was a useful marker of relapse in dogs with lymphoma that were in clinical remission following treatment with doxorubicin. Design Cohort study. Animals 12 dogs with lymphoma and 10 healthy dogs. Procedure Serum AGP concentration was measured in the healthy dogs and in the dogs with lymphoma before treatment, 3 weeks after the first dose of doxorubicin was administered, and every 3 weeks thereafter until relapse (ie, recurrence of clinically detectable disease such as palpable enlargement of peripheral lymph nodes). Serum AGP concentrations were determined by use of a radial immunodiffusion kit. Results Mean serum AGP concentration in healthy dogs was significantly less than concentration in dogs with lymphoma prior to treatment. Mean serum AGP concentrations after the first and each subsequent dose of doxorubicin were not significantly different from concentration in healthy dogs. However, mean serum AGP concentrations 3 weeks prior to and at the time of relapse were significantly higher than concentration measured after the first dose of doxorubicin, and were not significantly different from concentration measured before treatment. Clinical Implications Results suggest that measuring serum AGP concentration may be a useful method of predicting relapse before recurrence of clinically detectable disease in dogs with lymphoma undergoing treatment with doxorubicin. (J Am Vet Med Assoc 1999;214:1023–1025)

Cytokine modulation by PX differently affects specific acute phase proteins during sepsis in rats.

To explore the regulation of the acute phase response in vivo, the effects of pentoxifylline (PX) treatment (100 mg/kg ip 1 h before infection) were investigated in infected and pair-fed rats 2 and 6 days after an intravenous injection of live bacteria (Escherichia coli). PX treatment prevented the increase in plasma tumor necrosis factor (TNF)-alpha (peak 1.5 h after the infection) and resulted in an 84 and 61% inhibition of plasma interleukin (IL)-1beta and IL-6, respectively (peaks at 3 h). Plasma corticosterone kinetics were not modified by the treatment. Infection increased alpha1-acid glycoprotein (AGP), alpha2-macroglobulin (A2M), and fibrinogen plasma concentrations and decreased albumin levels. PX significantly reduced AGP plasma concentration as early as day 2 in infected animals but reduced A2M and fibrinogen plasma levels only at day 6. The treatment had no effect on the albumin plasma concentration. Hepatic AGP and fibrinogen mRNA levels increased in infected rats, whereas those of A2M were unchanged and those of albumin were decreased. Two days after infection, AGP and fibrinogen mRNA levels were reduced in treated infected animals. PX was ineffective in modifying those of A2M and albumin. These data demonstrate, in vivo, that different acute phase proteins are individually regulated in sepsis. The in vivo effects of PX treatment support the hypothesis that TNF-alpha plays an important role in the regulation of AGP production, whereas other factors seem to be involved in the regulation of A2M, fibrinogen, and albumin expression.

Cholesterol saturation, not proteins or cholecystitis, is critical for crystal formation in human gallbladder bile

Background & Aims: Biliary proteins are promoters of cholesterol crystallization in artificial model bile. However, their pathogenic importance for cholesterol precipitation in native gallbladder bile (GB) is uncertain. The aim of this study was to evaluate the significance of biliary lipids and proteins on cholesterol crystal detection time (ChCDT) of GB in patients with gallstones. Methods: ChCDT and concentrations of lipids, albumin, mucins, aminopeptidase N, α1-acid glycoprotein, haptoglobin, and immunoglobulins (Igs) were measured in GB of 92 patients, 52 of whom had cholesterol gallstones. Results: ChCDT was markedly reduced in gallstone patients. Compared with patients without gallstones, they had a significant increase in cholesterol saturation and total protein, albumin, mucin, and IgG biliary concentrations. In univariate analysis, ChCDT of GB was significantly correlated with cholesterol saturation and total lipid, protein, Ig, aminopeptidase N, and α1-acid glycoprotein concentrations. However, stepwise logistic regression analysis showed that only cholesterol saturation independently correlated to ChCDT. Gallbladder inflammation correlated with the concentration of Igs, but subtraction of IgG from GB did not modify the ChCDT. Conclusions: Biliary cholesterol transport and saturation, but not proteins, appear critical for the cholesterol crystallization abnormality observed in native bile from patients with gallstones. GASTROENTEROLOGY 1998;114:1016-1023

ロタウイルス感染症の下痢黒毛和種子牛における血清ハプトグロビンおよび&amp;alpha;1-酸性糖タンパク質濃度と血清添加によるリンパ球幼若化能の抑制

本実験は,下痢子牛における血清ハプトグロビン(HP)およびα1-酸性糖タンパク質(α1-AGP)濃度と下痢子牛の血清添加によるリンパ球幼若化能への影響を検討するために実施した.黒毛和種の健康な子牛8頭とロタウイルス感染症を原因とし下痢発現から12-24時間経過した黒毛和種子牛24頭を用いた.正常子牛では,HPは血清中に検出されなかったが,下痢子牛では血清中にHPが認められた(599±414μg/ml).一方,血清α1-AGP濃度には,正常子牛(398±100μg/ml)と下痢子牛(441±104μg/ml)の間には有意差は認められなかった.臨床的に健康な13ヵ月齢の黒毛和種去勢雄牛の末梢血から分離した単核細胞に,56°C30分間,熱非働化した子体血清を添加し,コンカナバリンAにより誘導されるリンパ球幼若化能を測定した.その結果,正常子牛血清はリンパ球幼若化能を抑制しなかった.しかし,下痢子牛血清はリンパ球幼若化能を有意に抑制し,血清HP濃度とリンパ球幼若化能との間には有意な負の相関が認められた(R2=0.696,P<0.01).一方,血清α1-AGP濃度とリンパ球幼若化能の間には有意な相関は認められなかった(R2=0.001).これらの結果から,ロタウイルス感染症子牛では,下痢発症後12-24時間に血清中にHPが出現し,その血清は血清HP濃度依存性にリンパ球幼若化能を抑制することが明らかにされた.

Effects of repeated clarithromycin administration on the pharmacokinetic properties of pindolol in rats.

The goal of the present work was to determine the effect of clarithromycin (CAM) administration on the pharmacokinetic properties of pindolol in rats. The binding of pindolol to serum components increases proportionally with increasing alpha1-acid glycoprotein (AGP) concentration, indicating that AGP might play a major role in the binding of pindolol. After intravenous administration of pindolol to rats, the CAM-treated group showed a decrease in the volume of distribution, an increase in AUC and no change in the half-life as compared to the control group. Treatment with CAM increased the AGP concentration only. The serum concentration of albumin and creatinine, as well as the metabolic activity of hepatic microsomes towards pindolol, were not altered. Good correlation was observed between the AUC of pindolol in rats and the AGP concentration in serum. Moreover, at 5 min after the administration of an intravenous bolus dose of pindolol to CAM-treated rats, the free concentration of pindolol was lower but the total concentration was higher, compared with the control rats. These results suggested that the influence of CAM on the pharmacokinetic properties of pindolol in CAM-treated rats can be explained by protein binding which, in turn, may be associated with variations in AGP concentration.

Pig-MAP, porcine acute phase proteins and standardisation of assays in Europe

The pattern of plasma proteins changes greatly following infection, inflammation or tissue injury. The concentration of some proteins referred to as acute phase proteins (APPs) significantly increases within hours or days after the onset of these processes. In contrast, the concentration of other proteins, such as albumin (Alb), called negative acute phase proteins, decreases. APPs have been extensively studied in man and rat, but less so in other species. In recent work, the APPs have been characterised in pigs in response to inflammation following turpentine injection. The concentrations of C reactive protein (CRP) and haptoglobin (Hp) increase 5–7 times 48 h after the injection. Porcine Alb, α-lipoprotein, fetuin and transferrin were negative APP. Finally, the concentration of α1-acid glycoprotein and α1-protease inhibitor (α1-antitrypsin) did not change significantly during the inflammation. In addition to CRP and Hp, a serum α2-globulin was observed to be the major acute phase (MAP) protein in pigs. Pig-MAP is a new mammalian plasma protein, which is the pig counterpart of a recently cloned human serum protein denominated PK-120 or IHRP. Pig-MAP shows promise as a prominent positive APP and has been shown to be a good marker of different pig pathologies.

Changes in plasma α1-acid glycoprotein and albumin concentrations during late pregnancy in rhesus monkeys

Plasma protein concentrations are an important determinant of maternal-fetal drug transfer in the perinatal period. Plasma concentrations of α 1-acid glycoprotein (AAGP) and albumin were measured in pregnant rhesus monkeys using radial immunodiffusion assays at weekly intervals during the third trimester ( n = 12), at 3-day intervals in the 2 weeks prior to full term ( n = 10), and at 0, 1, 12, and 60 h after birth ( n = 4). AAGP concentrations increased significantly, and albumin concentrations decreased significantly, from weeks 13 to 21 gestation as well as from day 150 gestation to birth. No changes were seen in the postpartum period. AAGP and albumin concentrations were highly negatively correlated from day 150 gestation to birth. The data suggest that AAGP and albumin concentrations are jointly but inversely regulated by physiological or hormonal conditions that precede delivery.