Synthesis of N-Acetyllactosamine and N-Acetyllactosamine-Based Bioactives.

N-Acetyllactosamine (LacNAc) or more specifically ß-d-galactopyranosyl-1,4-N-acetyl-d-glucosamine is a unique acyl-amino sugar and a key structural unit in human milk oligosaccharides, an antigen component of many glycoproteins, and an antiviral active component for the development of effective drugs against viruses. LacNAc is useful itself and as a basic building block for producing various bioactive oligosaccharides, notably because this synthesis may be used to add value to dairy lactose. Despite a significant amount of information in the literature on the benefits, structures, and types of different LacNAc-derived oligosaccharides, knowledge about their effective synthesis for large-scale production is still in its infancy. This work provides a comprehensive analysis of existing production strategies for LacNAc and important LacNAc-based structures, including sialylated LacNAc as well as poly- and oligo-LacNAc. We conclude that direct extraction from milk is too complex, while chemical synthesis is also impractical at an industrial scale. Microbial routes have application when multiple step reactions are needed, but the major route to large-scale biochemical production will likely lie with enzymatic routes, particularly those using ß-galactosidases (for LacNAc synthesis), sialidases (for sialylated LacNAc synthesis), and ß-N-acetylhexosaminidases (for oligo-LacNAc synthesis). Glycosyltransferases, especially for the biosynthesis of extended complex LacNAc structures, could also play a major role in the future. In these cases, immobilization of the enzyme can increase stability and reduce cost. Processing parameters, such as substrate concentration and purity, acceptor/donor ratio, water activity, and temperature, can affect product selectivity and yield. More work is needed to optimize these reaction parameters and in the development of robust, thermally stable enzymes to facilitate commercial production of these important bioactive substances.

Using intervention mapping approach to finding socio-cognitive determinants of diabetes preventive behaviors.

INTRODUCTION: Diabetes is one of the most common chronic illnesses with complications. The objective of this study was to determine socio-cognitive determinants of diabetes preventive behaviors among sample of at risk group based on intervention mapping approach (IM) in Kermanshah, the west of Iran. METHODS: This cross-sectional study conducted among a total of 200 male and female aged more than 30 years old referred to health centers that randomly selected to participate voluntarily, during 2018. Participants filled out a self-report questionnaire. Data were analyzed by SPSS version 16 using bivariate correlations and linear regression at 95% significant level. RESULTS: The mean age of respondents was 38.4 years [95% CI: 37.3, 39.4], ranged from 30 to 56 years. Socio-cognitive determinants were accounted for 40% of the variation in diabetes prevention behaviors F = 35.559, P < 0.001. As well as, perceived self-efficacy, perceived severity, and perceived barrier were the most influential predictors on diabetes preventive behaviors. CONCLUSIONS: It seems that planning health promotion programs to reduce barrier to perform diabetes preventive behaviors and increase confidence towards ability to perform preventive behaviors, and seriousness about sides effect of diabetes may be usefulness of the results in order to promotion of diabetes preventive behaviors among at risk group.

Survey of the prevalence of Toxocara cati in stray cats in Isfahan city, Iran by PCR method.

Toxocariasis is a parasitic zoonosis with worldwide distribution that affects both cats and dogs. This parasite is one of the factors contributing to visceral larva migrans and ocular larva migrans in humans. Therefore, it is crucial to gain a good understanding of how cats are infected by T. cati, so as to prevent citizens from infection. This study aimed to examine the prevalence of T. cati in Isfahan. In 2014-2015, a total of 147 feacal samples were collected from urban stray cats. The felid feaces were analyzed through PCR test and 26 cats (17.7%) were diagnosed with T. cati gene. Sixteen cats (10.88%) were female and 10 cats (6.8%) were male. In terms of age group, 9 cats (6.12%) were adult while 17 cats (11.56%) were immature. Unlike previous studies there was no significant relationship between age/sex and prevalence of the parasite. Since there is a close link between humans and cats with greater risk of transmitting common diseases particularly in children, it is critical to raise public awareness about the disease and advise adults to be more health-conscious outdoors.

Sarcoidois subcutánea con adenopatías hiliares / Subcutaneous sarcoidosis with hilar adenopathy

Presentamos el caso de una mujer con placas cutáneas y nódulos subcutáneos de pequeño tamaño en las rodillas, cuyo estudio histológico puso de manifiesto granulomas epitelioides no caseificados en la dermis y en el tejido celular subcutáneo, respectivamente, que se asociaba con adenopatías hiliares. Después de descartar otras posibles causas de granulomas, se llevó a cabo el diagnóstico de sarcoidosis sistémica. Se destaca el carácter excepcional de la sarcoidosis subcutánea (AU)

We report the case of a woman who presented with cutaneous plaques and very small subcutaneous nodules on the knees. Skin biopsy disclosed noncaseating epithelioid cell granulomas throughout the dermis and the subcutis, respectively. It was associated to hilar Iymphadenopathy. After ruling out granulomas due to some other causes, sistemis sarcoidosis was diagnosed. Subcutaneous sarcoidosis is a remarkable infrecuent form of sarcoidosis (AU)

RPR 119990, a novel alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid antagonist: synthesis, pharmacological properties, and activity in an animal model of amyotrophic lateral sclerosis.

Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor antagonists are of potential interest for the treatment of certain acute and chronic neurodegenerative diseases, including amyotrophic lateral sclerosis. Here, we describe the synthesis and pharmacological properties of 9-carboxymethyl-4-oxo-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-2-phosphonic acid (RPR 119990). The compound displaced [3H]AMPA from rat cortex membranes with a K(i) of 107 nM. In oocytes expressing human recombinant AMPA receptors, RPR 119990 depressed ion flux with a K(B) of 71 nM. The antagonist properties of this compound were confirmed on rat native AMPA receptors in cerebella granule neurons in culture and in hippocampal slices where it antagonized electrophysiological responses with IC50 values of 50 and 93 nM, respectively. RPR 119990 antagonized hippocampal evoked responses in vivo, demonstrating brain penetration at active concentrations. RPR 119990 is a potent anticonvulsant in the supramaximal electroshock in the mouse with an ED50 of 2.3 mg/kg 1 h post s.c. administration, giving it a workably long action. Pharmacokinetic studies show good passage into the plasma after subcutaneous administration, whereas brain penetration is low but with slow elimination. This compound was found active in a transgenic mouse model of familial amyotrophic lateral sclerosis (SOD1-G93A) where it was able to improve grip muscle strength and glutamate uptake from spinal synaptosomal preparations, and prolong survival with a daily dose of 3 mg/kg s.c.

Comparison of serum, cerebrospinal fluid and brain extracellular fluid pharmacokinetics of lamotrigine.

We investigated the rate of penetration into and the intra-relationship between the serum, cerebrospinal fluid (CSF) and regional brain extracellular fluid (bECF) compartments following systemic administration of lamotrigine in rat. The serum pharmacokinetics were biphasic with an initial distribution phase, (half-life approximately 3 h), and then a prolonged elimination phase of over 30 h. The serum pharmacokinetics were linear over the range 10 - 40 mg kg(-1). Using direct sampling of CSF with concomitant serum sampling, the calculated penetration half-time into CSF was 0.42+/-0.15 h. At equilibrium, the CSF to total serum concentration ratio (0.61+/-0.02) was greater than the free to total serum concentration (0.39+/-0.01). Using in vivo recovery corrected microdialysis sampling in frontal cortex and hippocampus with concomitant serum sampling, the calculated penetration half-time of lamotrigine into bECF, 0.51+/-0.11 h, was similar to that for CSF and was not area or dose dependent. At equilibrium, the bECF to total serum concentration ratio (0.40+/-0.04) was similar to the free to total serum concentration (0.39+/-0.01), and did not differ between hippocampus and frontal cortex. The species specific serum kinetics can explain the prolonged action of lamotrigine in rat seizure models. Lamotrigine has a relatively slow penetration into both CSF and bECF compartments compared with antiepileptic drugs used in acute seizures. Furthermore, the free serum drug concentration is not the sole contributor to the CSF compartment, and the CSF concentration is an overestimate of the bECF concentration of lamotrigine.

Microdialysis study of the neuropharmacokinetics of phenytoin in rat hippocampus and frontal cortex.

Acute administration of phenytoin (PHT) is used in the treatment of status epilepticus, yet little is known about the neuropharmacokinetics of PHT in brain extracellular fluid (ECF), the pharmacodynamically relevant compartment. To characterize the neuropharmacokinetics of brain ECF PHT we implanted microdialysis probes in rat hippocampus and frontal cortex and placed a catheter in the internal jugular vein. PHT (50 or 100 mg/kg intraperitoneally, i.p.) was then administered, and microdialysate and serum samples were collected. PHT was rapidly absorbed, with a time to maximum concentration (Tmax) of approximately 20 min for serum concentrations. PHT rapidly entered the brain ECF compartment, with Tmax values similar to those of serum. In brain ECF, PHT concentrations then plateaued for 40-60 min despite decreasing serum concentrations. The area under the brain ECF concentration-time curve (AUC) was higher in hippocampus than frontal cortex. The possible mechanisms for these observations include entry of PHT into specific brain areas both across capillaries and through the cerebrospinal fluid (CSF), extensive binding of PHT in brain white matter, and differing blood flow in different brain regions.

The use of microdialysis for the study of drug kinetics: some methodological considerations illustrated with antipyrine in rat frontal cortex.

1. The neuropharmacokinetics of antipyrine, a readily dialysable drug, in rat frontal cortex were studied and the effect of sampling time and contribution of period sampling and dialysate dead volume investigated in relation to tmax, Cmax, AUC and t1/2 values. 2. After i.p. administration, antipyrine (35 mg kg-1, n = 5) concentrations rose rapidly in rat frontal cortex (tmax, 12 min) and then declined exponentially tmax, Cmax, AUC and t1/2 values were determined after 2 min dialysate sampling and compared to values obtained from simulated sampling times of 4, 6, 8, 10 and 20 min. 3. Antipyrine tmax and Cmax values were directly dependent on sampling frequency. Thus, mean 2 min sampling tmax and Cmax values were 63% lower and 27% higher, respectively, compared to 20 min sampling values. AUC and t1/2 values were unaffected. 4. Adjustment for dialysate dead volume (the volume of dialysate within the dialysis probe and sampling tube) reduced tmax values significantly but did not affect the other neuropharmacokinetic parameters. 5. Contribution of period sampling on neuropharmacokinetic parameters were investigated by comparing plots of antipyrine concentration data at midpoint and at endpoint of sampling time interval. Only tmax values were affected with values decreasing with increasing sampling time interval. 6. In conclusion, although microdialysis is a useful method for monitoring events at the extracellular level and for kinetic studies, it is important to understand its inherent characteristics so that data can be interpreted appropriately. Sampling frequency, particularly during monitoring of periods of rapid change, is very important since Cmax and tmax values will be significantly underestimated and overestimated respectively, if sampling time is longer rather than shorter. These considerations are particularly important in relation to microdialysis studies of pharmacokinetic-pharmacodynamic interrelationships and modelling.

An evaluation of the epileptogenic properties of a rifampicin/clindamycin-impregnated shunt catheter.

A process has been developed by which ventriculoperitoneal hydrocephalus shunts, which are prone to bacterial colonisation, can be impregnated with antimicrobials in order to confer antibacterial activity. Concern that their use might be associated with an increased risk of postoperative seizures has been addressed here. Using two rat models, namely pentylenetetrazole (PTZ) and maximal electroconvulsive seizure (ECS) thresholds, the possible epileptogenic characteristics of the shunt catheters were determined. Animals implanted with impregnated catheters exhibited no significant difference in PTZ seizure threshold compared with controls. In contrast, the ECS threshold test showed an enhancement in seizure susceptibility in the non-impregnated catheter group, in accordance with that found in human subjects, but a significant reduction in the impregnated catheter group at 2 and 28 days, postoperatively. These data suggest that the use in human subjects of shunts impregnated with these antimicrobials will not increase the risk of postoperative seizures.

A freely moving and behaving rat model for the chronic and simultaneous study of drug pharmacokinetics (blood) and neuropharmacokinetics (cerebrospinal fluid): hematological and biochemical characterization and kinetic evaluation using carbamazepine.

A freely moving and behaving rat model for the chronic and simultaneous study of drug pharmacokinetics (blood) and neuropharmacokinetics [cerebrospinal fluid (CSF)] is described. The blood (jugular vein) and CSF (cisterna magna) catheters employed are simple, reliable, and inexpensive. The blood catheter was made of soft and flexible Silastic tubing and sealed with heparin. The CSF catheter consisted of intersliding polythene tubing and interlocking Silastic tubing, which allowed maneuverability within the cisternal magna space and thus prolonging patency for chronic studies. Both catheters were well tolerated by the animals, and the postoperative success rate was 80%-100%; after 8 days 80%-85% of catheters were still patent. Using a sampling protocol considered suitable for kinetic studies, we determined numerous biochemical and hematological parameters and compared them with those values obtained postsurgically and in control rats. The parameter changes associated with the sampling protocol did not affect the kinetics of the commonly prescribed antiepileptic drug carbamazepine and its primary pharmacologically active metabolite carbamazepine-10, 11-epoxide. Therefore, the model can be used to study the interrelationship between drug kinetics at central and peripheral sampling sites and mechanism(s) of drug action.

Regionally specific effects of acute and chronic nicotine on rates of catecholamine and 5-hydroxytryptamine synthesis in rat brain.

Acute (-)-nicotine administration (0.4 and 0.8 mg/kg s.c.) produced a regionally specific increase in the rate of catecholamine synthesis in the rat nucleus accumbens, hypothalamus and hippocampus but not elsewhere, including the caudate-putamen. In all regions rates of 5-hydroxytryptamine synthesis were unaffected. (-)-Cotinine (0.4 and 0.8 mg/kg), the major metabolite of (-)-nicotine was without effect. (-)-Nicotine-induced increase in catecholamine synthesis occurred by a direct stimulation of central nicotinic receptors, as mecamylamine (5 mg/kg) but not hexamethonium (5 mg/kg) was an effective antagonist. Following repeated daily injections of (-)-nicotine (0.8 mg/kg) for up to 28 days, the induced catecholamine response following a subsequent challenge was unaffected in the nucleus accumbens and hypothalamus, but was increased in the hippocampus. This effect persisted for up to 14 days following withdrawal. Rates of 5-hydroxytryptamine synthesis remained unaltered after chronic pretreatment.

Effect of denzimol on carbamazepine and carbamazepine-10,11-epoxide concentrations in serum, liver, spleen and different brain regions of the rat: an inhibitory metabolic interaction.

The effect of denzimol (DNZ) on the disposition of carbamazepine (CBZ) and its primary metabolite carbamazepine-10,11-epoxide (CBZ-E) in serum, liver, spleen and seven brain regions of the rat was assessed. Coadministration with DNZ for 5 or 10 days resulted in an increase in CBZ and a decrease in CBZ-E concentrations in serum, liver and spleen, consistent with a metabolic (hepatic cytochrome P450 mono-oxygenases) inhibitory interaction. After 15 days of co-administration the concentration of CBZ-E was also increased in these tissues, suggestive of epoxide hydratase inhibition in addition. The magnitude of these concentration changes was much greater in the brain indicating that the total serum concentration of CBZ or CBZ-E may not be a reliable index of the neuropharmacological severity of CBZ-DNZ interaction.