[Treatment options for drug-induced sialorrhea: Prescribing guidelines]. / Prise en charge de l'hypersialorrhée iatrogène : revue de la littérature et recommandations pratiques.

OBJECTIVES: Drug-induced hypersalivation is a frequent drug adverse event of psychotropic drugs. This excess salivary pooling in the mouth can cause an impairment of a patient's quality of life leading to low rates of medication adherence. The optimal management of hypersalivation is thus crucial to improve patient care. To date, no recommendations for limiting drug-induced hypersalivation have been published. In this study, we conducted a systematic review to investigate the effectiveness of interventions aimed at reducing drug-induced hypersalivation. METHODS: Treatment of drug-induced sialorrhea based on case reports and clinical studies were sought in May 2021 from PubMed, Google Scholar and Science Direct (keywords : « treatment ¼, « hypersalivation ¼, « induced ¼, « drug ¼, « clozapine ¼). Articles published between 1966 to May 2021 on the treatment of drug-induced hypersalivation were included in this study. RESULTS: Sixty-seven articles were selected in this narrative review. First, patient education associated with non-drug related management are essential to improve the compliance to drugs inducing hypersalivation. The non-drug related management should be initiated with an increase in the frequency of swallowing with chewing gum. In the case of ineffectiveness, the dosage of drug responsive of sialorrhea can be adjusted according to the patient's response and his/her medical history (i.e. reducing the dose or splitting the daily dose). Finally, if the problem persists, a symptomatic treatment can be added according to the type of sialorrhea (diurnal or nocturnal), preferred galenic by patient, tolerance and availability of drugs. Several drugs have been tested to reduce hypersalivation induced by clozapine (61/67), risperidone (3/67), quetiapine (2/67) and aripiprazole (2/67). Among the 63 articles targeting a specific corrective treatment, anticholinergic agents were most described in the literature (41 cases out of 63) with atropine, glycopyrrolate and scopolamine (6/41 each). Other agents were described as clinically effective on hypersalivation: dopamine antagonists (9/63) with amisulpride (5/9), alpha-2-adrenergic agonists (5/63) with clonidine (3/5), botulinic toxin (4/63), and terazosine, moclobemide, bupropion and N-acetylcysteine (for each 1/63). CONCLUSIONS: In the case of drug-induced hypersalivation, after failure of non-drug therapies and dosage optimization of the causative treatment, an anticholinergic drug can be initiated. In case of insufficient response, the different treatments presented can be used depending on the galenic form, tolerance and access to those medications. The assessment of the risk-benefit balance should be systematic. The heterogeneity of the studies, the little knowledge about the pharmacological mechanism of saliva flow modulation and the unavailability of corrective drugs are different factors contributing to the complexity of therapeutic optimization.

Nefopam hydrochloride compatibility and stability with selected proton pump inhibitors in bionolyte G5 injection for intravenous infusion.

BACKGROUND: The use of extemporaneously prepared admixtures of drugs must be supported by documentation of their chemical stability. OBJECTIVE: To assess the physical compatibility and the chemical stability of nefopam hydrochloride, a centrally acting non-opioid analgesic, when admixed with selected proton pump inhibitors (omeprazole, esomeprazole or pantoprazole), in bionolyte G5 injection for intravenous infusion. METHOD: Admixtures were assessed for periods of up to 72 h after storage at ambient temperature without protection from light and at +4 degrees C protected from light. A preparation was considered stable if the compounds of the mixture retained at least 90% of their original potency during the storage. Triplicate samples of nefopam and the selected proton pump inhibitors as well as the following mixtures (nefopam/omeprazole, nefopam/esomeprazole and nefopam/pantoprazole) were prepared in the concentrations required, in polypropylene bottles of bionolyte G5 injection. The physical compatibility was assessed by visual observation at each sampling interval. The chemical stability of the drugs was evaluated by high-performance liquid chromatography and by measurement of pH values. RESULTS: During refrigerated storage, nefopam as well as the selected proton pump inhibitors, when prepared separately in bionolyte G5 injection maintained chemical stability for up to 7 days. At ambient storage conditions, the protons pump inhibitors maintained chemical stability for 24 h, but thereafter their concentrations decreased significantly at day 1. Nefopam maintained chemical stability for up to 72 h at +25 degrees C. Nefopam/omeprazole and nefopam/esomeprazole mixtures in bionolyte were physically incompatible with the mixtures exhibiting a black colour. They underwent rapid and extensive loss, making the combination unacceptable within minutes of mixing. However, the nefopam/pantoprazole mixture was compatible over the study period, but with a reduced duration of the stability. CONCLUSION: Within the limits defined above, nefopam and the selected proton pump inhibitors may be prepared separately in advance in bionolyte G5 injection. The nefopam/pantoprazole mixture was stable for a short period, while the nefopam/omeprazole and the nefopam/esomeprazole mixtures were incompatible and unusable, immediately upon admixture.

[Evaluation of the in vitro activity of two betalactams on the oxidative metabolism of polymorphonuclear neutrophils]. / Evaluation in vitro de l'activité de deux bêtalactamines sur le métabolisme oxydatif de granulocytes neutrophiles.

STUDY AIMS: The aim was to evaluate the in vitro effects of amoxicillin and its combination with clavulanic acid, two beta-lactams intravenously injected, on the oxidative metabolism of polymorphonuclear neutrophils. These cells play the major role in the "respiratory burst" as they produce superoxide anion to kill the infectious agent. An activation of this process by the injected antibiotics could enhance the bactericidal action or explain some of adverse effects. MATERIALS AND METHODS: Two models were used to estimate the O(2)(-) amounts produced in the presence of the antimicrobial agents. In the cellular model, O(2)(-) was generated by neutrophils artificially stimulated or not (separated by a gradient centrifugation through Histopaque 1077). In the acellular model, O(2)(-) was produced by the xanthine-xanthine oxidase system. O(2)(-) was measured by spectrophotometry using the ferricytochrome C reduction. RESULTS: The O(2)(-) production by polymorphonuclear neutrophils was increased when both antibiotics were added to the reaction mixture. A significant activation of the cell oxidative metabolism was observed with amoxicillin using various stimulating agents, that was higher without stimulation and lower when amoxicillin and clavulanic acid were associated. CONCLUSION: Amoxicillin could either activate polymorphonuclear neutrophils NADPH-oxidase or cause its activation by a membrane effect, or interfere with the zymosan activation way. It could then be supposed that this antimicrobial agent intensified the bactericidal effects.

Diabetes and Ramadan: review of the literature.

During the month of Ramadan, Muslims fast every day from dawn to sunset. In the healthy subject, this fasting does not have any harmful consequences on health. However, it can induce several complications for patients with diabetes. The aim of this review twofold: first, it seeks to give some clues about methodological aspect of research during Ramadan and to show the impact of various diabetes monitoring and treatment, including biochemical and clinical parameters, diet and caloric intake, drug intake when fasting. Second, it intends to determine whether or not Ramadan fasting induces complications in patients with types 1 and 2 diabetes and ultimately to elaborate some advice as to the management of fasting patients. Several studies have shown that Ramadan fasting did not alter biochemical parameters in patients with type 2 diabetes. However, other studies have shown that there is either an increase or a decrease in biochemical parameters during Ramadan. Ramadan fasting would be acceptable for patients with well-balanced type 2 diabetes who are conscious of their disease and compliant with their diet and drug intake. If patients with type 1 diabetes wish to fast, it is necessary to advise them to undertake control of their glycaemia several times a day. Patients with type 1 diabetes who will fast during Ramadan may be better managed with fast absorption insulin.

Compatibility of nitroglycerin, diazepam and chlorpromazine with a new multilayer material for infusion containers.

The stability and compatibility of three drugs: nitroglycerin, diazepam and chlorpromazine, with a new multilayer infusion bag were studied. The study was carried out comparatively with PVC bags with which these drugs are incompatible. The drugs were diluted in 5% dextrose or in 0.9% sodium chloride isotonic solutions. Solutions were stored during 8 or 48 h with or without any protection against light. Remaining concentrations of drug were determined by high-performance liquid chromatography (HPLC) during the storage. The admixtures were also monitored for precipitation, color change and pH. Whatever the isotonic solution used, the loss of drugs is in discredit of the use of PVC bags for their storage. So, these three drugs would not be stored in PVC bags. In multilayer bags, no loss of drugs and no color change were detected throughout the storage period. pH values were stable during the same storage period. These three drugs were compatible with multilayer bags in all tested conditions for 8 or 48 h. The leaching of the plasticizer di-(2-ethylhexyl) phthalate (DEHP), that is incorporated into PVC to make the bags soft and pliable was not detected in the three drug solutions during storage period. Our study confirms that these three drugs are incompatible with PVC bags, on the contrary the new materiel tested was proved to be interesting for drug storage.

Evaluation of the direct toxicity of trioctyltrimellitate (TOTM), di(2-ethylhexyl) phthalate (DEHP) and their hydrolysis products on isolated rat hepatocytes.

Plasticizers are added to polyvinyl chloride (PVC) to confer flexibility to the polymer. Di(2-ethylhexyl) phthalate (DEHP) is the most commonly used of them. However, due to its non covalent bond to the PVC, DEHP tends to vaporize easily. A significant exposure has been recorded in dialyzed patients since medical tubings. Most animal species metabolize DEHP rapidly into monoethylhexyl phthalate (MEHP) and 2-ethylhexanol (2-EH). Because of the suspected toxicity of DEHP, an alternative plasticizer, trioctyltrimellitate (TOTM) has aroused increasing interest. The aim of this study was to determine on isolated rat hepatocytes in vitro, the direct hepatotoxic potential of both DEHP and TOTM and their hydrolytic products. To evaluate the possible toxic liver risk resulting from exposure to DEHP and TOTM, isolated rat hepatocytes were incubated with either DEHP, TOTM, MEHP or their common metabolite (2-EH) for 3 hours. Cell viability was periodically estimated thanks to trypan blue tests (15 - 180 min). The activity of lactate dehydrogenase (LDH) was also monitored (1h, 2h, 3h). The results obtained with trypan blue test and with direct LDH activity measurements, were satisfactorily correlated. Hepatocytes treated with both plasticizers and metabolites on the one hand, and the controls (untreated suspension) on the other hand, showed important differences as for cell viability. The acute toxicity on hepatocytes is mainly due to MEHP. Among DEHP, TOTM, MEHP, 2-EH and after intraperitoneal injection of those compounds, only DEHP and MEHP were able to induce a significant hydrogen peroxide (H2O2) production by the rat hepatocytes. These observations enable us to confirm the hypothesis according to which DEHP and MEHP cause an imbalance between the synthesis and the degradation of H2O2. Our results suggest a short-term in vitro cytotoxicity of MEHP. Even if trypan blue and LDH tests offered good results and were easily branded, further assays as well as MTT-tests should performed in order to confirm the cytotoxicity of the compounds tested.

Induction of propranolol metabolism in isolated rats hepatocytes treated by di(2-ethylhexyl) phthalate (DEHP) and mono(2-ethylhexyl) phthalate (MEHP).

Blood lines of polyvinyl chloride (PVC) for hemodialysis usually contain di(2-ethylhexyl) phthalate (DEHP) as a plasticizer. Previous studies show that 1 mg/kg of this plasticizer can leach into the blood during one dialysis session. It is rapidly metabolized in the liver. Mono(2-ehtylhexyl) phthalate (MEHP), its main metabolite can be detected as well. After oral administration to rodents, both compounds caused a variety of adverse biological effects such as testicular atrophy, peroxisome proliferation and hepatic peroxisomal enzyme induction. Male wistar rats were treated intraperitoneally by DEHP and MEHP using twice the dose of that involved in human exposure during a dialysis session. Propranolol metabolism by hepatocytes was investigated after fresh isolation from treated and untreated rats by means of reverse phase HPLC. The choice of propranolol as a substrate was made because of its rather quick liver metabolisation. Phenobarbital was chosen in the study as a reference of enzymatic inducer to evaluate the inducing effect of DEHP and MEHP. Propranolol was metabolized by the hepatocytes of both treated and untreated rats. Hepatocytes isolated from rats treated by phenobarbital, MEHP and DEHP were shown to have a higher speed constant of metabolism indicating a rapid metabolism of propranolol. Under these conditions, in fact, propranolol metabolisation was found to be respectively 6, 2.7, 2 times faster than the propranolol metabolisation of untreated rats. The hypothesis that DEHP and MEHP are enzymatic inducers, particularly cytochrome P450 (CYP) inducers of the xenobiotics metabolism on the intact liver after IP administration has become been found to be valid. The results obtained in this study confirm the value of isolated hepatocytes as an in vivo drug metabolism predictive model.

Evaluation of childhood exposure to di(2-ethylhexyl) phthalate from perfusion kits during long-term parenteral nutrition.

Leachability of the plasticizer di(2-ethylhexyl) phthalate (DEHP) from administration sets into intravenous parenteral emulsions containing fat was investigated. DEHP is added to polyvinyl chloride (PVC) to impart flexibility. However, DEHP is a lipid-soluble suspected carcinogen that is hepatotoxic and teratogenic in rodents, and has been shown to leach from PVC products containing lipophilic mixtures. Consequently, total parenteral nutrition (TPN) mixtures containing fat emulsions should be stored in ethylvinyl acetate (EVA) bags rather than PVC packs. However, while TPN bags are made of EVA, they contain PVC-DEHP residues and the lines used between TPN bags and venous catheters are made of PVC-DEHP. The present study quantified the amount of DEHP leached from bags and tubing that could potentially contaminate patients during home TPN. Four types of emulsions containing fat were studied. Levels of DEHP in the bag and at the outlet tubing were measured by high-performance liquid chromatography (HPLC). This was measured during simulated TPN at different times after starting perfusion, 1 day after reconstitution of solutions in the bags, and 1 week later after storage at 4 degrees C. Detectable and stable amounts of DEHP were found to leach from bags (0.2 +/- 0.008 mg to 0.7 +/- 0.02 mg) and DEHP content increased in the outlet tubing (0.8 +/- 0.09 mg to 2 +/- 0.07 mg) during simulated infusions. The same phenomenon was observed after 1 week of storage at 4 degrees C. DEHP extraction by TPN depends on the lipid content of each TPN preparation and the flow rate. These results suggest that children treated with prolonged TPN are regularly exposed to significant amounts of DEHP.

A model with original conditions and materials to test potential inhibitors of cyclooxygenase-2 versus cyclooxygenase-1 in isolated human blood cells.

The inflammatory process can be influenced by an enzyme known as cyclooxygenase, which exists in two isoforms: COX-1, the constitutive form, and COX-2, which is only synthesized in the case of inflammation and has negative side effects. To decrease these undesirable effects, current research seeks to discover compounds that selectively inhibit COX-2 versus COX-1. When added to the samples, arachidonic acid activates the synthesis of COX-2. This explains why the two isoforms proceed in different ways. As for COX-1, human lymphocytes and monocytes were activated with 50 microM of calcium ionophore for 1 h at 37 degrees C with 50 microM of arachidonic acid, and the quantity of thromboxane B(2) (TxB(2)) was measured by radioimmuno-assay (RIA). As for COX-2, cells were first incubated with acetylsalicylic acid to block COX-1, then stimulation of COX-2 was performed using 8 mcg/ml lipopolysaccharide (LPS) for 3 h at 37 degrees C with 50 microM arachidonic acid. The IC(50) values for reference compounds were reproducible, taking into consideration the passage through the plasmatic membrane and the transduction signal, while avoiding the problems of binding with plasma proteins and using identical cells, unlike other models.

Effects of Rosa canina fruit extract on neutrophil respiratory burst.

Respiratory burst leads polymorphonuclear neutrophils (PMN) to produce reactive oxygen species (ROS) such as superoxide anions (O(2)(o-)), hypochlorous acid (HOCl) and hydrogen peroxide (H(2)O(2)) which may possess deleterious effects for the organism. Rosa canina fruits are well known to contain a large amount of vitamin C which is antioxidant. This study was focused on the polyphenolics contained in rose hips to evaluate their antioxidative properties. We prepared a rose hip extract deprived of vitamin C. The extract contained mainly phenolics such as proanthocyanidins and flavonoids. We investigated its effects directly against (O(2)(o-)), HOCl and H(2)O(2) and investigated its effects on isolated PMN. For that, in vitro inflammatory conditions were reproduced by stimulating PMN with stimuli having different transductional pathways, in order to determine a possible mechanism of action. The results showed that the extract can inhibit ROS tested in acellular and cellular systems. The IC(50) obtained were 5.73 mg/L, 1.33 mg/L and 2.34 mg/L respectively for (O(2)(o-)), HOCl and H(2)O(2) in acellular experiments. For cellular experiments, the IC(50) were quite similar. Thus, the extract did not present an effect on PMN metabolism. Therefore, the antioxidative effects of Rosa canina are due not only to vitamin C but also to polyphenolics.

Comparative study of the leachability of di(2-ethylhexyl) phthalate and tri(2-ethylhexyl) trimellitate from haemodialysis tubing.

The leachability of both Di(2-ethylhexyl) phthalate (DEHP) and Tri(2-ethylhexyl) trimellitate (TEHTM) or Trioctyl trimellitate (TOTM) from haemodialysis tubing was investigated in 20 patients with chronic renal failure undergoing maintenance haemodialysis. The blood tubing made of common polyvinyl chloride (PVC) plasticized with DEHP (group 1 patients) were replaced with tubing plasticized with TOTM-DEHP (group 2 patients). The patient blood obtained from the inlet and the outlet of the dialyzer was analyzed during a 4 h-dialysis session. Thus, the circulating concentrations of both DEHP and TOTM resulting from the release from dialyzer tubes were estimated using High-performance Liquid chromatograph (HPLC). With the common PVC-DEHP blood tubing, a DEHP quantity of 122.95+/-33.94 mg was extracted from tubing during a single dialysis session (ranging from 55 to 166.21 mg). During the same period, the total amounts of DEHP retained by the patients were 27.30+/-9.22 mg (ranging from 12.50 to 42.72 mg). As for blood tubing plasticized with TOTM-DEHP, 41.80+/-4.47 mg of DEHP and 75.11+/-25.72 mg of TOTM were extracted. During the same period, the amounts of DEHP and TOTM retained by the patients were 3.42+/-1.37 mg and 4.87+/-2.60 mg, respectively. The extraction rate both plasticizers was correlated with serum lipid content (cholesterol+triglyceride) (r(2)=0.75 for DEHP and r(2)=0.64 for TOTM). In the present investigation, less TOTM and DEHP were apparently released from haemodialysis tubing plasticized with TOTM-DEHP than DEHP released from haemodialysis tubing plasticized with DEHP only. TOTM seems to be a superior alternative to DEHP for use in medical devices because of its potential lower leachability. To recommend it as an alternative plasticizer, its possible toxicity towards human body should be investigated before it can be used routinely. However, patients undergoing haemodialysis using tubing plasticized with DEHP only are regularly exposed to non negligible amounts of DEHP. In view of several biological effects previously reported, it is time to reconsider the use of DEHP only as a plasticizer.

High-performance liquid chromatographic method for the determination of di(2-ethylhexyl) phthalate in total parenteral nutrition and in plasma.

A simple, rapid and sensitive reversed-phase high-performance liquid chromatographic method with UV detection was developed for the quantification of di(2-ethylhexyl) phthalate (DEHP) in parenteral nutrition admixtures containing fat emulsion and in plasma samples of children daily treated by total parenteral nutrition. The analyte and the internal standard, di-n-heptyl phthalate, were extracted twice using hexane and the organic layer separated and dried under nitrogen. The residues were reconstituted with acetonitrile and 20 microl was injected into a Waters Spherisorb C18 column, the UV detector was set at 202 nm. The mobile phase was acetonitrile-aqueous buffer (triethylamine 0.08% adjusted to pH 2.8 with 1 M phosphoric acid) mixture (88:12, v/v) and it was pumped at 1 ml/min. Average recoveries were 97% or greater. This method was successfully used to investigate the amounts of DEHP which can leach from bags and tubing into fat emulsion and which could contaminate children under long-term parenteral nutrition. On the other hand, the circulating DEHP concentrations were estimated in four children under regular long-term parenteral nutrition.

Investigation of the inhibitory effects of chelerythrine chloride on the translocation of the protein kinase C betaI, betaII, zeta in human neutrophils.

The protein kinase C (PKC) is a serine/threonine kinase, consisting of different isoforms, implicated in numerous processes of signal transduction. To understand this enzyme well, different pharmacological tools were developed. To activate PKC specifically, phorbol esters were previously used but recent research has shown that these compounds are able to stimulate other proteins. Our model is the respiratory burst in the polymorphonuclear neutrophils. A decrease in the inflammatory process was measured using chelerythrine chloride. Action on PKC was proved by a binding study and by showing the absence of translocation of this enzyme from the cytoplasm to the plasmic membrane during stimulation.

Investigation of the inhibitory effects of HA-1077 and Y-32885 on the translocation of PKCbetaI, PKCbetaII and PKCzeta in human neutrophils.

To transmit the information inside the cell, one possibility is the action of an enzyme called kinase that phosphorylates other proteins. To study these enzymes, chemical compound synthesis was needed to know the function and the mechanism of activation. The major difficulty is creating a specific molecule for one kinase. In this study, we test the action of Rho-kinase inhibitors (HA-1077 and Y-32885) on protein kinase C (PKC) in the respiratory burst in the human polymorphonuclear neutrophils. We have shown that these compounds could inhibit the anion superoxide production. To prove their action on PKC, we have shown a decrease of binding of a specific ligand (phorbol-12,13-dibutyrate) with each inhibitor. During its activation, PKC was translocated from the cytoplasm to the plasmic membrane. We have also shown an inhibition of this translocation, proving an inhibition of PKC by HA-1077 and Y-32885.

A simple method for isolating human and rabbit polymorphonuclear neutrophils (PMNs).

We report the successful application to human venous blood of a novel method developed to purify rabbit polymorphonuclear neutrophils (PMNs) from whole blood. Human PMNs were separated from whole blood after sedimentation with dextran and histopaque density gradient centrifugation. 3.92 +/- 0.26 x 10(6) PMNs per ml of blood was harvested. The purity of the preparation was 92.00 +/- 1.10%. The PMNs isolated were capable of generating a high amount of reactive oxygen species (ROS) and elastase after stimulation with phorbol 12-myristate 13-acetate (PMA): 13.43 +/- 0.3 microM of O2-, 9.62 +/- 0.15 microM of H2O2 and 5.48 +/- 0.01 microM of elastase. This method gives equivalent yield and viability when applied to isolating human or rabbit PMNs, in comparison with standard methods used to isolate human PMNs. Our method could be usefully exploited for comparative studies of rabbit and human PMNs with a cellular model of inflammatory oxidative stress in which the monitoring parameters are ROS and elastase. Thus, the results of animal (rabbit) studies can be extended to human diseases.

Reduced ammonium chloride haemolysis time enhances the number of isolated functional rabbit polymorphonuclear neutrophils.

In the present study we compared seven different methods for isolating rabbit polymorphonuclear neutrophils (PMNs) with a view to assessing viability, lymphocyte contamination and isolation yield. The two methods offering the best isolation yield and functional PMNs were retained. Leukocyte-containing plasma fraction was obtained after erythrocyte sedimentation with dextran. First, PMNs were isolated from this fraction, using hypotonic ammonium chloride haemolysis followed by Histopaque density gradient centrifugation (Method-A). Second, PMNs were obtained from leukocyte-containing plasma after centrifugation on two Percoll layers (Method-B). These processes resulted in a high cellular yield: 2.66x10(6)+/-0.22 PMNs per ml of blood (Method-A) and 1.87x10(6)+/-0.37 PMNs per ml of blood (Method-B). In both cases the PMNs isolated were of high purity and viability. In comparison, when using the standard techniques for rabbit - consisting of ammonium chloride haemolysis taking at least four times as long--fewer PMNs were isolated. The PMNs isolated by Method-A and -B were able to generate a high amount of reactive oxygen species (ROS) after stimulation with phorbol 12-myristate 13-acetate (PMA). These methods to separate PMNs are recommended for in vitro studies.

Phenolic compounds and antioxidant activities of buckwheat (Fagopyrum esculentum Moench) hulls and flour.

The interest of polyphenolics as therapeutic agents against diseases involving radical damage is growing. The phenolic contents of the hulls and flour from the seeds of Fagopyrum esculentum (French variety 'La Harpe') (total phenols, flavonoids, total flavanols, oligomeric proanthocyanidins) are compared with the antioxidative effects of the extracts against reactive oxygen species: hydrogen peroxide, hypochlorous acid, superoxide anion. The higher efficiency of the flour extract can be related to its higher flavanolic content rather than to flavonoids which are predominant in the hull extract.

A pharmacokinetic interpretation of increasing concentrations of DEHP in haemodialysed patients.

The degree of exposure to DEHP was assessed in 11 patients with chronic renal failure undergoing maintenance haemodialysis. The amount of DEHP leached from the dialyser during a 4-h dialysis session was estimated by monitoring the DEHP blood concentration using a HPLC method. When a patient undergoes a dialysis treatment, the concentration of di-2-ethylhexyl phthalate (DEHP) in venous blood is increased when the blood crosses through the dialysis apparatus. This increase may be explained either because DEHP is not extracted by the dialyser or because DEHP comes from the dialysis bath due to contact of blood against plasticized pipes. To explain the increasing concentration of DEHP during treatment of renal failure using plasticized tubing, we propose a pharmacokinetic compartmental model in order to fit raw data obtained from dialysed patients and to get the amount of DEHP which enters the body by AUC calculations. Results obtained after HPLC analysis show a high degree of interpatient variability in DEHP retained. This amount can reach a toxicity level because of repetitive dialysis treatments over prolonged periods of time. In the coming years, it seems necessary to reconsider the use of DEHP as a plasticizer in medical devices. Highly unacceptable amounts of DEHP leached during the dialysis session could be easily avoided by careful selection of haemodialysis tubing.

High-performance liquid chromatographic determination of naltrexone in plasma of hemodialysis patients.

A simple, sensitive, selective and reliable reversed-phase high-performance liquid chromatographic (HPLC) method with UV detection is described for the determination of naltrexone in plasma samples. Naltrexone and the internal standard, naloxone, were isolated from plasma either with a liquid-liquid extraction method using ethyl acetate or with a solid-phase extraction method using Sep-Pack C18 cartridge before chromatography. The extracts were dried under a stream of nitrogen and the samples were reconstituted in the mobile phase, then 20 microL were injected on a Waters Symmetry C18 column (5 microm particle size, 4.6 x 150 mm). The mobile phase consisted of 0.06% triethylamine (pH 2.8)-acetonitrile (92:8, v/v) pumped at 1 mL/min. The peak-area ratio versus plasma concentration was linear over the range of 10-500 ng/mL and the detection limit was less than 8 ng/mL. Quantification was by ultra-violet detection at 204 nm. The present method was applied to the determination of the plasma concentration of naltrexone in dialyzed patients. Patients (n = 8) with severe generalized pruritus received 50 mg of naltrexone orally per day for 2 weeks. The variability in the therapeutic response in treated patients required plasma concentration investigations of this opioid antagonist.

Neurosedative and antioxidant activities of phenylpropanoids from ballota nigra.

Ballota nigra is a European plant known for its neurosedative properties. In this study, the ability of five phenylpropanoids (verbascoside, forsythoside B, arenarioside, ballotetroside, and caffeoyl malic acid) isolated from a hydroalcoholic extract, to bind to benzodiazepine, dopaminergic, and morphinic receptors was investigated. To carry out these studies, affinity tests with rat striata, entire brains and receptor rich preparations were employed. In addition, the phenolic aspect of these five phenylpropanoid esters led to investigate antioxidant activities using cell-free experiments and cellular experiments including isolated polymorphonuclear neutrophils (PMN). Effects of phenylpropanoid esters against reactive oxygen species as superoxide anion, peroxide hydrogen, hypochlorous acid and hydroxyl radical were tested. These molecules are liberated by PMN during inflammatory disorders, so that reproduction of this process in vitro stimulating PMN by chemical stimulants was undertaken. Results show that four of the five compounds are able to bind to the studied receptors. Inhibitory concentrations at 50% were determined and vary from 0.4 to 4.7 mg/ml. This may be in relation with the Ballota nigra known neurosedative activities. Results concerning antioxidant investigations evidence an ability to scavenge reactive oxygen species. Inhibitory concentrations at 50% obtained are comparable to those of known antioxidant drugs (mesna or N-acetyl cysteine). Moreover, the use of different stimuli having various pathways of action on PMN oxidative metabolism permits to establish that each phenylpropanoid ester has its own particular way of action by using proteine kinase C or phospholipase C pathways.