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PubMed2001

Over-the-counter medications for acute cough in children and adults in ambulatory settings.

BACKGROUND: Acute cough due to upper respiratory tract infection (URTI) is a common symptom. Many health practitioners recommend non-prescription over-the-counter (OTC) medicines as a first-line treatment for cough, but there is little evidence as to whether these drugs are effective. OBJECTIVES: To assess the effects of oral over-the-counter cough preparations for acute cough. SEARCH STRATEGY: We searched the Cochrane Acute Respiratory Infections Group specialised register, the Cochrane Controlled Trials Register, MEDLINE, EMBASE and the UK Department of Health National Research Register and reference lists of articles. We wrote to study investigators and pharmaceutical companies for information on further published or unpublished studies. There were no constraints based on language or publication status. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing oral OTC cough preparations with placebo in children and adults suffering from acute cough in ambulatory settings. We considered all cough outcomes (such as frequency and severity, continuous and categorical data, using different ways of measurement). The second outcomes of interest were adverse effects. DATA COLLECTION AND ANALYSIS: Two investigators screened potentially relevant citations independently. Any differences at any stage of the review were resolved by discussion. We also extracted data and assessed the quality of studies independently. We contacted investigators for additional information and performed quantitative analysis when appropriate data were available. MAIN RESULTS: Twenty two trials (16 on adults, eight in children) involving 4199 people (3716 adults and 483 children) were included. RESULTS OF STUDIES IN ADULTS 1. Antitussives Five trials compared antitussives with placebo. Codeine was no more effective than placebo in reducing cough symptoms. One study favoured dextromethorphan over placebo, whereas a second did not show an effect. Moguisteine was no more effective than placebo apart from a reduction of cough in a subgroup of participants with more severe night cough. 2. Expectorants Two trials compared guaifenesin with placebo. In the larger study, 75 per cent of participants taking guaifenesin stated that the medicine was helpful compared to 31 per cent in the control group (p less than 0.01). In the second study, both groups showed improvement with respect to cough frequency and severity, with no statistically significant differences between groups. 3. Mucolytics One trial compared a mucolytic with placebo. Active treatment reduced cough frequency and symptom scores on day four and eight. 4. Antihistamine-decongestant combinations Two studies compared antihistamine-decongestant combinations with placebo. Antihistamine-decongestant were significantly more effective than placebo (p less than 0.01). 5. Other drug combinations Three studies compared combinations of drugs other than antihistamine-decongestant with placebo. Two studies were effective in reducing cough symptoms, and one study showed relief at night but not during the day. 6. Antihistamines Three trials compared antihistamines with placebo. Antihistamines were no more effective than placebo in relieving cough symptoms. RESULTS OF STUDIES IN CHILDREN 1. Antitussives Antitussives were no more effective than placebo (one study) 2. Expectorants No studies using expectorants met our inclusion criteria. 3. Mucolytics The results of one trial favoured active treatment over placebo from day four until day 10 (p<0.01) 4. Antihistamine-decongestant combinations Two studies showed no difference between anthistamine-decongestant combinations and placebo. 5. Other drug combinations One trial tested two paediatric cough syrups. Compared to placebo, both preparations showed a 'satisfactory response' in 46 per cent and 56 per cent of children compared to 21 per cent of children in the placebo group. 6. Antihistamines In one trial that tested antihistamines active treatment was no more effective than placebo. REVIEWER'S CONCLUSIONS: There is no good evidence for or against the effectiveness of OTC medicines in acute cough. The results of this review have to be interpreted with caution due to differences in study designs, populations, interventions and outcomes between studies. The numbers of studies in each group were small, and studies often showed conflicting results. Effect sizes in many studies were unclear and it is questionable as to whether all of the positive results are clinically relevant.

Administration, Oral↗
PubMed2004

Over-the-counter medications for acute cough in children and adults in ambulatory settings.

BACKGROUND: Acute cough due to upper respiratory tract infection (URTI) is a common symptom. Many health practitioners recommend non-prescription over-the-counter (OTC) medicines as a first-line treatment for cough, but there is little evidence as to whether these drugs are effective. OBJECTIVES: To assess the effects of oral over-the-counter cough preparations for acute cough. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 2, 2004); MEDLINE (January 1966 to June Week 3, 2004); EMBASE (January 1990 to March 2004); and the UK Department of Health National Research Register (December 2003, http://www.update-software.com/National/nrr-frame.html). We also searched personal collections of references and reference lists of articles. We wrote to study investigators and pharmaceutical companies for information on further published or unpublished studies. There were no constraints based on language or publication status. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing oral OTC cough preparations with placebo in children and adults suffering from acute cough in ambulatory settings. We considered all cough outcomes (such as frequency and severity, continuous and categorical data, using different ways of measurement). The second outcomes of interest were adverse effects. DATA COLLECTION AND ANALYSIS: Two investigators screened potentially relevant citations independently. Any differences at any stage of the review were resolved by discussion. We also extracted data and assessed the quality of studies independently. We contacted investigators for additional information and performed quantitative analysis when appropriate data were available. MAIN RESULTS: Twenty four trials (17 in adults, seven in children) involving 3,392 people (2,876 adults and 516 children) were included. RESULTS OF STUDIES IN ADULTS: 1. Antitussives: Six trials compared antitussives with placebo. Codeine was no more effective than placebo in reducing cough symptoms. Two studies favoured dextromethorphan over placebo, whereas a third did not show an effect. Moguisteine was no more effective than placebo apart from a reduction of cough in a subgroup of participants with more severe night cough. 2. Expectorants: Two trials compared guaifenesin with placebo. In the larger study, 75 per cent of participants taking guaifenesin stated that the medicine was helpful compared to 31 per cent in the control group. In the second study, both groups showed improvement with respect to cough frequency and severity, with no statistically significant differences between groups. 3. Mucolytics: One trial compared a mucolytic with placebo. Active treatment reduced cough frequency and symptom scores on day four and eight. 4. Antihistamine-decongestant combinations: Two studies compared antihistamine-decongestant combinations with placebo. Antihistamine-decongestants were significantly more effective than placebo in one of the studies, whereas the other did not show any difference between the study groups. 5. Other drug combinations: Three studies compared combinations of drugs other than antihistamine-decongestant with placebo. Two studies were effective in reducing cough symptoms, and one study showed relief at night but not during the day. 6. Antihistamines: Three trials compared antihistamines with placebo. Antihistamines were no more effective than placebo in relieving cough symptoms. RESULTS OF STUDIES IN CHILDREN: 1. Antitussives: Antitussives were no more effective than placebo (one study) 2. Expectorants: No studies using expectorants met our inclusion criteria. 3. Mucolytics: The results of one trial favoured active treatment over placebo from day four until day 10. 4. Antihistamine-decongestant combinations: Two studies showed no difference between antihistamine-decongestant combinations and placebo. 5. Other drug combinations: One trial tested two paediatric cough syrups. Compared to placebo, both preparations showed a 'satisfactory response' in 46 per cent and 56 per cent of children compared to 21 per cent of children in the placebo group. One study compared an antitussive/bronchodilator combination in children, which showed no difference between the treatment groups. 6. Antihistamines: In one trial that tested antihistamines active treatment was no more effective than placebo. REVIEWERS' CONCLUSIONS: There is no good evidence for or against the effectiveness of OTC medicines in acute cough. The results of this review have to be interpreted with caution due to differences in study designs, populations, interventions and outcomes between studies. The numbers of studies in each group were small, and studies often showed conflicting results. Effect sizes in many studies were unclear and it is questionable as to whether all of the positive results are clinically relevant. More evidence about the effectiveness of OTC cough preparations would be helpful, as identification of effective self-care treatments may help reduce the burden of days lost at work due to acute cough as well as the number of consultations in primary care. Identification of ineffective preparations could avoid costs for consumers and health care providers.

Acute Disease↗
PubMed2007

A real reason for patients with pseudobulbar affect to smile.

Pseudobulbar affect (PBA) is a dramatic disorder of emotional expression and regulation characterized by uncontrollable episodes of laughing and crying that often cause embarrassment, curtailment of social activities, and reduction in quality of life. The disorder occurs in patients with brain injury caused by many types of neurological disease, including stroke, tumors, and neurodegenerative gray and white matter disorders. Although the pathophysiology is unknown, PBA may relate to release of brainstem emotional control centers from regulation by the frontal lobes. Diagnosis of PBA can be difficult and relies on careful characterization of episodes and differentiation from depression. Although there are no US Food and Drug Administration-approved treatments for PBA, several agents have been shown to be effective, including tricyclic antidepressants, selective serotonin reuptake inhibitors, and a new agent containing dextromethorphan and quinidine. The growing number of treatment options, some of great benefit to patients, highlights the importance of accurate diagnosis of this disorder.

Affective Symptoms↗
PubMed1989

N-methyl-D-aspartate antagonists: ready for clinical trial in brain ischemia?

Antagonists of the N-methyl-D-aspartate (NMDA) subclass of glutamate receptors may offer a new approach for the treatment of ischemic brain injury. This strategy is supported by a well-developed scientific foundation and encouraging results in a variety of in vivo and in vitro experimental models. Several specific antagonists, including MK-801, dextrorphan, dextromethorphan, and ketamine, have already been used at low doses in humans for other indications and are potential candidates for Phase I clinical trials.

Aspartic Acid↗
PubMed1977

Synthesis and antitussive activity of 3-azabicyclo[3.2.2]nonane derivatives.

Mannich bases derived from a number of substituted acetophenones and propiophenones and 3-azabicyclo[3.2.2]nonane have been evaluated for antitussive activity. One of these compounds was as potent as codeine and dextromethorphan in its antitussive activity. The most potent compound of the series, 3-(3-azabicyclo[2.2.2]nonan-3-yl)-4'-benzyloxy-2-methyl propiophenone, also exhibited antimorphine activity. There was no direct correlation between the antitussive effect and antimorphine activity.

Animals↗
PubMed2003

Capillary electrophoresis to assess drug metabolism induced in vitro using single CYP450 enzymes (Supersomes): application to the chiral metabolism of mephenytoin and methadone.

Capillary electrophoresis (CE) with multiwavelength absorbance detection is demonstrated to be an effective tool for the assessment of in vitro drug metabolism studies using microsomes containing single human cytochrome P450 enzymes (CYPs) expressed in baculovirus-infected insect cells (Supersomes). Mephenytoin (MEPH), dextromethorphan, diclofenac, caffeine, and methadone (MET) were successfully applied as test substrates for CYP2C19, CYP2D6*1, CYP2C9*1, CYP1A2, and CYP3A4, respectively. For each system, the CE-based assay could be shown to permit the simultaneous analysis of the parent drug and its targeted metabolite. Using a chiral micellar electrokinetic capillary chromatography assay, the aromatic hydroxylation of MEPH catalyzed by CYP2C19 could thereby be confirmed to be highly stereoselective, an aspect that is in agreement with data obtained via urinary analysis after intake of racemic MEPH by extensive metabolizer phenotypes. The MET to 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) conversion was investigated with a chiral zone electrophoresis assay. Incubation of racemic and nonracemic MET with CYP3A4 revealed no stereoselectivity for the transformation to EDDP, whereas no EDDP formation was observed with CYP1A2. CYP2C9 and CYP2C19 provided enhanced formation of R-EDDP and CYP2D6 incubation resulted in the preferential conversion to S-EDDP. Investigations using racemic MET and human liver microsomes revealed a modest stereoselectivity with an R/S EDDP ratio < 1 which is similar to the in vivo findings in urine.

Aryl Hydrocarbon Hydroxylases↗
PubMed1992

Characterization of specific binding sites for [3H]-1,3-di-o-tolyl-guanidine (DTG) in the rat glioma cell line C6-BU-1.

The aim of the present study was to find out if a cell line of glial origin possesses sigma and/or phencyclidine (PCP) binding sites. Binding of [3H]1,3-di-o-tolyl-guanidine (DTG), a highly selective ligand for sigma binding sites, and of [3H]N-[1-(2-thienyl)cyclohexyl] piperidine ([3H]TCP), a radioligand specific for PCP receptors, to C6-BU-1 glioma cells was investigated. Binding of [3H]DTG to C6-BU-1 cell membranes was reversible, saturable (Bmax = 10.5 pmol/mg protein), and of high affinity (KD = 26 nM). C6-BU-1 cells do not possess PCP receptors as indicated by negligible specific binding of [3H]TCP to C6-BU-1 cell membranes. Specific binding of [3H]DTG was reduced in the presence of Ca2+ and to a lesser extent by Mg2+. The rank order of potency of various PCP and sigma ligands was DTG > (+)3-[(3-hydroxy-phenyl)-N-n-propyl-piperidine] [(+)3-PPP] > haloperidol > pentazocine > (-)3-PPP > PCP > metaphit > dextromethorphan > (-)butaclamol > (+)butaclamol > (-)N-allylnormetazocine [(-)SKF 10,047] > MK801 > (+)SKF 10,047 > ketamine. The drug specificity, confirmed by a reversed stereoselectivity for the benzomorphan opiate SKF 10,047, indicated that these sites correspond to a subtype of sigma binding sites, the so-called sigma 2 binding site. Thus, the C6-BU-1 cell line is the first glial cell line demonstrated to have sigma 2 binding sites.

Animals↗
PubMed1998

Protease inhibitors as inhibitors of human cytochromes P450: high risk associated with ritonavir.

Four protease inhibitor antiviral agents (ritonavir, indinavir, nelfinavir, saquinavir) were evaluated as in vitro inhibitors of the activity of six human cytochromes using an in vitro model based on human liver microsomes. Ritonavir was a highly potent inhibitor of P450-3A activity (triazolam hydroxylation), having inhibitory potency slightly less than ketoconazole. Indinavir was also a potent 3A inhibitor, while nelfinavir and saquinavir were less potent. Ritonavir had high inhibition potency against cytochrome P450-2C9 (tolbutamide hydroxylation), -2C19 (S-mephenytoin hydroxylation), and -2D6 (dextromethorphan O-demethylation and desipramine hydroxylation), while the other protease inhibitors had one or more orders of magnitude lower inhibitory activity against these reactions. None of the protease inhibitors had important inhibitory potency against P450-1A2 (phenacetin O-deethylation) or -2E1 (chlorzoxazone hydroxylation). Thus, among available protease inhibitors, ritonavir carries the highest risk of incurring drug interactions due to inhibition of cytochrome P450 activity.

Antiviral Agents↗
PubMed2005

Activation of extracellular signal-regulated kinase 5 may play a neuroprotective role in hippocampal CA3/DG region after cerebral ischemia.

Extracellular signal-regulated kinase 5 (ERK5), the newest member of the mitogen-activated protein (MAP) kinase family of proteins, is widely expressed in many tissues, including the brain. Here we investigated the activation and subcellular localization of ERK5 by immunoblotting and immunohistochemistry as well as its potential role following cerebral ischemia in rat hippocampus. Transient cerebral ischemia was induced by the four-vessel occlusion method in Sprague-Dawley rats. Our results first indicated that the strongly activated ERK5 immunoreactivity was seen in the CA3/DG region but not in the CA1 pyramidal cell of rat hippocampus following reperfusion. In cytosol extracts, ERK5 activation was rapidly increased, with a peak at 30 min, and then gradually decreased to basal level at 3 days of reperfusion. In nucleus extracts, both phospho-ERK5 and its protein expression were persistently enhanced during the later reperfusion period (from 6 hr to 3 days). To elucidate further the possible role of ERK5 activation and subcellular localization in ischemic insult, rats were intraperitoneally administrated with nifedipine (ND) and dextromethorphan (DM), inhibitors of two types of calcium channels, 20 min prior to ischemia. Our findings showed that ND or DM significantly reduced activated ERK5 immunoreactivity in the nucleus and that most of the CA3/DG neurons were lost 3 days later. Most importantly, intracerebroventricular infusion of ERK5 antisense oligonucleotides (AS; every 24 hr for 3 days before ischemia), but not sense oligonucleotides or vehicle, not only markedly decreased the level of ERK5 and p-ERK5 but also largely caused neuronal loss in the CA3/DG region at 3 days of reperfusion. Taken together, the results strongly suggest that ERK5 was selectively activated in the hippocampal CA3/DG region and subsequently translocated from the cytosol to the nucleus through activation of N-methyl-D-aspartate receptor and L-type voltage-gated calcium channel, which might act as an important survival signal in ischemia-induced neuronal cell damage of the CA3/DG region.

Active Transport, Cell Nucleus↗
PubMed1984

Bare silica as a reverse-phase stationary phase: liquid chromatographic separation of antihistamines with buffered aqueous organic mobile phases.

Unbonded silica gel is an effective support for reverse-phase liquid chromatographic separations of lipophilic amines. Simple buffered aqueous-organic mobile phases provide rapid isocratic separations of antihistamines. Phenylpropanolamine hydrochloride, chlorpheniramine maleate, and dextromethorphan hydrobromide are separated in 8 min on bare silica with a mobile phase of 75% methanol and 25% water which is 0.01 M in (NH4)2HPO4. Quantitation is reproducible. A wide variety of additional compounds may be separated using the same mobile phase.

Chromatography, Liquid↗
PubMed1992

Interaction of opiate molecules with lipid monolayers and liposomes.

The interaction of opiate molecules (buprenorphine, codeine, dextromethorphan, diprenorphine, etorphine, meperidine, methadone, morphine, and naloxone) with lipids (phosphatidylcholine, phosphatidylinositol, phatidylinositol, phosphatidylserine, and cholesterol) by using liposomes and monomolecular layers as membrane models is described. The ability of opiates to induce leakage of carboxyfluorescin from liposomes is highly dependent on the hydrophobicity of the opiate molecules. Buprenorphine and etorphine increased the membrane permeability in all the experiments. On the contrary, naloxone, morphine, and codeine only caused a slight release of the entrapped dye in the presence of acidic phospholipids. Moreover, the leakage of carboxyfluorescein is directly related to the concentration of drug in the incubation media. Studies of the kinetics of the surface penetration of these molecules into monolayers of phospholipids were performed. Again, in this system, buprenorphine and etorphine exhibited stronger interactions than the most hydrophilic opiates. Nevertheless, in these experiments, differences among the opiate molecules are not so high as in the liposomes. The time course of the penetration of all of these molecules in the monolayers fits the Lineweaver-Burk equation. This fact suggests a lack of specific interactions and the predominance of hydrophobic factors. Moreover, the high percentage of release of entrapped dye caused by some opiate molecules suggests a possible toxic side-effect for these agents.

Chemical Phenomena↗
PubMed2004

Adult nonketotic hyperglycinemia (NKH) crisis presenting as severe chorea and encephalopathy.

We report on a patient with mild episodic nonketotic hyperglycinemia (NKH) on valproate who developed episodes of encephalopathy and chorea provoked by a fever and protein loading. After treatment with sodium benzoate and dextromethorphan, the patient's encephalopathy resolved and her chorea improved. The importance of this case is in recognizing this rare syndrome, which may present in the adult population.

Adult↗
PubMed2004

Fast screening method for the analysis of total flavonoid content in plants and foodstuffs by high-performance liquid chromatography/electrospray ionization time-of-flight mass spectrometry with polarity switching.

A liquid chromatography/electrospray ionization mass spectrometry (LC/ESI-MS) method based on time-of-flight (TOF) MS with polarity switching and continuous exact mass measurement using a LockSpray ion source was developed for fast evaluation of the total flavonoid content in plants and foodstuffs. No complicated sample preparation was needed, but only a dilution of the extracts. A fast generic gradient elution and wide mass range acquisition was used with good sensitivity. The total analysis time was only 23 min. The ion chromatograms for flavonoid compounds were automatically extracted, and the fragmentation patterns obtained using positive ion mode and exact mass data for both polarities were used for the tentative identification of compounds. Software-based automated searching of molecular ions for flavonoids and their glycosides (xylosides/arabinosides, rhamnosides, glucosides/galactosides) from total ion chromatograms was used. The compounds were quantified using quercetin, quercitrin, rutin and kuromanine as external standards and dextromethorphan as an internal standard. The detection limits ranged from 0.01-0.04 microg/mL, while the quantitation ranges obtained were 0.2-10 microg/mL for anthocyanins and 0.2-4 microg/mL for the other flavonoids. The accuracies within these ranges varied between 80-120% and precision was in the range 0-14% (relative standard deviation). Flavonoid contents of two medicinal plants (Hypericum perforatum and Rhodiola rosea), two grape red wines, two orange juices and two green teas were evaluated using the method, and the results obtained were in good agreement with those published previously.

Calibration↗
PubMed2005

High-throughput screening of inhibitory potential of nine cytochrome P450 enzymes in vitro using liquid chromatography/tandem mass spectrometry.

The early detection of potential drug-drug interactions is an important issue of drug discovery that has led to the development of high-throughput screening (HTS) methods for potential drug interactions. We developed a HTS method for potential interactions of inhibitory drugs for nine human P450 enzymes using cocktail incubation and tandem mass spectrometry in vitro. This new method involves incubation of two cocktail doses and single cassette analysis. The two cocktail doses in vitro were developed to minimize solvent effects and mutual drug interactions among substrates: cocktail A was composed of phenacetin for CYP1A2, coumarin for CYP2A6, paclitaxel for CYP2C8, S-mephenytoin for CYP2C19, dextromethorphan for CYP2D6, and midazolam for CYP3A4; and cocktail B was composed of three substrates including bupropion for CYP2B6, tolbutamide for CYP2C9, and chlorzoxazone for CYP2E1. In the incubation study of these cocktails, the reaction mixtures were pooled and simultaneously analyzed using liquid chromatography/tandem mass spectrometry employing a fast gradient. The method was validated by comparing the inhibition data obtained from the incubation of each individual probe substrate alone with data from the new method. The IC50 value of each inhibitor in the cocktail agreed well with that of the individual probe drug as well as with values previously reported in the literature. As a HTS method for potential interactions of the inhibition of these nine P450 enzymes, this new method will be useful in the drug discovery process and for the mechanistic understanding of drug interactions.

Chromatography, Liquid↗
PubMed2006

Ultra-low flow nanospray for the normalization of conventional liquid chromatography/mass spectrometry through equimolar response: standard-free quantitative estimation of metabolite levels in drug discovery.

Nanospray experiments were performed on an ensemble of drug molecules and their commonly known metabolites to compare performance with conventional electrospray ionization (ESI) and to evaluate equimolar response capabilities. Codeine, dextromethorphan, tolbutamide, phenobarbital, cocaine, and morphine were analyzed along with their well-known metabolites that were formed via hydroxylation, dealkylation, hydrolysis, and glucuronidation. Nanospray exhibited a distinct trend toward equimolar response when flow rate was reduced from 25 nL/min to less than 10 nL/min. A more uniform response between the parent drug and the corresponding metabolites was obtained at flow rates of 10 nL/min or lower. The largest discrepancy was within +/-50% for plasma samples. Nanospray was used as a calibrator for conventional ESI liquid chromatography/tandem mass spectrometry (LC/MS/MS) and normalization factors were applied to the quantitation of an acyl-glucuronide metabolite of a proprietary compound in rat plasma. A nanospray calibration method was developed with the standard curve of the parent drug to generate quantitative results for drug metabolites within +/-20% of that obtained with reference standards and conventional ESI. The nanospray method provides a practical solution for the quantitative estimation of drug metabolites in drug discovery when reference standards are not available.

Calibration↗
PubMed1990

Pharmacology of N-methyl-D-aspartate-induced brain injury in an in vivo perinatal rat model.

Intrastriatal injection of the glutamate analogue N-methyl-D-aspartate (NMDA, 25 nmol) in postnatal day (PND) 7 rats provides a rapid, sensitive, and reproducible assay in which potential neuroprotective strategies against excitotoxic neuronal injury can be examined in vivo. Brain injury is quantified 5 days postinjection by comparison of the weights of the injected and contralateral cerebral hemispheres. Intraperitoneal injections (15 minutes post-NMDA) of competitive and noncompetitive NMDA receptor antagonists attenuated the severity of NMDA-induced brain injury. The rank order of neuroprotective potency of these antagonists was CGS-19755 greater than DOIPG greater than dextromethorphan greater than HA-966. Of these compounds only the competitive antagonist CGS-19755 provided complete neuroprotection. NMDA-mediated brain injury was also reduced by the specific sigma receptor ligands +PPP and haloperidol (35% reduction). In contrast, drugs that reduce presynaptic neurotransmitter release (adenosine) or enhance neuronal inhibition (baclofen) were not effective against NMDA toxicity. Although all five of the anticonvulsants tested limited NMDA-induced seizure activity, only carbamazepine reduced NMDA-mediated brain injury (36% reduction). These findings extend earlier observations that NMDA receptor antagonists can limit NMDA-induced toxicity in vivo and suggest that sigma receptors contribute to the pathophysiology of NMDA-mediated brain injury in vivo. Furthermore, NMDA-induced seizures and brain injury appear dissociable in this in vivo model. The results illustrate important practical limitations of neuroprotection in vivo vs. in vitro.

Animals↗
PubMed1995

Neuroprotective sigma ligands interfere with the glutamate-activated NOS pathway in hippocampal cell culture.

We studied neuroprotective properties of 12 structurally different sigma site ligands in primary rat hippocampal cell cultures and analyzed whether they interfere with glutamate-induced activation of the nitric oxide synthase (NOS) pathway. Neurotoxicity was triggered with 1 mM glutamate on day 8 of culture. Cells were treated with various concentrations of the compounds for 7 days before glutamate exposure (prolonged pretreatment), or during glutamate exposure (acute treatment). Protection was seen after prolonged pretreatment (long-term protection) with sabeluzole, opipramole, haloperidol, ifenprodil, fenpropimorph, carbetapentane, and tiospirone, with pIC50s of 7.30, 7.15, 6.87, 6.68, 6.66, 6.39, and 6.34, respectively. There was no protection with PD 128298, 1,3-ortho-di-tolylguanidine, BMY-14802, (+)3-(3-hydroxyphenyl)-N-1(propyl) piperidine, or dextromethorphan. Upon acute treatment, only ifenprodil was protective. Interference of the drugs with glutamate activation of the NOS pathway was determined by measuring glutamate-activated cGMP formation and citrulline levels. Glutamate-activated cGMP formation was reduced by all neuroprotective sigma ligands after prolonged pretreatment but not after acute treatment. Sigma ligands added to cell culture lysate did not reduce citrulline formation, evidence that there was no direct effect on the NOS enzyme. We conclude that some but not all sigma ligands exert long-term protective properties against glutamate-induced neurotoxicity in primary hippocampal cultures, and that this protection is accompanied by attenuation of cGMP formation in the NOS pathway. However, inhibition of cGMP formation by itself appeared not sufficient for obtaining neuroprotective effects, as inhibition of glutamate-activated cGMP formation by N omega-nitro-L-arginine, haemoglobin, or PD128298 did not provide neuroprotection.

Animals↗
PubMed1995

A new cytochrome P450 form belonging to the CYP2D in dog liver microsomes: purification, cDNA cloning, and enzyme characterization.

A new form of cytochrome P450 (P450 DUT2) was purified from untreated male dog liver microsomes. The final preparation (a specific content of 19.1 nmol P450/mg protein) showed a single band with an apparent monomeric molecular weight of 50,000 on sodium dodecyl sulfate-polyacrylamide gel electrophoresis, but was further separated into two apoproteins (P450 DUT2a and P450 DUT2b) by reverse-phase HPLC. Both proteins had identical NH2-terminal amino acid sequences, but the first three amino acids of P450 DUT2b were truncated in P450 DUT2a. Purified P450 DUT2 showed 5 to 18 times higher catalytic activities than did hepatic microsomes toward desipramine, metoprolol, and dextromethorphan. These activities in dog liver microsomes were strongly inhibited by anti-P450 DUT2-IgG. A 1.7-kilobase pair cDNA (cDUT2) encoding a male dog liver P450 of 500 amino acid residues (molecular weight 56,400) was isolated and sequenced. The first 35 NH2-terminal amino acid sequence of P450 DUT2b coincided with the deduced amino acid sequence of cDUT2 at 2-36. The deduced total amino acid sequence of cDUT2 shared high similarity with the reported 2D forms (with 2D6, 74.6%; 2D14, 75.4%; 2D1, 65.4%; and 2D9, 63.6%). Moreover, the expressed P450 DUT2 in COS-7 cells had catalytic activities similar to those of purified P450 DUT2. Therefore, this paper is the first report about dog CYP2D. Furthermore, Northern and Western blot analyses indicated that the expressed levels of mRNA and protein were almost equal between male and female dogs. Western blot analysis suggested that P450 DUT2 is a constitutive and major (approximately 20% of the total P450) form, indicating that the 2D subfamily P450 in dog liver is quite unique from CYP2D members of other species.

Amino Acid Sequence↗