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Biomedical subjects

D M Lambert

Publications and source records attributed to D M Lambert.

At least 55 records · Page 3Linked to original sources
PubMed1997

Computed tomography exclusion of osseous paranasal sinus injury in blunt trauma patients: the "clear sinus" sign.

PURPOSE: This prospective study was designed to assess the association of clear paranasal sinuses (no free fluid) as shown by facial computed tomography (CT) with the absence of fractures involving the paranasal sinus walls. PATIENTS AND METHODS: All facial CT scans performed during a 12-month period to rule out maxillofacial injury in blunt trauma patients were reviewed. The scans were made using 5-mm slice thickness and 4-mm table incrementation. They were assessed for the presence or absence of free paranasal sinus fluid (hemorrhage) and the presence and location of facial fractures. RESULTS: A total of 366 CT scans of the face were performed during the study. Among them, 180 scans (49%) were identified that showed no evidence of free paranasal fluid. Twenty-two (12%) of these 180 CT studies showed isolated nasal fractures (n = 13) or zygomatic arch fractures (n = 9). No patient without free paranasal sinus fluid had any midfacial fracture involving a paranasal sinus wall (P < .001 by Fischer exact test). CONCLUSION: The absence of free paranasal sinus fluid after facial trauma is a highly reliable criterion to exclude fractures involving the paranasal sinus walls. Other fractures involving osseous structures not contiguous with the paranasal sinus walls, such as nasal or zygomatic arch fractures, are not excluded. The CT "clear sinus" sign is a simple, rapid method to exclude paranasal sinus fractures.

Exudates and Transudates↗
PubMed1997

Anticonvulsant and neurotoxicological properties of 4-amino-N-(2-ethylphenyl)benzamide, a potent ameltolide analogue.

A well documented study on the anticonvulsant properties of 4-amino-N-(2-ethylphenyl)benzamide (4-AEPB) is here provided. Initial screening in mice dosed intraperitoneally and rats dosed orally indicated that 4-AEPB is active against maximal electroshock-induced seizures (MES), but does not protect animals against subcutaneous pentylenetetrazole (sc Ptz)-induced seizures. Quantitative evaluation of anti-MES activity and neurotoxicity of 4-AEPB given intraperitoneally to mice provided ED50 and TD50 values amounting to 28.6 and 96.3 mumol/kg respectively, resulting in a protective index (PI = TD50/ED50) equal to 3.36. Further quantitative evaluation in rats dosed orally indicated that the respective ED50 and TD50 values for 4-AEPB were 29.8 and more than 1,530 mumol/kg, resulting in a very high PI value of over 51. Comparison anticonvulsant properties and neurotoxicity of 4-AEPB with those previously reported in the literature for two 4-aminobenzamide derivatives, 4-amino-N-(2,6-dimethylphenyl)benzamide (or ameltolide, an antiepileptic drug prototype developed by Eli Lilly), and phenytoin, underlines the value of 4-AEPB for future pharmacological development. In this perspective, an additional favorable element is represented by the ability of 4-AEPB to increase the seizure threshold in the intravenous Ptz seizure threshold test in mice dosed intraperitoneally. Molecular modeling studies show that the translocation of one carbon unit in the isomerization of the 2,6-dimethylphenyl moiety of ameltolide to the 2-ethylphenyl counterpart succeeds in maintaining the conformational low energy presentation adopted by ameltolide, providing clues as to why the 4-AEPB here described is an anticonvulsant agent derived from the 4-aminobenzamide pharmacophore platform as potent as ameltolide.

Administration, Oral↗
PubMed1997

Anticonvulsant activity of pyrid-3-yl-sulfonyl ureas and thioureas.

The N-[(4-cycloheptylaminopyrid-3-yl)sulfonyl]-N'-cycloheptyl urea, a neuroprotective agent, and 10 chemically related sulfonyl(thio)ureas were evaluated in the maximal electroshock seizure test in mice. This sulfonylurea, BM 27, and two structurally related sulfonylthioureas, BM 11 and BM 34, emerged with a 50% effective dose (ED50) of 2.87, 1.72, and 1.19 mg/kg, respectively. Their anticonvulsant profiles were found to be similar to that of phenytoin: active in the maximal electroshock seizure (MES) test and inactive in chemically induced seizures (pentetrazole, strychnine, bicuculline, picrotoxine, N-methyl-D,L-aspartic acid). These compounds exhibited a higher protective index and potency than those of phenytoin. Additional work remains necessary, however, to determine whether BM 27 is of clinical interest.

Animals↗
PubMed1996

Potent inhibition of HIV type 1 infection of mononuclear phagocytes by synthetic peptide analogs of HIV type 1 protease substrates.

The HIV-1 genome encodes a protease that is required for viral processing of the precursor polyproteins Pr55gag and Pr160gag-pol. Interference with this process in human lymphocytes inhibits production of infectious virus. We tested the ability of several protease inhibitors to decrease replication of HIV-1BaL in human monocytes and peritoneal macrophages. The compounds tested are oligopeptide analogs of HIV-1 protease substrates in which the scissile dipeptide has been replaced by a hydroxyethylene isostere. The protease inhibitors were added only once, 1 hr prior to inoculation with virus. Every 3-5 days, half the medium was replaced with fresh medium. Inhibition of virus production was assessed by measuring reverse transcriptase (RT) activity in supernatant medium 14 days after infection. The concentration of drug required to inhibit infection by 50% (IC50) in monocytes ranged from 0.17 to 2.99 microM; IC50 values for peritoneal macrophages ranged from 0.21 to 1.9 microM. The IC50 values for these compounds were 1.1- to 10-fold higher when tested in monocytes compared to their inhibitory effect in lymphocytes, although still potently effective in the dosage range that appeared nontoxic to cells. Cell toxicity was seen only at concentrations greater than 10 microM, and varied among the drugs tested. Immunoblot analysis of two of the drugs (SB205700 and SB108922) confirmed inhibition of polyprotein processing. In control cells, 22% of viral protein pr55 was processed to p24 by 24 hr, and 51% was processed by 48 hr. In cells treated with the protease inhibitors (2 microM), Pr55 processing was inhibited 77% at 24 hr and 89% at 48 hr. Thus, these synthetic peptide analogs potently inhibit productive infection of mononuclear phagocytes by HIV-1. Drugs of this class may be useful for the treatment of HIV-1 infection in humans.

HIV Protease Inhibitors↗
PubMed1996

Peptides from conserved regions of paramyxovirus fusion (F) proteins are potent inhibitors of viral fusion.

The synthetic peptides DP-107 and DP-178 (T-20), derived from separate domains within the human immunodeficiency virus type 1 (HIV-1) transmembrane (TM) protein, gp4l, are stable and potent inhibitors of HIV-1 infection and fusion. Using a computer searching strategy (computerized antiviral searching technology, C.A.S.T.) based on the predicted secondary structure of DP-107 and DP-178 (T-20), we have identified conserved heptad repeat domains analogous to the DP-107 and DP-178 regions of HIV-1 gp41 within the glycoproteins of other fusogenic viruses. Here we report on antiviral peptides derived from three representative paramyxoviruses, respiratory syncytial virus (RSV), human parainfluenza virus type 3 (HPIV-3), and measles virus (MV). We screened crude preparations of synthetic 35-residue peptides, scanning the DP-178-like domains, in antiviral assays. Peptide preparations demonstrating antiviral activity were purified and tested for their ability to block syncytium formation. Representative DP-178-like peptides from each paramyxovirus blocked homologous virus-mediated syncytium formation and exhibited EC50 values in the range 0.015-0.250 microM. Moreover, these peptides were highly selective for the virus of origin. Identification of biologically active peptides derived from domains within paramyxovirus F1 proteins analogous to the DP-178 domain of HIV-1 gp4l is compelling evidence for equivalent structural and functional features between retroviral and paramyxoviral fusion proteins. These antiviral peptides provide a novel approach to the development of targeted therapies for paramyxovirus infections.

Amino Acid Sequence↗
PubMed1996

Mitochondrial phylogeny of trematomid fishes (Nototheniidae, Perciformes) and the evolution of Antarctic fish.

The subfamily of fishes Trematominae is endemic to the subzero waters of antarctica and is part of the longer notothenioid radiation. Partial mitochondrial sequences from the 12S and 16S ribosomal RNA (rRNA) genes and a phylogeny for 10 trematomid species are presented. As has been previously suggested, two taxa, Trematomus scotti and T. newnesi, do not appear to be part of the main trematomid radiation. The genus Pagothenia is nested within the genus Trematomus and has evolved a unique cyropelagic existence, an association with pack ice. Using a mitochondrial rRNA molecular clock rate of 0.14% transversion changes per million years, the average age of the trematomids is estimated at 3.4 million years (MY). If the age of the trematomids is approximately 3.4 MY, this group could have speciated during the period of deglaciation in Antarctica 2.5-4.8 million years ago. This era was marked by significant changes on the Antarctic shores, such as the opening of fjords, which might have provided a stimulus for specification.

Animals↗
PubMed1996

The uptake of Mn-DPDP by hepatocytes is not mediated by the facilitated transport of pyridoxine.

Manganese-dipyridoxal diphosphate (Mn-DPDP) is a liver-selective contrast agent selectively taken up by the hepatocytes. Because of the analogy of structure with pyridoxine (vitamin B6), it was previously suggested that this compound can be selectively taken up by the facilitated transport of vitamers B6. To understand the uptake mechanism, an in vivo binding study was performed based on a competition between 54Mn-DPDP and pyridoxine on the one hand, and Mn-DPDP and [3H]pyridoxine on the other. We found that the [3H]pyridoxine levels in the liver were not significantly different 5 min after intravenous administration of several doses of Mn-DPDP (5 nmol/kg to 50 mumol/kg): 5.0 +/- 0.3% of the injected dose/g tissue. The content of 54Mn (administered as 54Mn-DPDP) in the liver was not affected by a saturation dose of pyridoxine (1 mmol/kg) and was found to be constant (+/- 10% of the injected dose/g tissue) for 60 min. These experiments showed that the uptake of Mn-DPDP is not mediated by the transporter of pyridoxine.

Animals↗
PubMed1996

Bioavailability and anticonvulsant activity of 2-cyanoguanidinophenytoin, a structural analogue of phenytoin.

Phenytoin is extensively used in Europe and the United States for the treatment of generalized tonic clonic seizures (grand mal). However, the efficacy is lowered by the erratic bioavailability after oral administration. The current study was conducted in order to investigate the physicochemical properties, the bioavailability, and the anticonvulsant activity of cyanoguanidinophenytoin (CNG-DPH), a structural analogue of phenytoin, which was obtained by the replacement of the urea moiety by a cyanoguanidine moiety. CNG-DPH was prepared under homogeneous Biltz conditions and under heterogeneous phase-transfer conditions. CNG-DPH is poorly water soluble and has a pKa of 5.3. At pH 7.4, log P was 1.16, from which a pH-independent log P of 3 can be calculated. Pharmacokinetic parameters were obtained after oral administration of CNG-DPH to rats and were compared to those of phenytoin after administration of an equimolar amount. AUC, tmax, and Cmax were significantly increased compared to those of phenytoin. The anticonvulsant profile was similar to the profile of phenytoin. CNG-DPH was active in the maximal electroshock seizure test, albeit 7-fold less active than phenytoin. The analogue did not protect animals against convulsions induced by chemicals such as pentylenetetrazole, picrotoxin, N-methyl-aspartate, strychnine, and bicuculline. It is concluded that while the bioisosteric exchange of the urea moiety of the molecule with the cyanoguanidine moiety dramatically changed the physicochemical and pharmacokinetic parameters compared to those of phenytoin, the concomitant change of the affinity toward molecular targets reduced the pharmacological activity and the therapeutic efficacy of the compound.

Administration, Oral↗
PubMed1996

Targeting of drug to the hepatocytes by fatty acids. Influence of the carrier (albumin or galactosylated albumin) on the fate of the fatty acids and their analogs.

PURPOSE: The aim of this study was to evaluate the potential of fatty acids as shuttles to deliver xenobiotic inside the hepatocytes as well as to study the mechanism of incorporation into isolated hepatocytes when bound to native albumin or galactosylated albumin. Theoretically, they can enter into the hepatocytes after recognition of the Fatty Acid Binding Protein (FABPPM), or remain bound to galactosylated proteins and enter into these cells by a process known as receptor mediated endocytosis after selective recognition of the asialoglycoprotein receptor (ASGPR). METHODS: We synthesized a 3H-benzoyl adduct of lauric acid (BLA) (benzoyl adduct chosen to mimic any low molecular weight drug or contrast agent), and compared the behavior of BLA with oleic acid for their binding properties to carrier-proteins and the uptake mechanism by isolated hepatocytes. RESULTS: No significant difference was found in the binding properties of BLA for albumin and galactosylated albumin. The incorporation into the hepatocytes was found essentially depending on the FABPPM transport system whenever BLA was bound to albumin or to galactosylated albumin in the incubation medium: indeed, the transport was inhibited by phloretin (inhibitor of sodium dependent transport), increased when the free part of BLA was higher, and BLA was recovered in the cytosolic fraction of the hepatocytes. CONCLUSIONS: This study showed the convenience in using fatty acids as drug carriers possessing tropism for the hepatocytes.

Albumins↗
PubMed1996

Molecular sexing of the communally breeding pukeko: an important ecological tool.

A central biological parameter in the study of any animal population is the accurate assignment of sex. Indeed any ecological study of a population requires information on sex composition in relation to such biological factors as behaviour, movement, mortality and birth rate. However, our ability to assign the sex of adults of many avian species is poor and the sexing of young is universally difficult. We report here the successful application of a molecular technique for the assignment of sex in the communally breeding pukeko or purple swamphen (Porphyrio porphyrio melanotus). W- and Z-linked chromosome fragments in digested genomic DNA of pukeko were detected with the DNA probe pMg1. We consequently show that this species breeds in polyandrous, polygynous and polygynandrous groups. Finally we discuss why recent molecular methods represent important new tools in ecology.

Animals↗
PubMed1995

Probing the hydrophobic pocket of the active site of aromatase with 4-phenoxy-7 alpha-(phenylthio)-4-androstene-3,17-dione.

In order to examine the nature of the hydrophobic pocket at the active site of aromatase, we carried out the synthesis, biochemical evaluation, and molecular modeling studies on 4-phenoxy-7 alpha-(phenylthio)-4-androstenedione 2. Aromatase inhibitory activity of 2 was found to be significantly weaker than that of the 4- and 7 alpha-mono(phenylthio)-substituted derivatives of androstenedione. These results along with those obtained from the modeling studies suggest the existence of a single hydrophobic pocket corresponding to the alpha-face in the C4, C6, C7 region of androstenedione.

Androstenedione↗
PubMed1995

Bioavailability and anticonvulsant activity of a monoglyceride-derived prodrug of phenytoin after oral administration to rats.

The plasma levels of phenytoin after oral administration of phenytoin and phenytoin 2-monoglyceride, a phenytoin prodrug, to rats were determined by gas chromatography. Compared to the application of the parent drug, administration of the prodrug resulted in a 3-fold increase of Cmax and a 4-fold increase of the AUC. This correlated with an earlier onset and peaking of the anticonvulsant activity determined in the maximal electroschock (MES) test. The peak effect was reached 1 h after dosing the monoglyceride compared to 2 h after application of phenytoin itself. On the basis of the median effective dose, the prodrug was 3 times more effective antagonizing MES-induced seizures than the parent drug. It is concluded that phenytoin 2-monoglyceride might be a useful prodrug for the oral delivery of phenytoin.

Administration, Oral↗
PubMed1995

Synthesis and pharmacological properties of 2-[S-acetylthiorphan]-1,3- diacylaminopropan-2-ol derivatives as chimeric lipid drug carriers containing an enkephalinase inhibitor.

The design of 1,3-dacylaminopropan-2-ols as CNS-directed carrier groups is based on their resemblance to endogenous lipids and the properties of pseudotriglyceride esters to facilitate the brain penetration of therapeutic agents. 2-[S-acetylthiorphan]-1,3-diacylaminopropan-2-ols, differing from the nature of 1,3-acyl chains, were synthesized and evaluated in vivo using the hot-plate jump test. The compounds exhibited naloxone reversible analgesic properties. The effects were superior to those of parent compounds thiorphan and S-acetylthiorphan. The palmitoyl derivative showed also activity at 0.8 mmol/kg after oral administration. Like acetorphan, a thiorphan prodrug, these compounds were poor substrates for brain enkephalinase, suggesting the release of the pharmacological active inhibitor at the site of action in the brain.

Administration, Oral↗
PubMed1995

Bioavailability of phenytoin following oral administration of phenytoin-lipid conjugates to rats.

The bioavailability of phenytoin was evaluated in rats upon oral administration of phenytoin-lipid conjugates obtained by covalent binding of 3-hydroxymethylphenytoin to 1,3-dimyristoylglyceride via a succinidyl linkage, to 2-(1,3-dimyristoyl-2-glyceryl)butyric acid and to 3-myristoyloxy-2-methylpropionic acid. Despite differences of the phenytoin plasma concentrations all three compounds approximately doubled the AUC compared with the dosing of phenytoin itself. The early onset and the long duration of the anticonvulsant activity after administration of the triglyceride-derived conjugate could be correlated to the increased phenytoin plasma levels. It is concluded that drug-lipid conjugates may be useful prodrugs for the oral delivery of poorly water-soluble drugs.

Administration, Oral↗
PubMed1995

Anticonvulsant activity of phenytoin-lipid conjugates, a new class of phenytoin prodrugs.

The anticonvulsant activity of phenytoin-lipid conjugates obtained by covalent binding of 3-hydroxy-methylphenytoin to dimyristoylglycerides via a succinidyl linkage, to 2-(1,3-dimyristoylglyceryl)butyric acid and to 3-myristoyl-2-myristoylmethylpropionic acid was evaluated in the maximal electroshock (MES) test and the seizure threshold test with subcutaneous pentetrazol. The phenytoin-lipid conjugates were less active than the parent drug in the MES test after intraperitoneal administration as suspensions, but exhibited comparable activity when injected as a solution in dimethylsulphoxide. They also protected mice from MES-induced seizures following oral administration of aqueous suspensions of the compounds or when incorporated into emulsions. The anticonvulsant activity could be correlated to in-vitro pancreatic lipase-mediated hydrolysis. The bis-deacyl derivatives were at least as active but in some cases also more toxic than phenytoin. Oral administration of two of the lipid conjugates resulted in a faster onset of the anticonvulsant activity compared with the administration of an equimolar dose of phenytoin itself. All compounds were inactive in the subcutaneous pentetrazol test. It is concluded that the lipids act as prodrugs of phenytoin, which is generated by lipolysis upon oral administration.

Administration, Oral↗