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Biomedical subjects

P R Lowe

Publications and source records attributed to P R Lowe.

14 recordsLinked to original sources
PubMed2006

Inhibition of neuronal nitric oxide synthase reduces isoflurane MAC and motor activity even in nNOS knockout mice.

BACKGROUND: The glutamate-nitric oxide-cyclic GMP pathway has been identified as a potential target for volatile anaesthetic agents as acute inhibition of nitric oxide synthase (NOS) reduces the minimum alveolar concentration (MAC) in most animal studies. However, mice deficient in the type I NOS isoform (nNOS) are reported to have a similar MAC for isoflurane and are not affected by non-isoform specific inhibitors. METHODS: We determined whether the nNOS specific inhibitor, 7-nitroindazole (7-NI), had an effect on isoflurane MAC and righting reflex (RRF) and investigated spontaneous motor activity in an open-field study in wild-type (WT) and knockout (KO) mice. RESULTS: 7-NI reduced isoflurane MAC and RRF in both WT and KO animals (all P<0.04). 7-NI profoundly reduced spontaneous motor activity in both the WT and KO animals in the open-field study as indicated by a reduction in the number of line crossings and rearings in both WT and KO mice (both P<0.001). CONCLUSION: We conclude that isoform specific inhibition of nNOS reduces MAC and spontaneous motor activity even in nNOS KO animals. Our results indicate that the NMDA receptor-nitric oxide-cyclic GMP pathway remains a credible target in modulating the effects of isoflurane.

Anesthetics, Inhalation↗
PubMed2006

Inhibition of neuronal nitric oxide synthase reduces the propofol requirements in wild-type and nNOS knockout mice.

BACKGROUND AND OBJECTIVE: The glutamate-nitric oxide-cyclic guanosine monophosphate pathway has been identified as a potential target for anaesthetic agents. However, mice deficient in neuronal nitric oxide synthase have a similar susceptibility to volatile anaesthetic agents to wild-type mice and are not affected by non-isoform selective inhibitors. We hypothesized that the neuronal nitric oxide synthase selective inhibitor, 7-nitroindazole, would also reduce the propofol requirements in wild-type mice but would have no effect in neuronal nitric oxide synthase knockout mice. METHODS: We determined the time to loss of righting reflex, time to painful stimulus and time to regaining the righting reflex in neuronal nitric oxide synthase knockout and wild-type mice following the intraperitoneal injection of propofol in untreated, 7-nitroindazole and vehicle only treated animals (n = 6 per group). Propofol (200 mg kg(-1)) resulted in loss of righting reflex in the untreated and vehicle only groups but was lethal in 7-nitroindazole pre-treated mice, requiring a reduced dose of propofol (100 mg kg(-1)). RESULTS: 7-nitroindazole pre-treatment significantly reduced the loss of righting reflex (P < 0.001) in both wild-type and knockout mice when compared to untreated and vehicle only pre-treated animals, but had no effect on time to painful stimulus or regaining of the righting reflex. 7-nitroindazole reduced the propofol requirements in knockout mice to the same extent as in wild-type animals. CONCLUSIONS: Propofol exerts its anaesthetic effects at least partially via the glutamate-nitric oxide-cyclic guanosine monophosphate pathway. The neuronal nitric oxide synthase knockout mice are sensitive to neuronal nitric oxide synthase selective inhibition suggesting that compensatory pathways in neuronal nitric oxide synthase knockout mice exist.

Anesthetics, Intravenous↗
PubMed2003

Genotype and interleukin-10 responses after cardiopulmonary bypass.

BACKGROUND: The pro- and anti-inflammatory cytokine balance has been implicated in outcome from inflammatory conditions, and cardiopulmonary bypass is associated with a marked inflammatory response. Interleukin-10 (IL-10) is an anti-inflammatory cytokine and levels have been shown to be highest in those patients who develop sepsis after trauma or surgery. IL-10 levels vary between individuals and genotype may dictate the IL-10 response. We therefore investigated IL-10 genotype, circulating IL-10 concentrations and outcome in terms of organ dysfunction 24 h after cardiopulmonary bypass. METHODS: Blood samples were obtained from 150 patients before, and 3, and 24 h after cardiopulmonary bypass. IL-10 was measured by enzyme immunoassay. The single nucleotide polymorphism at -1082 base pairs was detected by restriction fragment length polymorphism analysis. Post-bypass organ system dysfunction was defined prospectively. RESULTS: IL-10 concentrations were increased 3 h after bypass (P<0.0001) and were still increased at 24 h (P<0.0001). Homozygosity for the G allele was associated with lower median (range) maximal IL-10 levels at 3 h (44 (13-136) pg ml(-1)) compared with the A allele (118 (39-472) pg ml(-1); P=0.042). Those patients who developed at least one organ dysfunction (n=33) had higher IL-10 levels 3 h after surgery (242 (18-694) pg ml(-1)) compared with those without organ dysfunction (77 (7-586) pg ml(-1); P=0.001, n=117). CONCLUSIONS: The G allele of the -1082 base pair single nucleotide polymorphism in the IL-10 gene is associated with lower IL-10 release after cardiopulmonary bypass. High levels of IL-10 secretion are associated with organ dysfunction 24 h after surgery.

Adult↗
PubMed2000

A new amidrazone derivative with antimycobacterial activity.

Of a series of pyridine-2-carboxamidrazone derivatives with activity against mycobacteria, the N(1)-[4-(1,1-dimethylpropyl)benzylidene] derivative reported here, C(18)H(22)N(4), is one of the most active. The predicted E isomer about the C11=N12 double bond is confirmed and intramolecular hydrogen bonding involving both amino H atoms helps to keep the molecule flat. The same donor and acceptor atoms also form intermolecular hydrogen bonds.

Journal Article↗
PubMed2000

A T-shaped selenenyl halide.

The title selenenyl halide complex, 3-iodo-2-phenyl-3H-3-selenaindazole, C(12)H(9)IN(2)Se, has an almost planar conformation and a nearly ideal T-shape for the Se(INC) moiety [Se-I 2.8122 (12), Se-C 1.881 (7) and Se-N2 2.051 (6) A; C-Se-N 79.6 (3), C-Se-I 96.8 (2) and N-Se-I 176.17 (17) degrees ]. This arrangement, together with the two selenium lone pairs, leads to a distorted trigonal-bipyrimidal geometry about the Se atom. Intermolecular interactions are largely limited to stacking forces.

Journal Article↗
PubMed1995

8-Acid derivative of the antitumour agent mitozolomide.

The crystal structure of 3-(2-chloroethyl)-3,4-dihydro-4-oxoimidazo[5,1-d][1,2,3,5]tetra zine-8- carboxylic acid, C7H6CIN5O3, a derivative of the novel bicyclic antitumour agent mitozolomide, 3-(2-chloroethyl)-3,4-dihydro-4-oxoimidazo[5,1-d][1,2,3,5]tetra zine-8- carboxamide, has been determined at 293 K. The expected dimer, hydrogen bonded via the two carboxyl groups, does not occur. In preference, the two molecules in the asymmetric unit utilize hydrogen bonding between the carboxyl group of one and the N atom and CH in the imidazo ring of the other. These two then further interact via the same scheme with their centrosymmetrically related pair to produce a fully hydrogen-bonded planar tetramer.

Antineoplastic Agents↗
PubMed1994

DCMCIT, an analogue of the antitumour drugs mitozolomide and temozolomide.

The crystal structure of 3-(2-chloroethyl)-N,N-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-d]-1,2 ,3,5- tetrazine-8-carboxamide, (1), C9H11C1N6O2, an analogue of the novel bicyclic antitumour agents mitozolomide (2) and temozolomide (3), has been determined at 290 K. Although, as in structures (2) and (3), the imidazotetrazinone ring system is essentially planar, the substitution of the--CONH2 group at C8 by a--CON(CH3)2 group in (1) negates the possibility of forming an intramolecular hydrogen bond at either N7 or N1 and thus allows rotation of this group about the C8-C81 bond by ca 45 degrees.

Antineoplastic Agents↗
PubMed1992

Antitumor imidazotetrazines. 25. Crystal structure of 8-carbamoyl-3-methylimidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (temozolomide) and structural comparisons with the related drugs mitozolomide and DTIC.

The antitumor imidazotetrazinone, temozolomide (5), C6H6N6O2, forms crystals with unit cell dimensions a = 17.332 (3), b = 7.351 (2), c = 13.247 (1), beta = 109.56 (1) degree and space group P21/c. A doubly hydrogen-bonded dimer constitutes the asymmetric unit. One carboxamide group forms an additional intermolecular NH...O hydrogen bond; in both molecules the carboxamide group is coplanar with the heterocycle and its NH2 group interacts with the imidazole nitrogen atom N(7). Molecular orbital calculations show the carbonyl carbon C(4) to be the most electron deficient atom, with relatively weak N(3)-C(4) and C(4)-N(5) bonds confirming that temozolomide should ring-open at this position in solution. The energy barrier to carboxamide group rotation of approximately 20 kJ mol-1 should permit interconversion between rotamers. In temozolomide and the related drug mitozolomide (4), N(7) is more negatively charged than N(1), which favors the formation of hydrogen bonds to the former atom in spite of their poor geometry. The relevance of these structural features to the action of temozolomide as a major-groove-directed prodrug of the alkylating agent MTIC (3) is discussed.

Antineoplastic Agents↗
PubMed1991

Structural studies on tazobactam.

Tazobactam (3, C10H12N4O5S) is an effective inhibitor of bacterial beta-lactamases. It crystallizes with unit cell dimensions a = 10.230 (2) A, b = 14.396 (2) A, and c = 17.291 (2) A in space group P2(1)2(1)2(1). Compared to the related inhibitor sulbactam (2), which lacks the triazole ring, crystalline tazobactam exhibits very similar beta-lactam geometry and the same S(1) envelope conformation of the thiazolidine ring. However, in both independent molecules of 3 a triazole ring nitrogen atom accepts an intermolecular hydrogen bond; similar interaction by this moiety of 3 with a hydrogen-bond donor on the enzyme, which is impossible for 2, could account for its enhanced inhibitory power. Semiempirical molecular orbital calculations show pronounced negative potential there. Molecular mechanics supports the hypothesis that the carboxyl group can rotate freely and the triazole ring can "flip".

Computer Simulation↗
PubMedDate not supplied

X-ray crystallographic and theoretical studies of an anticonvulsant enaminone: methyl 4-(4'-bromophenyl)amino-6-methyl-2-oxocyclohex-3-en-1-oate.

OBJECTIVE: The aims of this study were to establish the structure of the potent anticonvulsant enaminone methyl 4-(4'-bromophenyl)amino-6-methyl-2-oxocyclohex-3-en-1-oate (E139), and to determine the energetically preferred conformation of the molecule, which is responsible for the biological activity. MATERIALS AND METHODS: The structure of the molecule was determined by X-ray crystallography. Theoretical ab initio calculations with different basis sets were used to compare the energies of the different enantiomers and to other structurally related compounds. RESULTS: The X-ray crystal structure revealed two independent molecules of E139, both with absolute configuration C11(S), C12(R), and their inverse. Ab initio calculations with the 6-31G, 3-21G and STO-3G basis sets confirmed that the C11(S), C12(R) enantiomer with both substituents equatorial had the lowest energy. Compared to relevant crystal structures, the geometry of the theoretical structures shows a longer C-N and shorter C=O distance with more cyclohexene ring puckering in the isolated molecule. CONCLUSION: Based on a pharmacophoric model it is suggested that the enaminone system HN-C=C-C=O and the 4-bromophenyl group in E139 are necessary to confer anticonvulsant property that could lead to the design of new and improved anticonvulsant agents.

Anticonvulsants↗