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1.
Br J Oral Maxillofac Surg ; 45(6): 490-2, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17110004

RESUMO

We report a modification of the operation of mandibular release or 'visor drop down'. It allows more accurate repositioning and more permanent fixation of the genioglossus, geniohyoid, and digastric muscles using a small anterior osteotomy. We hope that this more accurate and reliable repositioning will give improved outcomes in terms of speech, chewing, and swallowing.


Assuntos
Mandíbula/cirurgia , Soalho Bucal/cirurgia , Neoplasias Bucais/cirurgia , Procedimentos Cirúrgicos Bucais/métodos , Língua/cirurgia , Humanos , Esvaziamento Cervical , Músculos do Pescoço/cirurgia
2.
J Med Chem ; 35(12): 2306-14, 1992 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-1319497

RESUMO

A series of 2-acetylpyridine thiocarbonohydrazones was synthesized for evaluation as potential antiherpetic agents. The compounds were prepared by the condensation of 2-acetylpyridine with thiocarbonohydrazide followed by treatment with isocyanates or isothiocyanates. Many were found that were potent inactivators of ribonucleotide reductase encoded by HSV-1 and weaker inactivators of human enzyme. Several thiocarbonohydrazones (e.g. 38 and 39) inactivated HSV-1 ribonucleotide reductase at rate constants as much as seven times that of lead compound 2. In general, those substituted with weak electron-attracting groups offered the best combination of potency and apparent selective activity against the HSV-1 enzyme. Seven new thiocarbonohydrazones (21, 25, 31, 36, 38, 39, and 40) were apparently greater than 50-fold more selective than 2 against HSV-1 ribonucleotide reductase versus human enzyme. The results indicated new compounds worthy of further study as potentiators of acyclovir in combination topical treatment of herpes virus infections.


Assuntos
Antivirais/síntese química , Hidrazonas/síntese química , Piridinas/síntese química , Ribonucleotídeo Redutases/antagonistas & inibidores , Simplexvirus/enzimologia , Antivirais/farmacologia , Humanos , Hidrazonas/química , Hidrazonas/farmacologia , Cinética , Estrutura Molecular , Piridinas/química , Piridinas/farmacologia , Relação Estrutura-Atividade
3.
Proc Natl Acad Sci U S A ; 86(3): 1051-5, 1989 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-2536930

RESUMO

2-Acetylpyridine 5-[(dimethylamino)thiocarbonyl]thiocarbonohydrazone (A1110U) was found to be a potent inactivator of the ribonucleotide reductases (EC 1.17.4.1) encoded by herpes simplex virus types 1 and 2 and by varicella-zoster virus and to be a weaker inactivator of human ribonucleotide reductase. It also markedly potentiated the antiherpetic activity of acyclovir against these viruses in tissue culture. A1110U both decreased the dGTP pool that builds up when infected cells are treated with acyclovir and induced a large increase in the pool of acyclovir triphosphate. The resultant 100-fold increase in the ratio of the concentrations of acyclovir triphosphate to dGTP should facilitate the binding of the fraudulent nucleotide to its target enzyme, herpes virus-encoded DNA polymerase, and could account for the synergy between A1110U and acyclovir. A similar change in the acyclovir triphosphate-to-dGTP ratio was previously reported to be induced by another ribonucleotide reductase inhibitor, 2-acetylpyridine 4-(2-morpholinoethyl)thiosemicarbazone (A723U). However, A1110U is considerably more potent and may have better clinical potential. Synergistic toxic interactions between A1110U and acyclovir were not detected in uninfected cells.


Assuntos
Aciclovir/farmacologia , Antivirais/farmacologia , Herpesvirus Humano 3/enzimologia , Hidrazonas/farmacologia , Piridinas/farmacologia , Ribonucleotídeo Redutases/antagonistas & inibidores , Simplexvirus/enzimologia , Sinergismo Farmacológico , Herpesvirus Humano 3/efeitos dos fármacos , Herpesvirus Humano 3/fisiologia , Hidrazonas/síntese química , Cinética , Piridinas/síntese química , Ribonucleotídeo Redutases/isolamento & purificação , Simplexvirus/efeitos dos fármacos , Simplexvirus/fisiologia , Replicação Viral/efeitos dos fármacos
4.
J Med Chem ; 30(1): 40-5, 1987 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-2879918

RESUMO

Tetrahydrobiopterin (THB) analogues with 6-alkoxymethyl substituents, 3a-j, where the substituents were straight- and branched-chain alkyl ranging from methyl to octyl, have been synthesized by the Taylor method from pyrazine ortho amino nitriles by guanidine cyclization, hydrolysis in aqueous NaOH, and catalytic hydrogenation over Pt in trifluoroacetic acid (TFA). The best of these compounds, 3b, is an excellent cofactor for phenylalanine hydroxylase, tyrosine hydroxylase (V = 154% of THB), and tryptophan hydroxylase, does not destablize the binding of substrate (Kmtyr = 23 microM), and is recycled by dihydropteridine reductase (V = 419% of THB). The compounds are being evaluated as cofactor replacements in biopterin-deficiency diseases.


Assuntos
Biopterinas/síntese química , Concentração de Íons de Hidrogênio , Fenilalanina Hidroxilase/metabolismo , Triptofano Hidroxilase/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo , Medula Suprarrenal/enzimologia , Animais , Biopterinas/análogos & derivados , Biopterinas/farmacologia , Tronco Encefálico/enzimologia , Bovinos , Indicadores e Reagentes , Cinética , Fígado/enzimologia , Ratos , Relação Estrutura-Atividade
6.
Proc Natl Acad Sci U S A ; 82(12): 4254-7, 1985 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-2987969

RESUMO

Compound A723U, a 2-acetylpyridine thiosemicarbazone, produced apparent inactivation of herpes simplex virus type 1 (HSV-1) ribonucleotide reductase. Inactivation occurred after A723U formed a reversible complex with the enzyme and only while the enzyme was catalyzing the formation of deoxynucleotides. A723U inhibited HSV-1 replication at concentrations that were not toxic to the confluent host cells. Most importantly, A723U and acyclovir (ACV) were found to exhibit mutual potentiation of their antiviral activities. Subinhibitory concentrations of either compound greatly reduced the ED50 (median effective dose) of the other. Studies of the deoxynucleotide pool sizes and the levels of ACV triphosphate (ACV-P3) revealed that A723U not only significantly reduced the pool of dGTP but also increased the level of ACV-P3 in infected cells. The net result was an 80-fold increase in the ratio of ACV-P3 to dGTP. This should greatly facilitate the initial binding of ACV-P3 to HSV-1 DNA polymerase and probably accounts for the mechanism of potentiation.


Assuntos
Aciclovir/farmacologia , Piridinas/farmacologia , Ribonucleotídeo Redutases/antagonistas & inibidores , Simplexvirus/efeitos dos fármacos , Tiossemicarbazonas/farmacologia , Desoxirribonucleotídeos/metabolismo , Sinergismo Farmacológico , Fosforilação , Simplexvirus/enzimologia , Replicação Viral/efeitos dos fármacos
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