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1.
PLoS One ; 9(2): e89300, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24586674

RESUMO

When microbicides used for HIV prevention contain antiretroviral drugs, there is concern for the potential emergence of drug-resistant HIV following use in infected individuals who are either unaware of their HIV infection status or who are aware but still choose to use the microbicide. Resistant virus could ultimately impact their responsiveness to treatment and/or result in subsequent transmission of drug-resistant virus. We tested whether drug resistance mutations (DRMs) would emerge in macaques infected with simian immunodeficiency virus expressing HIV reverse transcriptase (SHIV-RT) after sustained exposure to the potent non-nucleoside reverse transcriptase inhibitor (NNRTI) MIV-150 delivered via an intravaginal ring (IVR). We first treated 4 SHIV-RT-infected animals with daily intramuscular injections of MIV-150 over two 21 day (d) intervals separated by a 7 d drug hiatus. In all 4 animals, NNRTI DRMs (single and combinations) were detected within 14 d and expanded in proportion and diversity with time. Knowing that we could detect in vivo emergence of NNRTI DRMs in response to MIV-150, we then tested whether a high-dose MIV-150 IVR (loaded with >10 times the amount being used in a combination microbicide IVR in development) would select for resistance in 6 infected animals, modeling use of this prevention method by an HIV-infected woman. We previously demonstrated that this MIV-150 IVR provides significant protection against vaginal SHIV-RT challenge. Wearing the MIV-150 IVR for 56 d led to only 2 single DRMs in 2 of 6 animals (430 RT sequences analyzed total, 0.46%) from plasma and lymph nodes despite MIV-150 persisting in the plasma, vaginal fluids, and genital tissues. Only wild type virus sequences were detected in the genital tissues. These findings indicate a low probability for the emergence of DRMs after topical MIV-150 exposure and support the advancement of MIV-150-containing microbicides.


Assuntos
Farmacorresistência Viral/genética , Piridinas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Síndrome de Imunodeficiência Adquirida dos Símios/tratamento farmacológico , Vírus da Imunodeficiência Símia/efeitos dos fármacos , Vírus da Imunodeficiência Símia/genética , Ureia/análogos & derivados , Administração Intravaginal , Animais , Anti-Infecciosos Locais/administração & dosagem , Feminino , Injeções Intramusculares , Macaca mulatta , Mutação , Piridinas/administração & dosagem , Inibidores da Transcriptase Reversa/administração & dosagem , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Fatores de Tempo , Ureia/administração & dosagem , Ureia/farmacologia , Carga Viral
2.
AIDS Res Hum Retroviruses ; 28(11): 1467-75, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22816564

RESUMO

We previously showed that a carrageenan (CG) gel containing 50 µM MIV-150 (MIV-150/CG) reduced vaginal simian/human immunodeficiency virus (SHIV)-RT infection of macaques (56%, p>0.05) when administered daily for 2 weeks with the last dose given 8 h before challenge. Additionally, when 100 mg of MIV-150 was loaded into an intravaginal ring (IVR) inserted 24 h before challenge and removed 2 weeks after challenge, >80% protection was observed (p<0.03). MIV-160 is a related NNRTI with a similar IC(50), greater aqueous solubility, and a shorter synthesis. To objectively compare MIV-160 with MIV-150, herein we evaluated the antiviral effects of unformulated MIV-160 in vitro as well as the in vivo protection afforded by MIV-160 delivered in CG (MIV-160/CG gel) and in an IVR under regimens used with MIV-150 in earlier studies. Like MIV-150, MIV-160 exhibited potent antiviral activity against SHIV-RT in macaque vaginal explants. However, formulated MIV-160 exhibited divergent effects in vivo. The MIV-160/CG gel offered no protection compared to CG alone, whereas the MIV-160 IVRs protected significantly. Importantly, the results of in vitro release studies of the MIV-160/CG gel and the MIV-160 IVR suggested that in vivo efficacy paralleled the amount of MIV-160 released in vitro. Hundreds of micrograms of MIV-160 were released daily from IVRs while undetectable amounts of MIV-160 were released from the CG gel. Our findings highlight the importance of testing different modalities of microbicide delivery to identify the optimal formulation for efficacy in vivo.


Assuntos
Carragenina/farmacologia , Inibidores Enzimáticos/farmacologia , Transcriptase Reversa do HIV/antagonistas & inibidores , Reto/efeitos dos fármacos , Síndrome de Imunodeficiência Adquirida dos Símios/prevenção & controle , Vírus da Imunodeficiência Símia/efeitos dos fármacos , Tiazóis/farmacologia , Tioureia/análogos & derivados , Vagina/efeitos dos fármacos , Administração Intravaginal , Administração Retal , Animais , Feminino , Humanos , Macaca mulatta , Piridinas/farmacologia , Reto/patologia , Reto/virologia , Síndrome de Imunodeficiência Adquirida dos Símios/tratamento farmacológico , Síndrome de Imunodeficiência Adquirida dos Símios/patologia , Tioureia/farmacologia , Resultado do Tratamento , Ureia/análogos & derivados , Ureia/farmacologia , Vagina/patologia , Vagina/virologia
3.
AIDS Res Hum Retroviruses ; 28(11): 1476-84, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22737981

RESUMO

Previously we showed that repeated vaginal application of a MIV-150/zinc acetate carrageenan (MIV-150/ZA/CG) gel and a zinc acetate carrageenan (ZA/CG) gel significantly protected macaques from vaginal simian human immunodeficiency virus reverse transcriptase (SHIV-RT) infection. Gels were applied either daily for 2 weeks or every other day for 4 weeks, and the animals were challenged 4-24 h later. Herein, we examined the effects of a single vaginal dose administered either before or after virus challenge. Encouraged by the vaginal protection seen with MIV-150/ZA/CG, we also tested it rectally. Vaginal applications of MIV-150/ZA/CG, ZA/CG, and CG gel were performed once 8-24 h before, 1 h after, or 24 h before and 1 h after vaginal challenge. Rectal applications of MIV-150/ZA/CG and CG gel were performed once 8 or 24 h before rectal challenge. While vaginal pre-challenge and pre/post-challenge application of MIV-150/ZA/CG gel offered significant protection (88%, p<0.002), post-challenge application alone did not significantly protect. ZA/CG gel reduced infection prechallenge, but not significantly, and the effect was completely lost post-challenge. Rectal application of MIV-150/ZA/CG gel afforded limited protection against rectal challenge when applied 8-24 h before challenge. Thus, MIV-150/ZA/CG gel is a highly effective vaginal microbicide that demonstrates 24 h of protection from vaginal infection and may demonstrate efficacy against rectal infection when given close to the time of HIV exposure.


Assuntos
Anti-Infecciosos/farmacologia , Herpes Genital/prevenção & controle , Herpesvirus Humano 2/efeitos dos fármacos , Piridinas/farmacologia , DNA Polimerase Dirigida por RNA/efeitos dos fármacos , Síndrome de Imunodeficiência Adquirida dos Símios/prevenção & controle , Vírus da Imunodeficiência Símia/efeitos dos fármacos , Ureia/análogos & derivados , Acetato de Zinco/farmacologia , Administração Intravaginal , Administração Retal , Animais , Anti-Infecciosos/farmacocinética , Feminino , Herpes Genital/tratamento farmacológico , Herpes Genital/patologia , Humanos , Piridinas/farmacocinética , Reto/patologia , Reto/virologia , Síndrome de Imunodeficiência Adquirida dos Símios/tratamento farmacológico , Síndrome de Imunodeficiência Adquirida dos Símios/patologia , Fatores de Tempo , Resultado do Tratamento , Ureia/farmacocinética , Ureia/farmacologia , Vagina/patologia , Vagina/virologia , Cremes, Espumas e Géis Vaginais , Acetato de Zinco/farmacocinética
4.
Antimicrob Agents Chemother ; 56(1): 358-68, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22064530

RESUMO

Topical microbicides that block the sexual transmission of HIV and herpes simplex virus 2 (HSV-2) are desperately needed to reduce the incidence of HIV infections worldwide. Previously we completed phase 3 testing of the carrageenan-based gel Carraguard. Although the trial did not show that Carraguard is effective in preventing HIV transmission during vaginal sex, it did show that Carraguard is safe when used weekly for up to 2 years. Moreover, Carraguard has in vitro activity against human papillomavirus (HPV) and HSV-2 and favorable physical and rheological properties, which makes it a useful vehicle to deliver antiviral agents such as zinc acetate. To that end, we previously reported that a prototype zinc acetate carrageenan gel protects macaques against vaginal challenge with combined simian-human immunodeficiency virus reverse transcriptase (SHIV-RT). Herein, we report the safety and efficacy of a series of zinc acetate and/or carrageenan gels. The gels protected mice (75 to 85% survival; P < 0.001) against high-dose (10(6)-PFU) HSV-2 vaginal or rectal challenge. In contrast, zinc acetate formulated in HEC (hydroxyethylcellulose; or the Universal Placebo) failed to protect mice against the high-dose vaginal HSV-2 challenge (similar to aqueous zinc acetate solution and the placebo controls). The gels were found to be effective spreading gels, exhibited limited toxicity in vitro, caused minimal damage to the architecture of the cervicovaginal and rectal mucosae in vivo, and induced no increased susceptibility to HSV-2 infection in a mouse model. Our results provide a strong rationale to further optimize and evaluate the zinc acetate/carrageenan gels for their ability to block the sexual transmission of HIV and HSV-2.


Assuntos
Carragenina/administração & dosagem , Infecções por HIV/prevenção & controle , HIV/efeitos dos fármacos , Herpes Genital/prevenção & controle , Herpesvirus Humano 2/efeitos dos fármacos , Acetato de Zinco/administração & dosagem , Animais , Anti-Infecciosos Locais/administração & dosagem , Anti-Infecciosos Locais/uso terapêutico , Antivirais/administração & dosagem , Antivirais/uso terapêutico , Carragenina/uso terapêutico , Estabilidade de Medicamentos , Feminino , Géis , HIV/fisiologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Herpes Genital/tratamento farmacológico , Herpes Genital/mortalidade , Herpes Genital/virologia , Herpesvirus Humano 2/fisiologia , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Camundongos Endogâmicos BALB C , Membrana Mucosa/efeitos dos fármacos , Membrana Mucosa/virologia , Reto/efeitos dos fármacos , Reto/virologia , Reologia , Taxa de Sobrevida , Vagina/efeitos dos fármacos , Vagina/virologia , Acetato de Zinco/uso terapêutico
5.
AIDS Res Hum Retroviruses ; 27(9): 1019-24, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21309617

RESUMO

Over-the-counter personal lubricants are used frequently during vaginal and anal intercourse, but they have not been extensively tested for biological effects that might influence HIV transmission. We evaluated the in vitro toxicity anti-HIV-1 activity and osmolality of popular lubricants. A total of 41 lubricants were examined and compared to Gynol II and Carraguard as positive and negative controls for toxicity, respectively. Cytotoxicity was assessed using the XTT assay. The MAGI assay with R5 and X4 HIV-1 laboratory strains was used to evaluate antiviral activity. The effect of the lubricants on differentiated Caco-2 cell monolayers (transepithelial electrical resistance, TEER) was also measured. None of the lubricants tested showed significant activity against HIV-1. Surprisingly, four of them, Astroglide Liquid, Astroglide Warming Liquid, Astroglide Glycerin & Paraben-Free Liquid, and Astroglide Silken Secret, significantly enhanced HIV-1 replication (p<0.0001). A common ingredient in three of these preparations is polyquaternium-15. In vitro testing of a chemically related compound (MADQUAT) confirmed that this similarly augmented HIV-1 replication. Most of the lubricants were found to be hyperosmolar and the TEER value dropped approximately 60% 2 h after exposure to all lubricants tested. Cells treated with Carraguard, saline, and cell controls maintained about 100% initial TEER value after 2-6 h. We have identified four lubricants that significantly increase HIV-1 replication in vitro. In addition, the epithelial damage caused by these and many other lubricants may have implications for enhancing HIV transmission in vivo. These data emphasize the importance of performing more rigorous safety testing on these products.


Assuntos
Células Epiteliais/efeitos dos fármacos , Células Epiteliais/fisiologia , Infecções por HIV/transmissão , HIV-1/efeitos dos fármacos , Lubrificantes/efeitos adversos , Replicação Viral/efeitos dos fármacos , Células CACO-2 , Sobrevivência Celular/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana/métodos , Coloração e Rotulagem/métodos , Sais de Tetrazólio/metabolismo
6.
PLoS One ; 6(1): e15835, 2011 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-21246052

RESUMO

BACKGROUND: Repeated use, coitus-independent microbicide gels that do not contain antiretroviral agents also used as first line HIV therapy are urgently needed to curb HIV spread. Current formulations require high doses (millimolar range) of antiretroviral drugs and typically only provide short-term protection in macaques. We used the macaque model to test the efficacy of a novel combination microbicide gel containing zinc acetate and micromolar doses of the novel non-nucleoside reverse transcriptase inhibitor MIV-150 for up to 24 h after repeated gel application. METHODS AND FINDINGS: Rhesus macaques were vaginally challenged with SHIV-RT up to 24 h after repeated administration of microbicide versus placebo gels. Infection status was determined by measuring virologic and immunologic parameters. Combination microbicide gels containing 14 mM zinc acetate dihydrate and 50 µM MIV-150 afforded full protection (21 of 21 animals) for up to 24 h after 2 weeks of daily application. Partial protection was achieved with the MIV-150 gel (56% of control at 8 h after last application, 11% at 24 h), while the zinc acetate gel afforded more pronounced protection (67% at 8-24 h). Marked protection persisted when the zinc acetate or MIV-150/zinc acetate gels were applied every other day for 4 weeks prior to challenge 24 h after the last gel was administered (11 of 14 protected). More MIV-150 was associated with cervical tissue 8 h after daily dosing of MIV-150/zinc acetate versus MIV-150, while comparable MIV-150 levels were associated with vaginal tissues and at 24 h. CONCLUSIONS: A combination MIV-150/zinc acetate gel and a zinc acetate gel provide significant protection against SHIV-RT infection for up to 24 h. This represents a novel advancement, identifying microbicides that do not contain anti-viral agents used to treat HIV infection and which can be used repeatedly and independently of coitus, and underscores the need for future clinical testing of their safety and ability to prevent HIV transmission in humans.


Assuntos
Antirretrovirais/administração & dosagem , Piridinas/administração & dosagem , Síndrome de Imunodeficiência Adquirida dos Símios/prevenção & controle , Ureia/análogos & derivados , Acetato de Zinco/administração & dosagem , Administração Intravaginal , Animais , Combinação de Medicamentos , Feminino , Géis/administração & dosagem , Géis/uso terapêutico , Transcriptase Reversa do HIV/antagonistas & inibidores , Humanos , Macaca , Piridinas/uso terapêutico , Vírus da Imunodeficiência Símia , Resultado do Tratamento , Ureia/administração & dosagem , Ureia/uso terapêutico , Acetato de Zinco/uso terapêutico
7.
Synlett ; 10: 1651-1654, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-20442797

RESUMO

A catalytic, highly diastereoselective process for the synthesis of trans-beta-lactams is reported. This system is based on a phosphonium fluoride precatalyst that both activates the nucleophile and directs the reaction process for high yield and diastereoselectivity.

8.
J Am Chem Soc ; 130(50): 17085-94, 2008 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-19053448

RESUMO

We report a detailed synthetic and mechanistic study of an unusual bifunctional, sequential hetero-Diels-Alder/ring-opening reaction in which chiral, metal complexed ketene enolates react with o-quinones to afford highly enantioenriched, alpha-hydroxylated carbonyl derivatives in excellent yield. A number of Lewis acids were screened in tandem with cinchona alkaloid derivatives; surprisingly, trans-(Ph(3)P)(2)PdCl(2) was found to afford the most dramatic increase in yield and rate of reaction. A series of Lewis acid binding motifs were explored through molecular modeling, as well as IR, UV, and NMR spectroscopy. Our observations document a fundamental mechanistic "switch", namely the formation of a tandem Lewis base/Lewis acid activated metal enolate in preference to a metal-coordinated quinone species (as observed in other reactions of o-quinone derivatives). This new method was applied to the syntheses of several pharmaceutical targets, each of which was obtained in high yield and enantioselectivity.


Assuntos
Ácidos/química , Hidroxiácidos/química , Catálise , Cloranila/química , Modelos Anatômicos , Estrutura Molecular , Paládio/química , Fosfitos/química , Espectrofotometria , Estereoisomerismo
9.
Acc Chem Res ; 41(5): 655-63, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18402470

RESUMO

In the field of catalytic, asymmetric synthesis, there is a growing emphasis on multifunctional systems, in which multiple parts of a catalyst or multiple catalysts work together to promote a specific reaction. These efforts, in part, are result-driven, and they are also part of a movement toward emulating the efficiency and selectivity of nature's catalysts, enzymes. In this Account, we illustrate the importance of bifunctional catalytic methods, focusing on the cooperative action of Lewis acidic and Lewis basic catalysts by the simultaneous activation of both electrophilic and nucleophilic reaction partners. For our part, we have contributed three separate bifunctional methods that combine achiral Lewis acids with chiral cinchona alkaloid nucleophiles, for example, benzoylquinine (BQ), to catalyze highly enantioselective cycloaddition reactions between ketene enolates and various electrophiles. Each method requires a distinct Lewis acid to coordinate and activate the electrophile, which in turn increases the reaction rates and yields, without any detectable influence on the outstanding enantioselectivities inherent to these reactions. To place our results in perspective, many important contributions to this emerging field are highlighted and our own reports are chronicled.


Assuntos
beta-Lactamas/síntese química , Alumínio/química , Catálise , Ciclização , Etilenos/química , Iminas/química , Cetonas/química , Estrutura Molecular , Naftóis/química , Fosfinas/química , Estereoisomerismo , beta-Lactamas/química
10.
J Org Chem ; 72(14): 5380-2, 2007 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-17555354

RESUMO

A catalytic, asymmetric process for the synthesis of 1,4-benzoxazinones from o-benzoquinone imides and ketene enolates is reported. Addition of Lewis acids (Zn(OTf)2, In(OTf)3, and in particular Sc(OTf)3) creates a bifunctional catalytic system that dramatically increases the reaction rate and the yield of these non-natural amino acid precursors while preserving the remarkable enantioselectivity inherent to the reaction. Cocatalyst Sc(OTf)3 increases the yield by up to 42% while producing products in >99% ee.


Assuntos
Aminoácidos/química , Aminoácidos/síntese química , Produtos Biológicos/química , Catálise , Metais/química , Estrutura Molecular , Estereoisomerismo
11.
J Am Chem Soc ; 128(41): 13370-1, 2006 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-17031945

RESUMO

In this Communication, we report a system in which an achiral Lewis acid (activating the diene) works in concert with a chiral nucleophile (dienophile) to effect the first highly enantio- and regioselective catalytic inverse electron demand Diels-Alder [4 + 2] cycloaddition reaction to form biologically active quinoxalinones from ketene enolates and o-benzoquinone diimides in good to excellent yields with >99% ee.


Assuntos
Álcoois/química , Alcadienos/química , Benzoquinonas/química , Elétrons , Etilenos/química , Imidas/química , Cetonas/química , Catálise , Modelos Químicos , Estereoisomerismo
13.
J Am Chem Soc ; 128(6): 1810-1, 2006 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-16464078

RESUMO

We report catalytic, enantioselective [4 + 2]-cycloadditions of o-quinones with ketene enolates (derived from readily available acid chlorides) using cinchona alkaloid derivatives as catalysts to produce products in high enantiomeric excess (ee) and good to excellent yields. The thermodynamic driving force for these reactions is due in part to the restoration of aromaticity to the products. The resulting chiral, bicycloadducts can be synthetically manipulated in a variety of useful ways, for example to provide a flexible synthesis of alpha-oxygenated carboxylic acid derivatives.


Assuntos
Ácidos Carboxílicos/síntese química , Etilenos/química , Cetonas/química , Quinonas/química , Catálise , Cloranila/análogos & derivados , Cloranila/química , Ciclização , Oxirredução , Estereoisomerismo
14.
Org Lett ; 7(16): 3461-3, 2005 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-16048317

RESUMO

Trans-disubstituted beta-lactams show increasing utility and prominence in numerous pharmaceutical applications, making their asymmetric synthesis an attractive goal for chemists. We introduce an anionic, nucleophilic catalyst system that provides an efficient, diastereoselective route to trans-disubstituted beta-lactams, a complement to our previously described catalytic methodology for generating the corresponding cis diastereomers. This catalytic, "switch mechanism" process allows for flexibility in the stereoselective synthesis of beta-lactams, producing either cis or trans products as desired from the same substrates. [reaction: see text]


Assuntos
beta-Lactamas/síntese química , Ânions/química , Catálise , Ciclização , Estereoisomerismo , beta-Lactamas/química
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