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1.
Mol Diagn Ther ; 22(3): 369-380, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29651790

RESUMO

BACKGROUND: Isocitrate dehydrogenase 1 (IDH1) is a dimeric enzyme responsible for supplying the cell's nicotinamide adenine dinucleotide phosphate (NADPH) reserves via dehydrogenation of isocitrate (ICT) and reduction of NADP+. Mutations in position R132 trigger cancer by enabling IDH1 to produce D-2-hydroxyglutarate (2-HG) and reduce inhibition by ICT. Mutant IDH1 can be found as a homodimer or a heterodimer. OBJECTIVE: We propose a novel strategy to inhibit IDH1 R132 variants as a means not to decrease the concentration of 2-HG but to provoke a cytotoxic effect, as the cell malignancy at this point no longer depends on 2-HG. We aim to inhibit the activity of the mutant heterodimer to block the wild-type subunit. Limiting the NADPH reserves in a cancerous cell will enhance its susceptibility to the oxidative stress provoked by chemotherapy. METHODS: We performed a virtual screening using all US FDA-approved drugs to replicate the loss of inhibition of mutant IDH1 by ICT. We characterized our results based on molecular interactions and correlated them with the described phenotypes. RESULTS: We replicated the loss of inhibition by ICT in mutant IDH1. We identified 20 drugs with the potential to inhibit the heterodimeric isoform. Six of them are used in cancer treatment. CONCLUSIONS: We present 20 FDA-approved drugs with the potential to inhibit IDH1 wild-type activity in mutated cells. We believe this work may provide important insights into current and new approaches to dealing with IDH1 mutations. In addition, it may be used as a basis for additional studies centered on drugs presenting differential sensitivities to different IDH1 isoforms.


Assuntos
Antineoplásicos/química , Dasatinibe/química , Inibidores Enzimáticos/química , Isocitrato Desidrogenase/antagonistas & inibidores , Pirimidinas/química , Sulfonamidas/química , Compostos de Tosil/química , Sequência de Aminoácidos , Sítios de Ligação , Di-Hidroergotamina/química , Epirubicina/química , Expressão Gênica , Ensaios de Triagem em Larga Escala , Humanos , Isocitrato Desidrogenase/química , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismo , Simulação de Acoplamento Molecular , Mutação , Pivampicilina/química , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Multimerização Proteica , Termodinâmica , Interface Usuário-Computador
2.
BMJ Case Rep ; 20152015 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-26424818

RESUMO

Good's syndrome is a rare primary immunodeficiency associated with adult thymoma. Complications are mainly autoimmune manifestations and recurrent infections with encapsulated bacteria. Only one possible case of combined granulomatous-lymphocytic interstitial lung disease (GL-ILD) and Good's syndrome have been described earlier, but the patient died at the time of diagnosis. This is the first case of GL-ILD in Good's syndrome with a successful outcome. We present a case of a 43-year-old man with GL-ILD, who suffered from recurrent infections of Haemophilus influenzae and Pneumocystis jirovecii, with 8-year follow-up. After a thymectomy, he was diagnosed with Good's syndrome and GL-ILD. He was treated with prophylactic pivampicillin, quinolones and cephalosporins for his recurrent P. jirovecii and H. influenzae infections, an approach that proved unsuccessful due to resistance, with relapse after cessation. He was stabilised with oral diaminodiphenyl-sulfone for P. jirovecii and colistimethate-sodium inhalations for H. influenzae, which is a new approach to prophylactic treatment.


Assuntos
Granuloma/microbiologia , Infecções por Haemophilus/patologia , Doenças Pulmonares Intersticiais/microbiologia , Adulto , Agamaglobulinemia/patologia , Antibacterianos/uso terapêutico , Cefalosporinas/uso terapêutico , Granuloma/patologia , Infecções por Haemophilus/microbiologia , Haemophilus influenzae/isolamento & purificação , Humanos , Síndromes de Imunodeficiência/microbiologia , Síndromes de Imunodeficiência/patologia , Doenças Pulmonares Intersticiais/tratamento farmacológico , Masculino , Neoplasias Epiteliais e Glandulares/patologia , Pivampicilina/uso terapêutico , Infecções por Pneumocystis/microbiologia , Infecções por Pneumocystis/patologia , Pneumocystis carinii/isolamento & purificação , Quinolonas/uso terapêutico , Doenças Raras , Timoma/patologia , Neoplasias do Timo/patologia
3.
Res Vet Sci ; 92(1): 111-5, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21144541

RESUMO

Ampicillin concentrations in pulmonary epithelial lining fluid (PELF) and plasma was studied after single intravenous ampicillin administration (15mg/kg) or single intragastric administration of its prodrug, pivampicillin (19.9mg/kg) to horses and discussed in relation to minimum inhibitory concentrations (MIC) of common equine respiratory pathogens. After intravenous administration, elimination of ampicillin was fast and not detectable in plasma after 12h in three out of six horses. Pivampicillin was absorbed well in non-fasted horses with an oral bioavailability of 36%. The degree of penetration of ampicillin into PELF, as described by the AUC(PELF)/AUC(plasma) ratio from 0 to 12h was 0.40 after intravenous administration and 1.00 after pivampicillin administration. In horses, ampicillin administered either intravenously or orally, in the form of pivampicillin, can provide clinically relevant drug concentrations in PELF for at least 12h, when treating susceptible equine respiratory pathogens (e.g. streptococci). Treatment of other bacterial pathogens requires susceptibility testing and possibly more frequent dosing, depending of minimum inhibitory concentrations (MIC) values.


Assuntos
Ampicilina/farmacocinética , Antibacterianos/farmacocinética , Cavalos/metabolismo , Pivampicilina/farmacocinética , Administração Oral , Ampicilina/administração & dosagem , Ampicilina/sangue , Animais , Antibacterianos/administração & dosagem , Antibacterianos/sangue , Disponibilidade Biológica , Líquido da Lavagem Broncoalveolar/química , Cromatografia Líquida de Alta Pressão/veterinária , Feminino , Cavalos/sangue , Injeções Intravenosas/veterinária , Pivampicilina/administração & dosagem , Pivampicilina/sangue
4.
J Pharm Sci ; 99(2): 1078-86, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19623605

RESUMO

Although prodrugging (prodrug derivatization) is a powerful technique for improving the pharmacokinetic characteristics of drugs, the intestinal pharmacokinetics of prodrugs has yet to be elucidated fully. A previous article reported the kinetic requirement of prodrugs to overcome membrane barriers. In the present article, the luminal degradation of prodrugs was kinetically assessed to understand crucial factors in the intestinal absorption of prodrugs and to show a rational development procedure. A kinetic model equation involving luminal degradation clearance (CL(deg)) was derived, and CL(deg) was estimated according to the equation with in vitro and in vivo reported data of two kinds of ampicillin prodrugs (lenampicillin and pivampicillin) and one acyclovir prodrug (valacyclovir). For lenampicillin ((2,2-dimethyl-1-oxopropoxy)methyl ester derivative), CL(deg) was approximately 1.7 times as large as absorption clearance (CL(abs)), whereas for pivampicillin ((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester derivative), CL(deg) was approximately one tenth of CL(abs). For valacyclovir (acyclovir prodrug), CL(deg) was negligible. These results indicate that not only membrane permeability but also luminal stability should be assessed for the rational development of orally effective prodrugs, and that luminal stabilization can improve the intestinal absorption of prodrugs. A procedure was proposed to develop orally effective prodrugs considered for luminal degradation as well as membrane permeability.


Assuntos
Desenho de Fármacos , Absorção Intestinal , Pró-Fármacos/farmacocinética , Aciclovir/análogos & derivados , Aciclovir/farmacocinética , Administração Oral , Algoritmos , Ampicilina/análogos & derivados , Ampicilina/farmacocinética , Antibacterianos/farmacocinética , Antivirais/farmacocinética , Modelos Estatísticos , Permeabilidade , Pivampicilina/farmacocinética , Pró-Fármacos/administração & dosagem , Valaciclovir , Valina/análogos & derivados , Valina/farmacocinética
5.
Can Fam Physician ; 55(1): 60-7, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19155372

RESUMO

OBJECTIVE: To compare the effectiveness and toxicity of semisynthetic penicillins (SSPs) (amoxicillin, ampicillin, pivampicillin) and trimethoprim-based regimens (trimethoprim, trimethoprim-sulfamethoxazole, trimethoprim-sulfadiazine) in treating acute bacterial exacerbations of chronic bronchitis (ABECB). DATA SOURCES: We searched MEDLINE, EMBASE, Current Contents, and the Cochrane Central Register of Controlled Trials to identify and extract data from relevant randomized controlled trials (RCTs). STUDY SELECTION: Only RCTs comparing penicillins with trimethoprim-based regimens for the treatment of patients with ABECB that reported data on effectiveness, toxicity, or mortality were considered eligible for this meta-analysis. SYNTHESIS: Out of 134 RCTs identified in the search, 5 RCTs involving 287 patients were included in the analysis. There were no differences between patients with ABECB treated with SSPs and those treated with trimethoprim, alone or in combination with a sulfonamide, in treatment success (intention-to-treat patients: n = 262, odds ratio [OR] 1.68, 95% confidence interval [CI] 0.91-3.09; clinically evaluable patients: n = 246, OR 1.59, 95% CI 0.79-3.20) or number of drug-related adverse events in general (n = 186 patients, OR 0.37, 95% CI 0.11-1.24), frequency of diarrhea or skin rashes, or number of withdrawals due to adverse events (n = 179 patients, OR 0.27, 95% CI 0.07-1.03). CONCLUSION: Based on limited evidence leading to wide CIs of the estimated treatment effects, SSPs and trimethoprim-based regimens seem to be equivalent in terms of effectiveness and toxicity for ABECB.


Assuntos
Amoxicilina/uso terapêutico , Anti-Infecciosos/uso terapêutico , Bronquite Crônica/tratamento farmacológico , Pivampicilina/uso terapêutico , Combinação Trimetoprima e Sulfametoxazol/uso terapêutico , Doença Aguda , Quimioterapia Combinada , Humanos , Guias de Prática Clínica como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
6.
Biol Pharm Bull ; 30(7): 1344-9, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17603179

RESUMO

Bacampicillin was developed as a prodrug to improve the intestinal absorption of its metabolite ampicillin. This study was undertaken to characterize bacampicillin transport in Caco-2 cells. The uptake of bacampicillin in Caco-2 cells was significantly greater than those of ampicillin and pivampicillin. An Eadie-Hofstee plot obtained from 5-min uptake of 0.2-5 mM bacampicillin was linear, indicating the presence of a saturable transport system for bacampicillin with K(m) and V(max) of 3.6 mM and 23.9 nmol/mg protein/min, respectively. Hydrophilic organic cations such as choline, cimetidine, guanidine, nicotinamide, 1-methylnicotiamide, and tetraethylammonium failed to modulate bacampicillin uptake in Caco-2 cells whereas diphenhydramine, procainamide, and thiamine significantly depressed it. Moreover, when thiamine was preloaded in Caco-2 cells, bacampicillin uptake was significantly increased, indicating that this cationic vitamin was capable of trans-stimulating bacampicillin transport across the apical membrane of Caco-2 cells. However, trans-stimulated bacampicillin uptake was not observed in the presence of diphenhydramine. Bacampicillin uptake increased with elevation of the medium pH, and the known modulators of thiamine transport such as amiloride and oxythiamine significantly inhibited bacampicillin uptake. Thiamine also significantly decreased the apical-to-basolateral transport of bacampicillin across Caco-2 cell monolayers. However, thiamine did not exert any modulating effect on pivampicillin uptake and its apical-to-basolateral permeation in Caco-2 cells. These results suggest that bacampicillin is transported in Caco-2 cells, sharing a carrier-mediated system with thiamine.


Assuntos
Ampicilina/análogos & derivados , Antibacterianos/farmacocinética , Tiamina/metabolismo , Ampicilina/farmacocinética , Transporte Biológico/efeitos dos fármacos , Células CACO-2 , Difenidramina/farmacologia , Humanos , Concentração de Íons de Hidrogênio , Proteínas de Membrana Transportadoras/fisiologia , Transportador 1 de Peptídeos , Pivampicilina/farmacocinética , Simportadores/fisiologia , Tiamina/farmacologia
7.
Antimicrob Agents Chemother ; 49(4): 1279-88, 2005 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15793098

RESUMO

Pivampicillin (PIVA), an acyloxymethylester of ampicillin, is thought to enhance the oral bioavailability of ampicillin because of its greater lipophilicity compared to that of ampicillin. The fate of PIVA in intestinal cells and the exact location of its conversion into ampicillin have, however, never been unambiguously established. Polarized Caco-2 cells have been used to examine the handling of PIVA and the release of ampicillin from PIVA by the intestinal epithelium. Experiments were limited to 3 h. Cells incubated with PIVA (apical pole) showed a fast accumulation of ampicillin and transport toward the basolateral medium, whereas PIVA itself was only poorly accumulated and transported. Cells incubated with free ampicillin accumulated and transported only minimal amounts of this drug. Release of ampicillin from cells incubated with PIVA was unaffected by PEPT1 and OCTN2 inhibitors but was sharply decreased after ATP depletion or addition of bis(4-nitrophenyl)-phosphate (BNPP; an esterase inhibitor). PIVA incubated with Caco-2 lysates released free ampicillin, and this release was inhibited by BNPP. Efflux studies showed that the ampicillin that accumulated in cells after incubation with PIVA was preferentially transported out of the cells through the basolateral pole. This efflux was decreased by multidrug resistance-associated protein (MRP) inhibitors (probenecid, MK-571) and by ATP depletion. A phthalimidomethylester of ampicillin that resists cellular esterases failed to cause any significant release (cell lysate) or transport (polarized Caco-2 cells) of ampicillin. These results show that when PIVA is given to Caco-2 cells from their apical pole, ampicillin is released intracellularly and that ampicillin is thereafter preferentially effluxed into the basolateral medium through an MRP-like transporter.


Assuntos
Ampicilina/farmacocinética , Antibacterianos/farmacocinética , Polaridade Celular , Colo/metabolismo , Pivampicilina/farmacocinética , Pró-Fármacos/farmacocinética , Transporte Biológico , Células CACO-2 , Humanos
8.
J Antimicrob Chemother ; 52(4): 610-5, 2003 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-12972457

RESUMO

AIMS: To determine the intracellular accumulation in a macrophage cell line of ampicillin and ampicillin esters, and to measure their activity against intracellular Listeria monocytogenes. METHODS: Quantitative evaluation of the activity of ampicillin, phthalimidomethylampicillin (PIMA) or pivaloyloxymethylampicillin (PIVA) against intracellular L. monocytogenes, and direct measurement of cellular ampicillin concentration in J774 macrophages. RESULTS: Ampicillin, PIMA and PIVA caused a 0.5 log decrease in cell-associated cfu within 5 h when used at an extracellular concentration of 3.6 microM [10 x MIC of ampicillin (1.25 mg/L); 1.83 mg/L for PIMA and 1.67 mg/L for PIVA]. Addition of beta-lactamase in the extracellular milieu abolished the activity of ampicillin and of PIMA but not that of PIVA. At low extracellular concentrations [0.5 x MIC ampicillin (62.5 microg/L); equimolar concentrations for PIMA (91.5 microg/L) and PIVA (83.5 microg/L)], ampicillin and PIMA lost all activity (compared with controls), but PIVA remained as active as at the higher concentration. Incubation of cells with PIVA at the low concentration (83.5 microg/L) for 20 h caused a 2 log reduction of cfu if the medium was changed every 5 h (to compensate for the degradation of extracellular PIVA). Incubation of cells with PIVA allowed for a marked (four- to 25-fold) cell accumulation of ampicillin, whereas no ampicillin accumulation was seen for cells incubated with ampicillin or with PIMA. CONCLUSIONS: This is the first demonstration that PIVA (a prodrug of ampicillin) can be used to promote ampicillin cellular accumulation and, thereby to increase ampicillin intracellular activity. PIVA could be useful for control of the intracellular multiplication of L. monocytogenes.


Assuntos
Ampicilina/metabolismo , Líquido Intracelular/metabolismo , Listeria monocytogenes/metabolismo , Macrófagos/metabolismo , Ftalimidas/metabolismo , Pivampicilina/metabolismo , Ampicilina/análogos & derivados , Ampicilina/farmacologia , Animais , Linhagem Celular Tumoral , Líquido Intracelular/efeitos dos fármacos , Listeria monocytogenes/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Camundongos , Ftalimidas/farmacologia , Pivampicilina/farmacologia
9.
Pharm Res ; 20(4): 624-31, 2003 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-12739771

RESUMO

PURPOSE: The purpose of this work was to examine and understand the cellular pharmacokinetics of two basic esters of ampicillin, pivaloyloxymethyl (PIVA) and phthalimidomethyl (PIMA), in comparison with lysosomotropic drugs (chloroquine, azithromycin). METHODS: Cell culture studies (J774 macrophages) were undertaken to study uptake and release kinetics and to assess the influence of concentration, pH, proton ionophore (monensin), and MRP and P-gp inhibitors (probenecid, gemfibrozil, cyclosporin A, GF 120918). Equilibrium dialysis with liposomes were performed to directly asses the extent of drug binding to bilayers. Conformational analysis modeling of the drug penetration in bilayers was conducted to rationalize the experimental observations. RESULTS: PIVA and PIMA showed properties in almost complete contrast with those of chloroquine and azithromycin, i.e., fast apparent accumulation and fast release at 4 degrees C as well as at 37 degrees C, saturation of uptake (apparent Kd 40 microM), no influence of monensin, MRP, or P-gp inhibitors; tight binding to liposomes (Kd approx. 40 microM); and sharp increase in calculated free energy when forced in the hydrophobic domain. CONCLUSIONS: Although they are weak organic bases, PIVA and PIMA show none of the properties of lysosomotropic agents. We hypothesize that they remain locked onto the pericellular membrane and may never penetrate cells as such in significant amounts.


Assuntos
Ampicilina/análogos & derivados , Ampicilina/farmacocinética , Azitromicina/farmacocinética , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Cloroquina/farmacocinética , Ftalimidas/farmacocinética , Pivampicilina/farmacocinética , Técnicas de Cultura de Células , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Modelos Biológicos
10.
J Int Med Res ; 28(3): 101-10, 2000.
Artigo em Inglês | MEDLINE | ID: mdl-10983860

RESUMO

This single-blind, double-dummy, multicentre study compared oral azithromycin, administered as tablets, 500 mg once daily for 3 days, versus oral pivampicillin, 700 mg twice daily for 10 days, in adults with acute exacerbations of chronic bronchitis (not needing parenteral antibiotic therapy, hospitalization or oxygen support). Clinical success (cure + improvement) rates were similar for both groups at the end of treatment (day 10; azithromycin, 124 of 133 [93%]; pivampicillin, 79 of 92 [86%]) and at follow-up (day 52; 98 of 126 [78%] versus 66 of 81 [81%]). The treatments produced similar levels of pathogen eradication at the end of treatment (49 of 54 [91%] versus 32 of 37 [86%]). Azithromycin-treated patients had significantly reduced chest discomfort at the end of treatment, and a trend towards improved lung function. The two groups were similar with respect to improvements in other clinical symptoms and patient well-being, and to the incidences of adverse events and treatment discontinuations. This oral azithromycin regime is an effective treatment for acute exacerbations of chronic bronchitis, similar in efficacy to the longer pivampicillin regime and may offer superior patient compliance.


Assuntos
Antibacterianos/uso terapêutico , Azitromicina/uso terapêutico , Bronquite/tratamento farmacológico , Penicilinas/uso terapêutico , Pivampicilina/uso terapêutico , Adulto , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Azitromicina/administração & dosagem , Azitromicina/efeitos adversos , Bronquite/microbiologia , Bronquite/fisiopatologia , Doença Crônica , Qualidade de Produtos para o Consumidor , Tolerância a Medicamentos , Feminino , Humanos , Masculino , Penicilinas/administração & dosagem , Penicilinas/efeitos adversos , Pivampicilina/administração & dosagem , Pivampicilina/efeitos adversos , Método Simples-Cego , Resultado do Tratamento
11.
Acta Obstet Gynecol Scand ; 79(5): 379-83, 2000 May.
Artigo em Inglês | MEDLINE | ID: mdl-10830765

RESUMO

BACKGROUND: Pivampicillin is a prodrug which is widely used in Scandinavian countries for oral antibiotic therapy. The pivaloyl moiety has a carnitine depleting effect, which has caused doubts about the safety of administering pivampicillin during pregnancy. The aim of the study was to evaluate the risk of congenital malformations in general, preterm delivery and low birth weight in users of pivampicillin. METHODS: Seven hundred and ninety-one women who had redeemed a prescription of pivampicillin during their first pregnancy from 1 January 1991 to 31 December 1996 were identified in the North Jutland Pharmaco-Epidemiological Prescription Database. By linkage to the Danish Medical Birth Registry and Regional Hospital Discharge Registry we compared their birth outcomes (malformations, preterm delivery and low birth weight) with the outcomes in 7472 reference pregnancies on which the mother had not redeemed any prescription at all during pregnancy. RESULTS: The prevalence of malformations was 5.5% (11 cases) in offspring of 199 women who had used pivampicillin during the first trimester, and 5.6% (420 cases) in offspring of controls (OR: 0.95, 95% CI: 0.51-1.76). Furthermore, we did not find any significant risk of preterm delivery (OR: 0.75, 95% CI: 0.54-1.05) or low birth weight (OR: 0.93, 95% CI: 0.55-1.57). CONCLUSION: This study showed no increased risk of congenital malformations, preterm delivery or low birth weight in offspring of women who had redeemed a prescription for pivampicillin during pregnancy.


Assuntos
Anormalidades Induzidas por Medicamentos/epidemiologia , Penicilinas/efeitos adversos , Pivampicilina/efeitos adversos , Resultado da Gravidez , Pró-Fármacos/efeitos adversos , Adolescente , Adulto , Dinamarca/epidemiologia , Feminino , Seguimentos , Humanos , Recém-Nascido de Baixo Peso , Recém-Nascido , Recém-Nascido Prematuro , Modelos Lineares , Análise Multivariada , Trabalho de Parto Prematuro/induzido quimicamente , Penicilinas/uso terapêutico , Pivampicilina/uso terapêutico , Gravidez , Prevalência , Pró-Fármacos/uso terapêutico
12.
Ugeskr Laeger ; 162(7): 936-9, 2000 Feb 14.
Artigo em Dinamarquês | MEDLINE | ID: mdl-10740436

RESUMO

Ciprofloxacin 500 mg orally twice daily was compared to pivampicillin 700 mg orally twice daily for 10 days in 172 men (41-85 years) with acute epididymitis. Failure of treatment occurred in 48 patients, in 15/76 (19.7%) receiving ciprofloxacin versus in 33/82 (40.2%) receiving pivampicillin (p = 0.006). Ciprofloxacin 500 mg orally twice daily is more effective than pivampicillin 700 mg orally twice daily and has fewer adverse events.


Assuntos
Anti-Infecciosos/uso terapêutico , Ciprofloxacina/uso terapêutico , Epididimite/tratamento farmacológico , Penicilinas/uso terapêutico , Pivampicilina/uso terapêutico , Doença Aguda , Administração Oral , Adulto , Idoso , Anti-Infecciosos/administração & dosagem , Ciprofloxacina/administração & dosagem , Método Duplo-Cego , Epididimite/microbiologia , Humanos , Masculino , Pessoa de Meia-Idade , Penicilinas/administração & dosagem , Pivampicilina/administração & dosagem , Estudos Prospectivos , Recidiva , Resultado do Tratamento
13.
BJU Int ; 84(7): 827-34, 1999 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-10532980

RESUMO

OBJECTIVE: To compare the efficacy and safety of ciprofloxacin 500 mg orally twice daily with pivampicillin 700 mg orally twice daily for 10 days in men with acute epididymitis and over 40 years of age. PATIENTS AND METHODS: The study comprised 172 men who entered a prospective, controlled, randomized, double-blind, trial of pivampicillin and ciprofloxacin. The median (range) age of the 158 patients eligible for the efficacy analysis was 58 (41-85) years; 41% had previously had a urinary tract infection and 27% had previously had epididymitis. Only one patient had a urethral catheter and 38% were sexually active. About half of the patients were admitted to hospital. RESULTS: No bacteria could be cultured from samples in 53% of the patients; Escherichia coli could be cultured from 35% and the remaining isolates were the expected urinary pathogens. None of the patients had Gonococci and only one in each group had Chlamydia. Mycoplasma hominis was detected in three patients only and M. genitalium was detected in three, while Ureaplasma was detected in 24 (15%). The treatment failed in 48 patients; in 15 of 76 (20%) receiving ciprofloxacin and in 33 of 82 (40%) receiving pivampicillin. This corresponds to a reduction in the risk of failure of 20.5% (95% confidence limits 6.6-40.2%, P=0. 006). The principal cause of failure was an unsatisfactory clinical response requiring changed antibiotic treatment in 27 patients; adverse events were responsible for failure in 14. The in vitro resistance of cultured bacteria was low in both groups, at approximately 4%. Adverse events, mainly gastro-intestinal, occurred in 17 of 83 (21%) patients starting on ciprofloxacin and in 33 of 89 (37%) receiving pivampicillin (P=0.04). CONCLUSION: For epididymitis in men over the age of 40 years ciprofloxacin 500 mg orally twice daily is more effective than pivampicillin 700 mg orally twice daily. Furthermore, ciprofloxacin has a lower incidence of adverse events.


Assuntos
Anti-Infecciosos/administração & dosagem , Ciprofloxacina/administração & dosagem , Epididimite/tratamento farmacológico , Penicilinas/administração & dosagem , Pivampicilina/administração & dosagem , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Método Duplo-Cego , Humanos , Masculino , Pessoa de Meia-Idade , Falha de Tratamento
14.
Curr Med Res Opin ; 15(4): 300-9, 1999.
Artigo em Inglês | MEDLINE | ID: mdl-10640263

RESUMO

A prospective, randomised, single-blind comparative trial was carried out to determine whether double beta-lactam treatment with pivampicillin plus pivmecillinam is more effective than pivampicillin alone in the treatment of recurrent and chronic lung infections with Haemophilus influenzae in patients with chronic obstructive pulmonary disease (COPD) or cystic fibrosis (CF). Fifty-six children and young adults with COPD or CF were randomised to the clinical study. The patients were allocated at random to receive perorally either pivmecillinam, 40 mg/kg/day, combined with pivampicillin, 50 mg/kg/day, or pivampicillin 50 mg/kg/day alone for 14 days. A cross-over pharmacokinetic study using the same drugs was carried out in 10 CF patients to determine the antibiotic concentrations in serum and sputum after a single dose of each drug. The clinical study showed no significant differences in clinical scoring, lung function tests or adverse events after treatment with pivampicillin plus pivmecillinam or pivampicillin alone. Follow-up microbiological evaluation 2 and 6 weeks after the end of treatment showed that the offending pathogen was eradicated in 68% of the patients treated with pivampicillin plus pivmecillinam and in 67% of the patients treated with pivampicillin alone. Reinfection with another biotype was more common in the combination group (50% vs. 21%) than in the pivampicillin group. In the pharmacokinetic study the median peak serum concentration occurred two hours after intake of tablets. The efficacy of double beta lactam treatment in lung infections with H. influenzae appears to be equivalent to that of ampicillin on clinical lung symptoms, lung function tests, adverse effects and bacteriology.


Assuntos
Andinocilina Pivoxil/uso terapêutico , Quimioterapia Combinada/uso terapêutico , Infecções por Haemophilus/tratamento farmacológico , Haemophilus influenzae , Pneumopatias Obstrutivas/tratamento farmacológico , Penicilinas/uso terapêutico , Pivampicilina/uso terapêutico , Adolescente , Adulto , Andinocilina Pivoxil/efeitos adversos , Andinocilina Pivoxil/farmacocinética , Criança , Pré-Escolar , Estudos Cross-Over , Quimioterapia Combinada/efeitos adversos , Quimioterapia Combinada/farmacocinética , Feminino , Infecções por Haemophilus/metabolismo , Infecções por Haemophilus/microbiologia , Humanos , Lactente , Pneumopatias Obstrutivas/metabolismo , Pneumopatias Obstrutivas/microbiologia , Masculino , Penicilinas/efeitos adversos , Penicilinas/farmacocinética , Pivampicilina/efeitos adversos , Pivampicilina/farmacocinética , Estudos Prospectivos , Método Simples-Cego
17.
Eur J Pediatr ; 156(10): 795-9, 1997 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-9365072

RESUMO

UNLABELLED: Ten children receiving pivampicillin for 8 days were studied. On the first 4 days the drug was given alone (4 x 500 mg/day), and on the last 4 days in combination with carnitine (4 x 1 g/day). Pivampicillin treatment was associated with formation and urinary excretion of pivaloylcarnitine and administration of carnitine aided the elimination of pivalate as its carnitine ester. The resting respiratory quotient increased from 0.86 +/- 0.01 to 0.96 +/- 0.01 on the 4th day of pivampicillin treatment. A shift was observed in the metabolic fuel consumption: a significant decrease was found in the amount of fats oxidized (0.31 +/- 0.17 vs 1.27 +/- 0.17 g x kg[-1] x 24 h[-1]). while the utilization of carbohydrates increased (6.20 +/- 0.51 vs 4.00 +/- 0.50 g kg[-1] x 24 h[-1]). Administration of carnitine decreased the respiratory quotient to 0.90 +/- 0.01 on the 8th day of treatment, consumption of fats increased, and the oxidation of carbohydrates decreased. The resting energy expenditure was not affected by the treatment. CONCLUSION: Pivampicillin treatment results in inhibited oxidation of fats as metabolic fuel. This drug effect was partially reversed by carnitine which promotes the elimination of the pivaloyl moiety from the body.


Assuntos
Carnitina/administração & dosagem , Metabolismo Energético/efeitos dos fármacos , Penicilinas/efeitos adversos , Faringite/tratamento farmacológico , Pivampicilina/efeitos adversos , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estreptocócicas/tratamento farmacológico , Adolescente , Calorimetria Indireta , Criança , Gorduras na Dieta/metabolismo , Quimioterapia Combinada , Feminino , Humanos , Masculino , Penicilinas/administração & dosagem , Pivampicilina/administração & dosagem
18.
Vet Rec ; 141(7): 172-4, 1997 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-9290196

RESUMO

Diagnostic imaging and treatment of unilateral destructive temporomandibular joint disease in two horses is described and discussed. Computed tomography appeared to be the best imaging technique for these lesions. The disease can be followed by functional recovery after the infection has resolved.


Assuntos
Doenças dos Cavalos/diagnóstico por imagem , Doenças dos Cavalos/tratamento farmacológico , Infecções por Proteus/veterinária , Proteus mirabilis , Infecções Estreptocócicas/veterinária , Transtornos da Articulação Temporomandibular/veterinária , Ampicilina/uso terapêutico , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Clonixina/análogos & derivados , Clonixina/uso terapêutico , Doenças dos Cavalos/microbiologia , Cavalos , Masculino , Penicilinas/uso terapêutico , Fenilbutazona/uso terapêutico , Pivampicilina/uso terapêutico , Infecções por Proteus/diagnóstico por imagem , Infecções por Proteus/tratamento farmacológico , Proteus mirabilis/isolamento & purificação , Infecções Estreptocócicas/diagnóstico por imagem , Infecções Estreptocócicas/tratamento farmacológico , Streptococcus/isolamento & purificação , Articulação Temporomandibular/diagnóstico por imagem , Articulação Temporomandibular/microbiologia , Articulação Temporomandibular/patologia , Transtornos da Articulação Temporomandibular/diagnóstico por imagem , Transtornos da Articulação Temporomandibular/tratamento farmacológico , Tomografia Computadorizada por Raios X/veterinária
20.
Metabolism ; 45(12): 1501-7, 1996 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-8969283

RESUMO

To study the effect of carnitine depletion on physical working capacity, healthy subjects were administered pivaloyl-conjugated antibiotics for 54 days. The mean carnitine concentration in serum decreased from 35.0 to 3.5 mmicromol/L, and in muscle from 10 to 4.3 micromol/g noncollagen protein (NCP). Exercise tests were performed before and after 54 days' administration of the drug. At submaximal exercise, there was a slight increase in the concentration of 3-hydroxybutyrate in serum, presumably caused by decreased fatty acid oxidation in the liver. There was also a decreased consumption of muscle glycogen, indicating decreased glycolysis in the skeletal muscle. The muscle presumably had enough energy available, since there was no significant decrease in the concentration of adenosine triphosphate (ATP) and creatine phosphate during exercise. The work at maximal oxygen uptake (VO2max) and the maximal heart rate were reduced. Since VO2max is considered dependent on heart function, carnitine depletion seemed to affect cardiac function.


Assuntos
Andinocilina Pivoxil/efeitos adversos , Carnitina/deficiência , Exercício Físico , Pivampicilina/efeitos adversos , Adolescente , Adulto , Andinocilina Pivoxil/química , Glicemia/metabolismo , Ácidos Graxos não Esterificados/sangue , Feminino , Glicogênio/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Ácidos Pentanoicos/efeitos adversos , Pivampicilina/química , Triglicerídeos/sangue
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