RESUMO
Acyclovir (ACV) is almost entirely eliminated by the kidneys and has a terminal plasma half-life (t1/2) of 2 to 3 hr in subjects with normal renal function. To determine the drug's kinetics and tolerance in patients with severe renal failure, six anuric subjects on long-term hemodialysis were studied. Each received a 1-hr infusion of 2.5 mg/kg IV ACV. The kinetics are well described by a two-compartment open model. ACV terminal plasma t 1/2 and the total body clearance were 19.5 +/- 5.9 hr (mean +/- SD) and 28.6 +/- 9.5 ml/min/1.73 m2. Peak (end of infusion) and 8- and 24-hr plasma ACV concentrations were 37.5 +/- 23.3, 10.3 +/- 2.9, and 6.4 +/- 2.4 microM. Approximately 48 hr after the start of the infusion the subjects were hemodialyzed for 6 hr. The pre- and posthemodialysis ACV plasma levels were 2.74 +/- 1.38 and 1.11 +/- 0.60 microM. The terminal ACV t1/2 during hemodialysis was 5.7 +/- 0.85 hr. During hemodialysis paired arterial and venous samples showed that ACV was readily dialyzed, with a mean coefficient of extraction of 0.45 +/- 0.12. The dialysis clearance of acyclovir was 81.8 +/- 12.6 ml/min. None of the patients had any ACV-related adverse effects. Since ACV elimination is markedly reduced in end-stage renal failure and because ACV is readily hemodialyzible, dosage modification are needed to avoid cumulation and to replace dialyzed drug.
Assuntos
Antivirais/metabolismo , Guanina/análogos & derivados , Falência Renal Crônica/metabolismo , Aciclovir , Adulto , Idoso , Antivirais/efeitos adversos , Antivirais/sangue , Feminino , Guanina/efeitos adversos , Guanina/sangue , Guanina/metabolismo , Humanos , Cinética , Masculino , Pessoa de Meia-Idade , Diálise Renal , Fatores de TempoRESUMO
The disposition and safety of the antiviral drug acyclovir were studied in 14 subjects with advanced malignancies. Acyclovir was administered by a 1-hr intravenous infusion at doses of 0.5, 1.0, 2.5, and 5.0 mg/kg. At the end of infusion, mean peak plasma levels (+/- SEM), determined by radioimmunoassay, were 6.4 +/- 0.7, 12.1 +/- 2.3, 14.9 +/- 2.7, and 33.7 +/- 7.1 microM. The plasma concentration-time profiles could be described by a biexponential equation. The half-life of acyclovir in the slow disposition phase ranged from 2.2 to 5 hr and the drug was detected in the plasma for at least 18 hr after infusion. The total body clearance ranged from 117 to 396 ml/min/1.73 m2. A proportionality between area under the curve and dose suggests that acyclovir exhibits dose-independent kinetics in the dose range studied. There was wide variation in cumulative urinary excretion of unchanged drug, ranging from 30 to 69% of the dose. From renal clearances of acyclovir, which were higher than creatinine clearances, it appears that both glomerular filtration and tubular secretion contribute to its renal excretion. Analysis of the urine by reverse-phase high-performance liquid chromatography revealed the presence of the metabolite 9-carboxymethoxymethylguanine. There was no indication of toxicity either clinically or from laboratory findings in any of the study subjects. This study demonstrates that in addition to selectivity and low toxicity, the kinetic profile and metabolic disposition of acyclovir make it an attractive candidate for therapy in a variety of herpes infections.
Assuntos
Antivirais/sangue , Guanina/análogos & derivados , Idoso , Antivirais/urina , Avaliação de Medicamentos , Feminino , Guanina/sangue , Guanina/urina , Meia-Vida , Infecções por Herpesviridae/tratamento farmacológico , Humanos , Cinética , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológicoRESUMO
Acyclovir tolerance has been explored in a broad range of human populations and dosage regimens with intravenous, topical, and oral formulations. Phase I pharmacokinetic/tolerance studies assured safety in special populations at unique risk of complicated herpes infections who were simultaneously at increased risk of toxicity to anti-DNA chemotherapeutic agents. Further safety evaluations accompanied placebo-controlled Phase II studies in infected patients who represent future users of acyclovir. These studies confirm acyclovir as the safest antiherpes agent to be explored in clinical studies to date.
Assuntos
Antivirais/efeitos adversos , Guanina/análogos & derivados , Herpes Simples/tratamento farmacológico , Infecções por Herpesviridae/tratamento farmacológico , Aciclovir , Adulto , Antivirais/administração & dosagem , Transplante de Medula Óssea , Criança , Pré-Escolar , Creatinina/sangue , Avaliação de Medicamentos , Feminino , Guanina/administração & dosagem , Guanina/efeitos adversos , Herpes Genital/tratamento farmacológico , Humanos , Lactente , Recém-Nascido , Transplante de Rim , MasculinoRESUMO
The pharmacokinetics of acyclovir administrated orally in a dose of 200 mg every four hours, five times a day to adults with herpes progenitalis was determined. Peak plasma acyclovir levels are found 1.5 to 1.75 hours after oral administration; peak levels range from 1.4 to 4.0 microM with a mean of 2.5 microM. Acyclovir levels in saliva are well correlated with simultaneous plasma levels, saliva levels being approximately 13 percent of plasma levels. Simultaneous plasma and vaginal secretion acyclovir levels are poorly correlated; peak levels in vaginal secretions range from 0.5 to 3.6 microM.
Assuntos
Antivirais/metabolismo , Guanina/análogos & derivados , Herpes Genital/tratamento farmacológico , Aciclovir , Administração Oral , Adulto , Feminino , Guanina/metabolismo , Humanos , Cinética , Masculino , Recidiva , Saliva/análise , Distribuição Tecidual , Vagina/metabolismoRESUMO
Sixteen immunocompromised patients with herpes virus infections were treated for three to five days with continuously administered intravenous acyclovir. Patients received initial acyclovir infusions over 5 minutes in dosages ranging from 1.5 to 5.0 mg/kg followed by continuously infused acyclovir at 7.2, 14.4, 21.6, 28.8, 36.0, or 43.2 mg/kg per day. The mean serum plateau levels of acyclovir determined by radioimmunoassay ranged from 4.1 microM for the 7.2 mg/kg per day dosage to 36.6 microM for the 43.2 mg/kg per day dose. A mean of 75 percent of acyclovir administered was recovered in the urine of patients treated. Eleven of 13 patients with varicella-zoster virus (VZV) infections had no new vesicle formation after three days of acyclovir treatment and all patients ceased to have new vesicles after five days of therapy. For the nine patients from whom complete viral cultures were available, six ceased to shed virus at three days, and viral shedding ceased by five days in all patients treated with acyclovir. No clinical or laboratory adverse reactions were associated with acyclovir therapy. These data suggest that acyclovir given by continuous intravenous infusion may be useful in the treatment of herpes virus infections in immunocompromised patients.
Assuntos
Antivirais/administração & dosagem , Guanina/análogos & derivados , Infecções por Herpesviridae/tratamento farmacológico , Tolerância Imunológica , Aciclovir , Adolescente , Adulto , Idoso , Antivirais/efeitos adversos , Antivirais/metabolismo , Avaliação de Medicamentos , Feminino , Guanina/administração & dosagem , Guanina/efeitos adversos , Guanina/metabolismo , Herpes Simples/tratamento farmacológico , Herpes Zoster/tratamento farmacológico , Humanos , Infusões Parenterais , Cinética , Masculino , Pessoa de Meia-IdadeRESUMO
A preliminary analysis is presented of the pharmacokinetics of acyclovir in neonatal patients with herpes simplex virus infections. Mean peak acyclovir levels (microM +/- SD) at 5, 10, and 15 mg/kg per dose were 30.0 +/- 9.9, 61.2 +/- 18.3, and 86.1 +/- 23.5, with corresponding mean trough levels (microM +/- SD) of 5.3 +/- 3.4, 10.1 +/- 8.4, and 13.8 +/- 11.1, respectively. The mean half-life (t 1/2 beta) of acyclovir was 3.78 +/- 1.21 hours. The mean percent urinary recovery of acyclovir (+/- SD) at each dosage level was similar, with an overall mean recovery of 65 percent. The mean acyclovir concentration in urine did not exceed the solubility of acyclovir in bladder urine (1,300 micrograms/ml). Generally, neonatal acyclovir pharmacokinetics was consistent with previous reports from studies of adults.
Assuntos
Antivirais/metabolismo , Guanina/análogos & derivados , Infecções por Herpesviridae/metabolismo , Doenças do Recém-Nascido/metabolismo , Aciclovir , Antivirais/administração & dosagem , Infecções por Citomegalovirus/metabolismo , Guanina/administração & dosagem , Guanina/metabolismo , Herpes Simples/metabolismo , Humanos , Lactente , Recém-Nascido , Infusões Parenterais , CinéticaRESUMO
Sixty-nine patients with first episodes and 111 with recurrent episodes of genital herpes simplex virus (HSV) infection were enrolled in a double-blind trial comparing a 5 percent topical acyclovir ointment versus placebo, polyethylene glycol (PEG). Among acyclovir recipients with first episodes of genital herpes, the mean duration of viral shedding from genital lesions, 2.0 days, mean duration of local pain or itching, 3.6 days, and mean time to healing of lesions, 11.2 days, were less than in placebo recipients 4.6, 6.7, and 15.8 days, respectively (p less than 0.05 for each comparison). Among patients with recurrent genital herpes, the mean duration of viral shedding from genital lesions was 0.8 days in acyclovir recipients compared with 1.7 days in placebo recipients (p less than 0.001). Among men with recurrent genital herpes, the mean time to crusting and healing of lesions was 3.5 and 7.5 days in acyclovir recipients compared with 5.0 and 9.7 days in placebo recipients, p = 0.03 and 0.07, respectively. No significant differences in the duration of symptoms or healing times were noted between acyclovir- and placebo-treated women with recurrent genital herpes. Acyclovir therapy was not associated with a decrease in frequency of clinical recurrences or an increase in the time of the next recurrence in patients with either first or recurrent genital herpes. Topical acyclovir appears effective in shortening some of the clinical manifestations of genital HSV infections.
Assuntos
Antivirais/uso terapêutico , Guanina/análogos & derivados , Herpes Genital/tratamento farmacológico , Aciclovir , Administração Tópica , Adulto , Antivirais/metabolismo , Ensaios Clínicos como Assunto , Método Duplo-Cego , Feminino , Guanina/metabolismo , Guanina/uso terapêutico , Humanos , Masculino , Recidiva , Fatores de Tempo , Vagina/análiseRESUMO
Forty-eight children, 1 month to 14 years of age, including 11 patients with untreated acute osteomyelitis, 8 with pretreated acute osteomyelitis, 12 with septic arthritis, and 11 with cellulitis or soft tissue abscess, were treated with clindamycin. Staphylococcus aureus was isolated from the blood, synovial fluid, bone, or soft tissues of 27 of these individuals while group A, beta-hemolytic streptococci or Clostridia were isolated from 9 patients. Clindamycin was provided intravenously until patients were afebrile for three days followed by orally administered clindamycin for one week in patients with cellulitis to as long as six months in patients with chronic osteomyelitis. Clinical and bacteriologic responses to treatment generally were excellent, most likely reflecting the excellent serum and tissue concentrations of clindamycin which were achieved. Serum concentrations of clindamycin following intravenous infusion at 20 to 30 mg/kg/day in three divided doses were 8- to 32-fold in excess of the minimal inhibitory concentrations of all organisms isolated in this study. Bone and synovial fluid concentrations of clindamycin were 60% to 85% of the serum concentrations measured concomitantly. Clindamycin provides an effective alternative treatment of osteomyelitis and septic arthritis in children who are sensitive to penicillin.
Assuntos
Artrite Infecciosa/tratamento farmacológico , Clindamicina/uso terapêutico , Infecções por Clostridium/tratamento farmacológico , Osteomielite/tratamento farmacológico , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estreptocócicas/tratamento farmacológico , Abscesso/tratamento farmacológico , Abscesso/microbiologia , Adolescente , Artrite Infecciosa/microbiologia , Celulite (Flegmão)/tratamento farmacológico , Celulite (Flegmão)/microbiologia , Criança , Pré-Escolar , Clindamicina/administração & dosagem , Clindamicina/sangue , Clostridium/isolamento & purificação , Avaliação de Medicamentos , Seguimentos , Humanos , Lactente , Osteomielite/microbiologia , Staphylococcus/isolamento & purificação , Streptococcus/isolamento & purificaçãoRESUMO
Disseminated varicella-zoster (V-Z) infection developed in three immunocompromised patients, with direct invasion of the central nervous system by virus. For two of these patients, diagnosis was confirmed by electron microscopic examination of cerebrospinal fluid (CSF) and detection of viral particles. Extensive immunologic evaluation demonstrated impairment of cellular immune function. All were treated with acyclovir at a dose of 1,500 mg/m2/day for 5-7 days. Peak and trough plasma levels of this antiviral agent were monitored during the course of therapy and were shown to be well above V-Z virustatic levels. Clinical response was noted by the third day of therapy. Vesicles and CSF were culture negative at termination of treatment. Administration of this high dose of acyclovir was not associated with hematologic, immunologic, hepatic, renal, or gastrointestinal toxicity as judged by frequent laboratory and clinical evaluation.
Assuntos
Aciclovir/uso terapêutico , Líquido Cefalorraquidiano/microbiologia , Herpes Zoster/tratamento farmacológico , Herpesvirus Humano 3/isolamento & purificação , Meningoencefalite/tratamento farmacológico , Adulto , Capsídeo , Criança , Pré-Escolar , Feminino , Herpesvirus Humano 3/ultraestrutura , Humanos , Masculino , Meningoencefalite/microbiologia , Microscopia EletrônicaRESUMO
The antistaphylococcal properties of orally administered minocycline and penicillin-V were compared for one hundred and fifteen patients receiving minocycline and one hundred and twenty-eight receiving penicillin-V for various types of cutaneous infections. The majority of bacterial isolates were staphylococcal organisms. Of these 82 percent showed initial in vitro sensitivity to minocycline while only 20 percent did to penicillin-V. The percentage of clinical cures was higher with minocycline (74 percent) than with penicillin-V (54 percent), however, most patients, in both groups, showed clinical improvement. The rate of clinical improvement appeared to be significantly faster with minocycline. There was a higher percentage of adverse, chiefly vestibular, effects in the minocycline group (16 percent vs 7 percent). The study clearly demonstrates the superior antistaphylococcal properties of minocycline as compared with penicillin-V.
Assuntos
Minociclina/uso terapêutico , Penicilina V/uso terapêutico , Dermatopatias Infecciosas/tratamento farmacológico , Infecções Estafilocócicas/tratamento farmacológico , Tetraciclinas/uso terapêutico , Adolescente , Adulto , Idoso , Criança , Ensaios Clínicos como Assunto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Minociclina/efeitos adversos , Resistência às Penicilinas , Penicilina V/efeitos adversos , Dermatopatias Infecciosas/microbiologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/isolamento & purificaçãoAssuntos
Antibacterianos/uso terapêutico , Infecções Bacterianas/tratamento farmacológico , Sulfato de Butirosina/uso terapêutico , Adulto , Idoso , Sulfato de Butirosina/administração & dosagem , Sulfato de Butirosina/metabolismo , Ensaios Clínicos como Assunto , Tolerância a Medicamentos , Infecções por Escherichia coli/tratamento farmacológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infecções por Proteus/tratamento farmacológico , Infecções por Pseudomonas/tratamento farmacológico , Fatores de Tempo , Infecções Urinárias/tratamento farmacológicoAssuntos
Aciclovir/uso terapêutico , Herpes Simples/tratamento farmacológico , Herpes Zoster/tratamento farmacológico , Aciclovir/administração & dosagem , Aciclovir/toxicidade , Administração Oral , Administração Tópica , Animais , Ensaios Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos , Tolerância a Medicamentos , Humanos , Injeções Intravenosas , Cinética , Simplexvirus/efeitos dos fármacosAssuntos
Antibacterianos/uso terapêutico , Resistência às Penicilinas , Pirrolidinas/uso terapêutico , Infecções Estafilocócicas/tratamento farmacológico , Antibacterianos/farmacologia , Criança , Pré-Escolar , Eritromicina/farmacologia , Furunculose/tratamento farmacológico , Glicosídeos/farmacologia , Glicosídeos/uso terapêutico , Humanos , Impetigo/tratamento farmacológico , Lactente , Lincomicina/uso terapêutico , Masculino , Testes de Sensibilidade Microbiana , Penicilinas/farmacologia , Pneumonia Estafilocócica/tratamento farmacológico , Pirrolidinas/farmacologia , Infecções Estafilocócicas/microbiologia , Staphylococcus/efeitos dos fármacos , Tetraciclina/farmacologiaRESUMO
The epidemiology, clinical course, diagnosis, and attempted treatments of herpes genitalis are reviewed. Herpes genitalis is an increasingly common sexually transmitted disease for which there is no effective treatment. It can occur in either sex and is mot commonly first found in patients 14 to 29 years old. Initial exposure to the virus may result in prolonged local symptoms (pain, itching, discharge) and signs (ulcerative lesions) as well as fever, malaise, myalgias, and fatigue. After the initial exposure, the virus may be found in a latent stage in the dorsal nerve root ganglia in the sacral area, and recurrences of disease may ensue. The frequency and clinical course of recurrent genital herpes can be of varying duration and severity. Although antiviral substances, immune potentiators, topical surfactants, and photodynamic inactivation have been used to treat genital herpes infections, there is no proven effective therapy.
Assuntos
Doenças dos Genitais Femininos/tratamento farmacológico , Doenças dos Genitais Masculinos/tratamento farmacológico , Herpes Simples/tratamento farmacológico , Adolescente , Adulto , Idoso , Antivirais/uso terapêutico , Ensaios Clínicos como Assunto , Feminino , Doenças dos Genitais Femininos/patologia , Doenças dos Genitais Masculinos/patologia , Herpes Simples/diagnóstico , Herpes Simples/patologia , Humanos , Masculino , Pessoa de Meia-Idade , RecidivaRESUMO
A randomized double-blind, placebo-controlled, multicenter investigation assessed the usefulness of acyclovir in the treatment of immunosuppressed children with chickenpox. Twelve patients received placebo and eight received acyclovir. If the event of clinical deterioration, patients could be removed from the study to receive acyclovir. Eighteen patients had skin lesions within 96 hours of admission to the study. Nineteen patients had malignancies. The two groups of patients were similar in age, in concomitant or preceding immunosuppressive therapy, in status of malignancy, and in presenting granulocyte and lymphocyte counts. Zoster immune globulin or plasma had been given to 50% of the placebo group but to only 25% of the acyclovir group. One patient in each group had pneumonitis at entry. Of the patients without pneumonitis at entry, five of the 11 placebo patients compared with none of the seven acyclovir patients developed pneumonitis during treatment (P = 0.054). No evidence of toxicity related to acyclovir was observed.
Assuntos
Aciclovir/uso terapêutico , Varicela/tratamento farmacológico , Terapia de Imunossupressão , Varicela/complicações , Criança , Ensaios Clínicos como Assunto , Método Duplo-Cego , Feminino , Humanos , Imunização Passiva , Masculino , Neoplasias/complicações , Distribuição AleatóriaRESUMO
In vitro lymphocyte blastogenic responses to the commonly employed mitogens phytohemagglutinin, pokeweed, and concanavalin A were evaluated when acyclovir, adenine arabinoside, cytosine arabinoside, and idoxuridine were added to the culture materials. Similarly, specific antigen-induced blastogenic responses, including herpes group antigens, and cytotoxicity and leukocyte inhibitory factor assays with herpes group viruses were determined in the presence and absence of antiviral agents. No depression of these cellular immmune responses by acyclovir or adenine arabinoside ws demonstrated. This was in contrast to the effects of cytosine arabinoside and idoxuridine, which severely inhibited blastogenic and cytotoxic responses but not leukocyte inhibitory factor production. Even at concentrations up to 20 microgram/ml, the antiviral agent acyclovir did not depress selected cellular immune responses that are important for successful elimination of invading herpes group viruses.
Assuntos
Antivirais/farmacologia , Citotoxicidade Imunológica/efeitos dos fármacos , Guanina/análogos & derivados , Fatores Inibidores da Migração de Leucócitos/biossíntese , Ativação Linfocitária/efeitos dos fármacos , Linfocinas/biossíntese , Aciclovir , Linhagem Celular , Citarabina/farmacologia , Citomegalovirus/imunologia , Guanina/farmacologia , Herpesvirus Humano 3/imunologia , Humanos , Idoxuridina/farmacologia , Linfócitos/imunologia , Simplexvirus/imunologia , Vidarabina/farmacologiaRESUMO
The in vitro activity of gentamicin, tobramycin, kanamycin, and amikacin in combination with ampicillin was determined against aminoglycoside-resistant group B streptococci. Synergy in each combination was determined by quantitative kill curves and demonstrated in all the combinations tested.
Assuntos
Ampicilina/farmacologia , Antibacterianos/farmacologia , Streptococcus agalactiae/efeitos dos fármacos , Aminoglicosídeos/farmacologia , Sinergismo FarmacológicoRESUMO
Thirteen patients severely infected with herpesvirus were treated with intravenous adenine arabinoside (ara-A), and two patients received placebo therapy. Blastogenic and cytotoxic responses specific for the virus infecting each patient were determined before, during, and after treatment. Blastogenic responses to three mitogens (phytohemagglutinin, pokeweed, and concanavalin-A) were examined, as were titers of viral antibody. In vitro responses during and after treatment with ara-A were unchanged or often enhanced as compared with values before treatment. Newborn infants, presumably infected at or shortly before birth, did not demonstrate cellular immune reactivity to the infecting virus until after four days of life. In this series of patients, prognosis appeared to be in part determined by the cellular immune competence of the host at the time of infection.