RESUMEN
Nafamostat mesylate (NM) affects coagulation and fibrinolysis and impedes obesity-associated protein demethylase activity, which regulates Na+/K+ transport properties and the NF-κB signaling pathway. NM significantly decreases macrophage, neutrophil, and T lymphocyte infiltration, thereby reducing inflammation and apoptosis after reperfusion and promoting recovery in patients with severe conditions such as near-fatal asthma and cardiac arrest. Extracorporeal life support (ECLS) devices are used for cardiac and/or pulmonary support as a bridge to recovery, decision, surgery, or transplant in patients with refractory cardio-circulatory or respiratory diseases and provide essential opportunities for organ support and patient survival. However, they can lead to some potential adverse events such as hemorrhage and thrombosis. NM provides a sustained innate immune response of coagulation and anti-inflammation in extracorporeal circuits, principally due to its activation of the contact and complement systems. Heparin is the main anticoagulant used in extracorporeal circuits; however, it may cause massive bleeding and heparin-induced thrombocytopenia. Although no antidote is available, NM has a very short half-life of approximately 8-10 min and might have positive effects on patients who require coagulation and anti-inflammation. NM has been used for anticoagulation in continuous renal replacement therapy, extracorporeal membrane oxygenation, hemodialysis, and left ventricular assist devices. In this review, we focused on the pharmacology, monitoring parameters, and considerations for the special use of NM in patients receiving ECLS. Our findings suggest that systemic anticoagulation with NM during ECLS might be a feasible and safe alternative with several advantages for critically ill patients with high-risk bleeding and might improve their prognosis.
Asunto(s)
Oxigenación por Membrana Extracorpórea , Anticoagulantes/efectos adversos , Benzamidinas/efectos adversos , Coagulación Sanguínea , Oxigenación por Membrana Extracorpórea/efectos adversos , Guanidinas , Hemorragia/etiología , Heparina/efectos adversos , HumanosRESUMEN
BACKGROUND: Many repurposed drugs have progressed rapidly to Phase 2 and 3 trials in COVID19 without characterisation of Pharmacokinetics /Pharmacodynamics including safety data. One such drug is nafamostat mesylate. METHODS: We present the findings of a phase Ib/IIa open label, platform randomised controlled trial of intravenous nafamostat in hospitalised patients with confirmed COVID-19 pneumonitis. Patients were assigned randomly to standard of care (SoC), nafamostat or an alternative therapy. Nafamostat was administered as an intravenous infusion at a dose of 0.2 mg/kg/h for a maximum of seven days. The analysis population included those who received any dose of the trial drug and all patients randomised to SoC. The primary outcomes of our trial were the safety and tolerability of intravenous nafamostat as an add on therapy for patients hospitalised with COVID-19 pneumonitis. FINDINGS: Data is reported from 42 patients, 21 of which were randomly assigned to receive intravenous nafamostat. 86% of nafamostat-treated patients experienced at least one AE compared to 57% of the SoC group. The nafamostat group were significantly more likely to experience at least one AE (posterior mean odds ratio 5.17, 95% credible interval (CI) 1.10 - 26.05) and developed significantly higher plasma creatinine levels (posterior mean difference 10.57 micromol/L, 95% CI 2.43-18.92). An average longer hospital stay was observed in nafamostat patients, alongside a lower rate of oxygen free days (rate ratio 0.55-95% CI 0.31-0.99, respectively). There were no other statistically significant differences in endpoints between nafamostat and SoC. PK data demonstrated that intravenous nafamostat was rapidly broken down to inactive metabolites. We observed no significant anticoagulant effects in thromboelastometry. INTERPRETATION: In hospitalised patients with COVID-19, we did not observe evidence of anti-inflammatory, anticoagulant or antiviral activity with intravenous nafamostat, and there were additional adverse events. FUNDING: DEFINE was funded by LifeArc (an independent medical research charity) under the STOPCOVID award to the University of Edinburgh. We also thank the Oxford University COVID-19 Research Response Fund (BRD00230).
Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Benzamidinas/uso terapéutico , Tratamiento Farmacológico de COVID-19 , Guanidinas/uso terapéutico , Administración Intravenosa , Adulto , Anciano , Anciano de 80 o más Años , Antiinflamatorios no Esteroideos/farmacocinética , Benzamidinas/efectos adversos , Benzamidinas/farmacocinética , Biomarcadores/sangre , Biomarcadores/metabolismo , COVID-19/mortalidad , COVID-19/virología , Esquema de Medicación , Femenino , Guanidinas/efectos adversos , Guanidinas/farmacocinética , Semivida , Humanos , Inmunofenotipificación , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , SARS-CoV-2/aislamiento & purificación , SARS-CoV-2/fisiología , Resultado del Tratamiento , Carga ViralAsunto(s)
Antiinfecciosos/efectos adversos , Hipersensibilidad Tardía/inducido químicamente , Hipersensibilidad Inmediata/inducido químicamente , Administración Intranasal , Administración Tópica , Anciano , Benzamidinas/administración & dosificación , Benzamidinas/efectos adversos , Diagnóstico Diferencial , Humanos , Masculino , Pruebas CutáneasRESUMEN
BACKGROUND: Continuous regional arterial infusion (CRAI) of protease inhibitor nafamostat mesilate (NM) is used in the context of predicted severe acute pancreatitis (SAP) to prevent the development of pancreatic necrosis. Although this therapy is well known in Japan, its efficacy and safety remain unclear. METHODS: This investigator-initiated and -driven, multicenter, open-label, randomized, controlled trial (UMIN000020868) enrolled 39 patients with predicted SAP and low enhancement of the pancreatic parenchyma on computed tomography (CT). Twenty patients were assigned to the CRAI group, while 19 served as controls and were administered NM at the same dose intravenously (IV group). The primary endpoint was the development of pancreatic necrosis as determined by CT on Day 14, judged by blinded central review. RESULTS: There was no difference between the CRAI and IV groups regarding the percentages of participants who developed pancreatic necrosis (more than 1/3 of the pancreas: 25.0%, range 8.7-49.1% vs. 15.8%, range 3.4-39.6%, respectively, P = 0.694; more than 2/3 of the pancreas: 20%, range 5.7-43.7% vs. 5.3%, range 0.1-26.0%, respectively, P = 0.341). The early analgesic effect was evaluated based on 24-h cumulative fentanyl consumption and additional administration by intravenous patient-controlled analgesia. The results showed that the CRAI group used significantly less analgesic. There were two adverse events related to CRAI, namely bleeding and splenic infarction. CONCLUSIONS: CRAI with NM did not inhibit the development of pancreatic necrosis although early analgesic effect of CRAI was superior to that of IV. Less-invasive IV therapy can be considered a viable alternative to CRAI therapy.
Asunto(s)
Benzamidinas/administración & dosificación , Guanidinas/administración & dosificación , Pancreatitis Aguda Necrotizante/prevención & control , Pancreatitis/tratamiento farmacológico , Inhibidores de Proteasas/administración & dosificación , Administración Intravenosa , Adulto , Anciano , Benzamidinas/efectos adversos , Femenino , Guanidinas/efectos adversos , Humanos , Infusiones Intraarteriales , Japón , Masculino , Persona de Mediana Edad , Pancreatitis/complicaciones , Pancreatitis Aguda Necrotizante/diagnóstico por imagen , Inhibidores de Proteasas/efectos adversos , Índice de Severidad de la Enfermedad , Tomografía Computarizada por Rayos X , Resultado del Tratamiento , Adulto JovenRESUMEN
A 31-year-old woman presented with mild keratitis of her left eye. The use of daily disposable contact lenses, regularly rinsed with tap water, and the development of perineural corneal infiltrates resulted in the clinical suspicion of infection with Acanthamoeba. Corneal epithelial scraping probe for polymerase chain reaction on Acanthamoeba confirmed the clinical diagnosis. Although the treatment was limited to low-dose propamidine monotherapy because of reduced tolerability, the keratitis healed with almost no scarring after 13 months of consequent medication.
Asunto(s)
Queratitis por Acanthamoeba/tratamiento farmacológico , Antiprotozoarios/uso terapéutico , Benzamidinas/uso terapéutico , Biguanidas/uso terapéutico , Complicaciones del Embarazo/tratamiento farmacológico , Queratitis por Acanthamoeba/diagnóstico , Adulto , Benzamidinas/efectos adversos , Biguanidas/efectos adversos , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Embarazo , Complicaciones del Embarazo/diagnóstico , Resultado del TratamientoRESUMEN
BACKGROUND: Sleeping sickness (human African trypanosomiasis [HAT]) is caused by protozoan parasites and characterized by a chronic progressive course, which may last up to several years before death. We conducted two Phase 2 studies to determine the efficacy and safety of oral pafuramidine in African patients with first stage HAT. METHODS: The Phase 2a study was an open-label, non-controlled, proof-of-concept study where 32 patients were treated with 100 mg of pafuramidine orally twice a day (BID) for 5 days at two trypanosomiasis reference centers (Angola and the Democratic Republic of the Congo [DRC]) between August 2001 and November 2004. The Phase 2b study compared pafuramidine in 41 patients versus standard pentamidine therapy in 40 patients. The Phase 2b study was open-label, parallel-group, controlled, randomized, and conducted at two sites in the DRC between April 2003 and February 2007. The Phase 2b study was then amended to add an open-label sequence (Phase 2b-2), where 30 patients received pafuramidine for 10 days. The primary efficacy endpoint was parasitologic cure at 24 hours (Phase 2a) or 3 months (Phase 2b) after treatment completion. The primary safety outcome was the rate of occurrence of World Health Organization Toxicity Scale Grade 3 or higher adverse events. All subjects provided written informed consent. FINDINGS/CONCLUSION: Pafuramidine for the treatment of first stage HAT was comparable in efficacy to pentamidine after 10 days of dosing. The cure rates 3 months post-treatment were 79% in the 5-day pafuramidine, 100% in the 7-day pentamidine, and 93% in the 10-day pafuramidine groups. In Phase 2b, the percentage of patients with at least 1 treatment-emergent adverse event was notably higher after pentamidine treatment (93%) than pafuramidine treatment for 5 days (25%) and 10 days (57%). These results support continuation of the development program for pafuramidine into Phase 3.
Asunto(s)
Antiprotozoarios/administración & dosificación , Antiprotozoarios/efectos adversos , Benzamidinas/administración & dosificación , Benzamidinas/efectos adversos , Tripanosomiasis Africana/tratamiento farmacológico , Administración Oral , Adolescente , Adulto , Angola , República Democrática del Congo/epidemiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pentamidina/administración & dosificación , Pentamidina/efectos adversos , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Sleeping sickness (human African trypanosomiasis [HAT]) is a neglected tropical disease with limited treatment options that currently require parenteral administration. In previous studies, orally administered pafuramidine was well tolerated in healthy patients (for up to 21 days) and stage 1 HAT patients (for up to 10 days), and demonstrated efficacy comparable to pentamidine. METHODS: This was a Phase 3, multi-center, randomized, open-label, parallel-group, active control study where 273 male and female patients with first stage Trypanosoma brucei gambiense HAT were treated at six sites: one trypanosomiasis reference center in Angola, one hospital in South Sudan, and four hospitals in the Democratic Republic of the Congo between August 2005 and September 2009 to support the registration of pafuramidine for treatment of first stage HAT in collaboration with the United States Food and Drug Administration. Patients were treated with either 100 mg of pafuramidine orally twice a day for 10 days or 4 mg/kg pentamidine intramuscularly once daily for 7 days to assess the efficacy and safety of pafuramidine versus pentamidine. Pregnant and lactating women as well as adolescents were included. The primary efficacy endpoint was the combined rate of clinical and parasitological cure at 12 months. The primary safety outcome was the frequency and severity of adverse events. The study was registered on the International Clinical Trials Registry Platform at www.clinicaltrials.gov with the number ISRCTN85534673. FINDINGS/CONCLUSIONS: The overall cure rate at 12 months was 89% in the pafuramidine group and 95% in the pentamidine group; pafuramidine was non-inferior to pentamidine as the upper bound of the 95% confidence interval did not exceed 15%. The safety profile of pafuramidine was superior to pentamidine; however, 3 patients in the pafuramidine group had glomerulonephritis or nephropathy approximately 8 weeks post-treatment. Two of these events were judged as possibly related to pafuramidine. Despite good tolerability observed in preceding studies, the development program for pafuramidine was discontinued due to delayed post-treatment toxicity.
Asunto(s)
Benzamidinas/administración & dosificación , Benzamidinas/efectos adversos , Pentamidina/administración & dosificación , Pentamidina/efectos adversos , Tripanosomiasis Africana/tratamiento farmacológico , Administración Oral , Adolescente , Adulto , Anciano , Angola , Niño , República Democrática del Congo , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Femenino , Humanos , Inyecciones Intramusculares , Enfermedades Renales/inducido químicamente , Enfermedades Renales/patología , Masculino , Persona de Mediana Edad , Embarazo , Sudán , Resultado del Tratamiento , Trypanosoma brucei gambiense , Adulto JovenRESUMEN
Abstract: BACKGROUND: There have been few studies on pentamidine in the Americas; and there is no consensus regarding the dose that should be applied. OBJECTIVES: To evaluate the use of pentamidine in a single dose to treat cutaneous leishmaniasis. METHODS: Clinical trial of phase II pilot study with 20 patients. Pentamidine was used at a dose of 7 mg/kg, in a single dose. Safety and adverse effects were also assessed. Patients were reviewed one, two, and six months after the end of treatments. RESULTS: there was no difference between the treatment groups in relation to gender, age, number or location of the lesions. Pentamidine, applied in a single dose, obtained an effectiveness of 55%. Mild adverse events were reported by 17 (85%) patients, mainly transient pain at the site of applications (85%), while nausea (5%), malaise (5%) and dizziness (5%) were reported in one patient. No patient had sterile abscess after taking medication at a single dose of 7mg/kg. CONCLUSIONS: Clinical studies with larger samples of patients would enable a better clinical response of pent amidine at a single dose of 7mg, allowing the application of more powerful statistical tests, thus providing more evidences of the decrease in the effectiveness of that medication. Hence, it is important to have larger studies with new diagrams and/or new medications.
Asunto(s)
Adolescente , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Antiprotozoarios/administración & dosificación , Benzamidinas/administración & dosificación , Leishmania guyanensis , Leishmaniasis Cutánea/tratamiento farmacológico , Éteres Fenílicos/administración & dosificación , Antiprotozoarios/efectos adversos , Benzamidinas/efectos adversos , Glucemia/análisis , Relación Dosis-Respuesta a Droga , Proyectos Piloto , Éteres Fenílicos/efectos adversos , Reproducibilidad de los Resultados , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: There have been few studies on pentamidine in the Americas; and there is no consensus regarding the dose that should be applied. OBJECTIVES: To evaluate the use of pentamidine in a single dose to treat cutaneous leishmaniasis. METHODS: Clinical trial of phase II pilot study with 20 patients. Pentamidine was used at a dose of 7 mg/kg, in a single dose. Safety and adverse effects were also assessed. Patients were reviewed one, two, and six months after the end of treatments. RESULTS: there was no difference between the treatment groups in relation to gender, age, number or location of the lesions. Pentamidine, applied in a single dose, obtained an effectiveness of 55%. Mild adverse events were reported by 17 (85%) patients, mainly transient pain at the site of applications (85%), while nausea (5%), malaise (5%) and dizziness (5%) were reported in one patient. No patient had sterile abscess after taking medication at a single dose of 7mg/kg. CONCLUSIONS: Clinical studies with larger samples of patients would enable a better clinical response of pent amidine at a single dose of 7mg, allowing the application of more powerful statistical tests, thus providing more evidences of the decrease in the effectiveness of that medication. Hence, it is important to have larger studies with new diagrams and/or new medications.
Asunto(s)
Antiprotozoarios/administración & dosificación , Benzamidinas/administración & dosificación , Leishmania guyanensis , Leishmaniasis Cutánea/tratamiento farmacológico , Éteres Fenílicos/administración & dosificación , Adolescente , Adulto , Antiprotozoarios/efectos adversos , Benzamidinas/efectos adversos , Glucemia/análisis , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Persona de Mediana Edad , Éteres Fenílicos/efectos adversos , Proyectos Piloto , Reproducibilidad de los Resultados , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
Several clinical trials have shown that antagonists of the glycoprotein IIb/IIIa receptor decreased the incidence of death, nonfatal myocardial infarction, and the need for urgent revascularization when administered immediately before or during the 24- to 48-hour period after percutaneous coronary intervention (PCI). However, these agents increased the risk of thrombocytopenia and periprocedural bleeding complications. Therefore, the relation between periprocedural bleeding complications during PCI and long-term outcome was assessed in 6,995 patients in the EXCITE trial. Periprocedural bleeding was classified as none, mild, moderate, and severe. Measured outcomes included the incidence of all-cause mortality or the composite end point (cardiovascular disease) of death, myocardial infarction, or stroke. Subjects were followed up for a median of 210 days (7 months). Mean patient age was 59.1 years, and 21.8% were women. Periprocedural bleeding complications occurred in 1,869 patients (26.7%), and blood transfusion was administered to 189 patients (2.7%). In multivariate analysis, periprocedural bleeding complications were significantly associated with increased risk of the composite outcome for mild (hazard ratio [HR] 0.80, 95% confidence interval [CI] 0.64 to 0.97), moderate (HR 2.38, 95% CI 1.78 to 3.20), and severe bleeding complications (HR 3.55, 95% CI 2.20 to 5.73) during follow-up. Also, the necessity of blood transfusion was an important predictor of the composite end point (HR 2.61, 95% CI 1.96 to 3.60). Patients in the United States were more likely to be administered a blood transfusion than non-US patients independently of cardiovascular risk factors. In conclusion, moderate and severe periprocedural bleeding complications increased the risk of mortality and incident cardiovascular events after PCI.
Asunto(s)
Angioplastia Coronaria con Balón/métodos , Benzamidinas/administración & dosificación , Enfermedad de la Arteria Coronaria/terapia , Trombosis Coronaria/prevención & control , Hemorragia Posoperatoria/etiología , Cuidados Preoperatorios/efectos adversos , Trombocitopenia/inducido químicamente , Administración Oral , Benzamidinas/efectos adversos , Angiografía Coronaria , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Trombosis Coronaria/epidemiología , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Electrocardiografía , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Inhibidores de Agregación Plaquetaria/administración & dosificación , Inhibidores de Agregación Plaquetaria/efectos adversos , Hemorragia Posoperatoria/sangre , Hemorragia Posoperatoria/epidemiología , Factores de Riesgo , Tasa de Supervivencia/tendencias , Trombocitopenia/sangre , Trombocitopenia/complicaciones , Factores de Tiempo , Resultado del Tratamiento , Estados Unidos/epidemiologíaRESUMEN
There is a high incidence of traumatic wounds. Such wounds often become infected which prolongs the wound healing process. Many patients will contact a pharmacy for antiseptic treatment. Various over-the-counter drugs can help as antiseptic treatment; Brulidine is a cream which is widely used for treating local skin infections. Its active component is dibrompropamidine. Some incidences of contact allergy have been reported after use of dibrompropamidine. As dibrompropamidine is sold as an over-the-counter drug, the incidence of contact allergy caused by it may be underreported. This article presents two case reports of patients with contact allergy to dibrompropamidine. The article also describes a diagnostic procedure with Users test and patch testing for diagnosising contact dermatitis.
Asunto(s)
Antiinfecciosos Locales/efectos adversos , Benzamidinas/efectos adversos , Dermatitis Alérgica por Contacto/etiología , Piel/lesiones , Infección de Heridas/tratamiento farmacológico , Adolescente , Brazo , Dermatitis Alérgica por Contacto/patología , Diagnóstico Diferencial , Cara , Femenino , Mano , Humanos , Masculino , Persona de Mediana Edad , Piel/microbiología , Piel/patología , Infección de Heridas/microbiología , Infección de Heridas/patologíaAsunto(s)
Antiinfecciosos Locales/efectos adversos , Dermatitis Alérgica por Contacto/etiología , Hipersensibilidad a las Drogas/etiología , Enfermedades de la Piel/tratamiento farmacológico , Benzamidinas/efectos adversos , Dermatitis Alérgica por Contacto/diagnóstico , Diagnóstico Diferencial , Hipersensibilidad a las Drogas/diagnóstico , HumanosRESUMEN
The choice of drugs for the treatment of sleeping sickness is extremely limited. To redress this situation, the recently synthesised diamidine, 2,5-bis(4-amidinophenyl)-furan (DB75, furamidine) and its methamidoxime prodrug, 2,5-bis(4-amidinophenyl)-furan-bis-O-methylamidoxime (DB289, pafuramidine) were, together with pentamidine, evaluated for efficacy in acute rodent models. The activity was compared in three common mouse models that mimic the first stage of human African trypanosomiasis. The mice were infected with the pleomorphic T .b. rhodesiense strains KETRI2537 and STIB900 or with the monomorphic T. b. brucei strain STIB795. Importantly, DB75 showed activity superior to that of pentamidine at comparable doses in all three mouse models. Complete cures were achieved with oral dosing of the prodrug DB289 in all three models without any overt toxicity. This shows that the prodrug strategy was successful in terms of reducing toxicity and increasing efficacy and oral bioavailability.
Asunto(s)
Antiprotozoarios/uso terapéutico , Benzamidinas/uso terapéutico , Profármacos/uso terapéutico , Trypanosoma brucei gambiense/efectos de los fármacos , Tripanosomiasis Africana/tratamiento farmacológico , Administración Oral , Animales , Antiprotozoarios/administración & dosificación , Antiprotozoarios/efectos adversos , Benzamidinas/administración & dosificación , Benzamidinas/efectos adversos , Femenino , Humanos , Ratones , Estructura Molecular , Pentamidina/administración & dosificación , Pentamidina/efectos adversos , Pentamidina/uso terapéutico , Profármacos/administración & dosificación , Profármacos/efectos adversosRESUMEN
PURPOSE: To identify characteristics associated with cataract occurring during the course of Acanthamoeba keratitis. DESIGN: Retrospective observational case series. PARTICIPANTS: Eighty-one laboratory-confirmed patients with Acanthamoeba keratitis. METHODS: Review of clinical records. MAIN OUTCOME MEASURES: Development of cataract during management of Acanthamoeba keratitis. RESULTS: Rapidly progressive crystalline lens opacification occurred in 9 eyes within 4 to 15 weeks after diagnosis of Acanthamoeba keratitis. Three were associated with inflammatory complications, including anterior scleritis (2 eyes) and iridocyclitis (1 eye). Six others had the abrupt onset of a dense cataract, including 5 with iris atrophy, that occurred during the initial 6 months of therapy with chlorhexidine, a diamidine, and adjunctive corticosteroid. Extracapsular cataract extraction was performed with or after penetrating keratoplasty. Secondary glaucoma developed in 6 of 9 eyes subsequent to iris atrophy (4 eyes) or a cyclitic membrane (2 eyes), and 3 eyes underwent trabeculectomy. CONCLUSIONS: Cataract may occur and progress during the management of Acanthamoeba keratitis in association with anterior segment inflammation, iris atrophy, and secondary glaucoma.
Asunto(s)
Queratitis por Acanthamoeba/tratamiento farmacológico , Antiprotozoarios/efectos adversos , Catarata/inducido químicamente , Iris/efectos de los fármacos , Iris/patología , Administración Tópica , Adulto , Anciano , Atrofia/inducido químicamente , Benzamidinas/efectos adversos , Biguanidas/efectos adversos , Extracción de Catarata , Clorhexidina/efectos adversos , Clorhexidina/análogos & derivados , Progresión de la Enfermedad , Desinfectantes/efectos adversos , Quimioterapia Combinada , Femenino , Glaucoma/etiología , Glaucoma/cirugía , Humanos , Queratoplastia Penetrante , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , TrabeculectomíaRESUMEN
A 37-year-old contact lens wearer was treated for herpes simplex keratitis. After an initial improvement the keratitis became much worse. An annular infiltrate gave rise to the suspicion of acanthamoeba keratitis even though the patient was not in pain. This diagnosis was confirmed by histological and microbiological examination of the corneal disc after keratoplasty. Acanthamoeba keratitis should be considered even in the absence of pain, especially when the patients are contact lens wearers.
Asunto(s)
Queratitis por Acanthamoeba/diagnóstico , Queratitis por Acanthamoeba/patología , Adulto , Antiprotozoarios/administración & dosificación , Antiprotozoarios/efectos adversos , Benzamidinas/administración & dosificación , Benzamidinas/efectos adversos , Biguanidas/administración & dosificación , Biguanidas/efectos adversos , Terapia Combinada , Lentes de Contacto de Uso Prolongado/parasitología , Lentes de Contacto Hidrofílicos/parasitología , Córnea/patología , Trasplante de Córnea , Diagnóstico Diferencial , Desinfectantes/administración & dosificación , Desinfectantes/efectos adversos , Quimioterapia Combinada , Humanos , Enfermedades del Aparato Lagrimal/diagnóstico , Enfermedades del Aparato Lagrimal/patología , Lentes Intraoculares , Masculino , Reoperación , Factores de RiesgoRESUMEN
PURPOSE: Two cases of acanthamoeba keratitis with almost identical clinical courses developed mature cataract and iris atrophy after prolonged treatment with chlorhexidine 0.02% and propamidine isethionate 0.1%. It is suggested that these complications were caused by the chemicals, rather than resulting from the amoebae-induced inflammation. METHODS: Penetrating keratoplasty was performed in both cases when perforation from peripheral ulceration was threatening. RESULTS AND CONCLUSIONS: The immediate results were good. From these two cases it seems possible that there is a maximum level of intensity of the medical treatment and also that surgery should be considered at an earlier stage, before intraocular complications develop.
Asunto(s)
Queratitis por Acanthamoeba/tratamiento farmacológico , Antiprotozoarios/efectos adversos , Benzamidinas/efectos adversos , Catarata/inducido químicamente , Clorhexidina/efectos adversos , Iris/efectos de los fármacos , Atrofia , Extracción de Catarata , Quimioterapia Combinada , Femenino , Humanos , Queratoplastia Penetrante , Implantación de Lentes Intraoculares , Persona de Mediana Edad , Agudeza VisualRESUMEN
DB-289, an oral diamidoxime prodrug of DB-75 from the University of North Carolina, Georgia State University, Auburn University and Duke University, is being developed by Immtech International as a potential treatment for Pneumocystis carinii pneumonia (PCP), tuberculosis, trypanosomiasis and malaria.
Asunto(s)
Antiprotozoarios/uso terapéutico , Antituberculosos/uso terapéutico , Benzamidinas/uso terapéutico , Profármacos/uso terapéutico , Animales , Antimaláricos/efectos adversos , Antimaláricos/química , Antimaláricos/farmacocinética , Antimaláricos/uso terapéutico , Antiprotozoarios/efectos adversos , Antiprotozoarios/química , Antiprotozoarios/farmacocinética , Antituberculosos/efectos adversos , Antituberculosos/química , Antituberculosos/farmacocinética , Benzamidinas/efectos adversos , Benzamidinas/química , Benzamidinas/metabolismo , Benzamidinas/farmacocinética , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Humanos , Profármacos/efectos adversos , Profármacos/química , Profármacos/farmacocinética , Relación Estructura-Actividad , Tripanocidas/efectos adversos , Tripanocidas/química , Tripanocidas/farmacocinética , Tripanocidas/uso terapéuticoRESUMEN
Recently, the use of the ribonucleotide reductase (RR) inhibitor hydroxyurea (HU) in combination with nucleoside analogs has gained attention as a potential strategy for anti-HIV-1 therapy. However, appeal for the long-term use of HU in HIV-1 infection may be limited by its propensity to induce hematopoietic toxicity. We report a comparison of the efficacy and bone marrow toxicity of HU (400 and 200 mg/kg/day) with the novel RR inhibitors and free radical-scavenging compounds didox (DX; 3,4-dihydroxybenzohydroxamic acid; 350 mg/kg/day) and trimidox (TX; 3,4,5-trihydroxybenzamidoxime; 175 mg/kg/day) in the murine AIDS (LPBM5 MuLV) model of retrovirus infection. Infected mice received daily drug treatment for 8 weeks. Efficacy was determined by measuring drug effects on retroviral-induced disease progression (i.e. development of splenomegaly and hypergammaglobulinemia) and by evaluating splenic levels of proviral DNA. Bone marrow toxicity was evaluated by measuring peripheral blood indices (WBC, hematocrit and reticulocyte counts), femoral cellularity and by determining the numbers of hematopoietic progenitor cells (CFU-GM, BFU-E) per femur and spleen. Compared to infected controls receiving no drug treatment, disease progression was significantly suppressed by TX, DX and HU. However, HU was associated with mortality and induced significant hematopoietic toxicity in a time- and dose-dependent manner. Conversely, TX and DX effectively inhibited retrovirus-induced disease but did not induce hematopoietic toxicity. These results suggest that due to their reduced hematopoietic toxicity and ability to inhibit disease progression in murine AIDS, TX and DX may offer effective alternatives to HU therapy in HIV-1 infection.
Asunto(s)
Benzamidinas/efectos adversos , Células de la Médula Ósea/efectos de los fármacos , Depuradores de Radicales Libres/efectos adversos , Ácidos Hidroxámicos/efectos adversos , Hidroxiurea/efectos adversos , Virus de la Leucemia Murina/efectos de los fármacos , Leucemia Experimental/patología , Síndrome de Inmunodeficiencia Adquirida del Murino/patología , Infecciones por Retroviridae/patología , Ribonucleótido Reductasas/antagonistas & inhibidores , Infecciones Tumorales por Virus/patología , Animales , Benzamidinas/química , Benzamidinas/uso terapéutico , ADN Viral , Femenino , Fémur/citología , Fémur/efectos de los fármacos , Depuradores de Radicales Libres/química , Depuradores de Radicales Libres/uso terapéutico , Células Madre Hematopoyéticas/efectos de los fármacos , Ácidos Hidroxámicos/química , Ácidos Hidroxámicos/uso terapéutico , Hidroxiurea/química , Hidroxiurea/uso terapéutico , Hipergammaglobulinemia/tratamiento farmacológico , Virus de la Leucemia Murina/genética , Leucemia Experimental/sangre , Leucemia Experimental/tratamiento farmacológico , Leucemia Experimental/inmunología , Ratones , Ratones Endogámicos C57BL , Síndrome de Inmunodeficiencia Adquirida del Murino/sangre , Síndrome de Inmunodeficiencia Adquirida del Murino/tratamiento farmacológico , Síndrome de Inmunodeficiencia Adquirida del Murino/inmunología , Provirus/genética , Infecciones por Retroviridae/sangre , Infecciones por Retroviridae/tratamiento farmacológico , Infecciones por Retroviridae/inmunología , Bazo/patología , Esplenomegalia , Infecciones Tumorales por Virus/sangre , Infecciones Tumorales por Virus/tratamiento farmacológico , Infecciones Tumorales por Virus/inmunologíaRESUMEN
We evaluated the ability of a short course of treatment with the ribonucleotide reductase (RR) inhibitor hydroxyurea (HU) and two novel RR inhibitors Trimidox (TX) and Didox (DX) to influence late-stage murine retrovirus-induced lymphoproliferative disease. LPBM5 murine leukaemia virus retrovirus-infected mice were treated daily with HU, TX or DX for 4 weeks, beginning 9 weeks post-infection, after development of immunodeficiency and lymphoproliferative disease. Drug effects on disease progression were determined by evaluating spleen weight and histology. Effects on haematopoiesis were determined by measuring peripheral blood indices (white blood cells and haematocrit) and assay of femur cellularity and femoral and splenic content of colony-forming units granulocyte-macrophage (CFU-GM) and burst-forming units-erythroid (BFU-E). HU, TX and DX partially reversed late-stage retrovirus-induced disease, resulting in spleen weights significantly below pre-treatment values. Spleen histology was also improved by RR inhibitor treatment (DX>TX>HU). However, as expected, HU was significantly myelosuppressive, inducing a reduction in peripheral indices associated with depletion of femoral CFU-GM and BFU-E. In contrast, although TX and DX were moderately myelosuppressive, both drugs were significantly better tolerated than HU. In summary, short-term treatment in late-stage murine retroviral disease with HU, TX or DX induced dramatic reversal of disease pathophysiology. However, the novel RR inhibitors TX and DX had more effective activity and significantly less bone marrow toxicity than HU.