Nanocarrier-based delivery of arsenic trioxide for hepatocellular carcinoma therapy.

Hepatocellular carcinoma (HCC) poses a severe threat to human health and economic development. Despite many attempts at HCC treatment, most are inevitably affected by the genetic instability and variability of tumor cells. Arsenic trioxide (ATO) has shown to be effective in HCC. However, time-consuming challenges, especially the optimal concentration in tumor tissue and bioavailability of ATO, remain to be overcome for its transition from the bench to the bedside. To bypass these issues, nanotechnology-based delivery systems have been developed for prevention, diagnosis, monitoring and treatment in recent years. This article is a systematic overview of the latest contributions and detailed insights into ATO-loaded nanocarriers, with particular attention paid to strategies for improving the efficacy of nanocarriers of ATO.

Hepatocellular carcinoma (HCC) is the leading cause of cancer-related death worldwide; it is highly aggressive, has a poor prognosis and is often diagnosed late in the disease course. Arsenic trioxide (ATO), an established agent for the treatment of acute promyelocytic leukemia, has shown powerful therapeutic potential in the treatment of HCC. However, its narrow therapeutic window and severe toxicity, as well as resistance to ATO, limit its application for HCC treatment. Nanocarriers have been employed to deliver ATO to achieve effective therapeutic outcomes in HCC. This review describes the application of various nanocarrier-based delivery systems for ATO to enhance the effectiveness of tumor therapy and reduce its side effects, thus making it a promising therapeutic strategy for in HCC.

Trióxido de arsénico en el tratamiento de leucemia mieloblástica aguda / Arsenic trioxide in the treatment of acute myeloblastic leukemia

PREGUNTAS DE INVESTIGACIÓN: El trióxido de arsénico es seguro para su uso en pacientes pediátricos con Leucemia Promielocítica aguda? El trióxido de arsénico es efectivo para inducir remisión en pacientes pediátricos con Leucemia Promielocítica Aguda en recaída? ESTRATEGIA DE BÚSQUEDA DE LA EVIDENCIA CIENTÍFICA: Se realizó una búsqueda en las principales bases de datos bibliográficas (Pubmed, Lilacs, Cochrane), Agencias de Evaluación de Tecnologías Sanitarias (Ej. NICE, CADTH) y Agencias Nacionales e Internacionales reguladoras de alimentos y medicamentos (Ej ANMAT, EMA) y en Sociedades Científicas (Sociedad Argentina de Pediatría, Sociedad Argentina de Hematología, National Comprehensive Cancer Network o NCCN) Se realizó además una búsqueda del precio de la tecnología en Manual Farmacéutico Kairos y de la cobertura de la misma dentro de los siguientes sistemas de salud/aseguradoras y/o prestadores de servicios de salud (Ej. AETNA, CADTH, SSS). Como estrategia de búsqueda se utilizaron las siguientes palabras clave: trióxido de arsénico, leucemia promielocítica, arsenic trioxide, promyelocytic leukemia. Se utilizaron como criterios de inclusión textos en inglés, español a los que se pueda tener acceso a texto completo, sin restricción de fecha de publicación. La búsqueda se limitó a menores de 18 años y se consideraron revisiones sistemáticas, metaanálisis y ensayos clínicos aleatorizados y controlados. Dada la escasa bibliografía encontrada, se amplió la búsqueda a población adulta priorizando revisones sistemáticas y metaanálisis. Se excluyeron textos en otro idioma, los que no se pudiera acceder a texto completo, aquellos que no fueran pertinentes de acuerdo al título y al resumen y los que no aplicaban para el objetivo del presente análisis. Se priorizó la inclusión de revisiones sistemáticas y meta-análisis, evaluaciones de tecnologías sanitarias e informes de seguridad. DESCRIPCIÓN DE LA TECNOLOGÍA: El mecanismo de acción del trióxido de arsénico no se conoce por completo. Produce cambios morfológicos y fragmentación del ácido desoxirribonucléico(ADN) característicos de apoptosis en las células de leucemia promielocítica NB4 humanas in vitro, y produce asimismo lesión o degradación de la proteína de fusión Leucemia promielocítica/ Receptor alfa del ácido retinoico (PML/RAR-alfa). INFORMACIÓN EPIDEMIOLÓGICA Y/O IMPORTANCIA SANITARIA DE LA CONDICIÓN CLÍNICA A LA QUE SE APLICA LA TECNOLOGÍA: La LPM representa el 5-10% de las LMA pediátricas en series internacionales. La edad media de diagnóstico es de 7-9 años. Raramente se presenta en pacientes menores de 1 año. En Argentina se reporta una incidencia cercana al 20%. Los pacientes se estratifican en 2 grupos de riesgo según el recuento inicial de leucocitos. CONCLUSIONES: A pesar del bajo poder estadístico de los estudios en función del número de pacientes incluidos en los mismos, los resultados favorecen el uso de trióxido de arsénico en pacientes con LPA recaídos o refractarios. Se requieren más ensayos clínicos, multicéntricos y de N suficiente de pacientes para conclusiones definitivas, en particular en población pediátrica. Dada la condición clínica para la cual se aplica la tecnología, el riesgo del uso en pediatría podría asumirse en base a los resultados obtenidos en población adulta.

Cost-Effectiveness Analysis of Treating Acute Promyelocytic Leukemia Patients With Arsenic Trioxide and Retinoic Acid in the United States.

INTRODUCTION: This study estimated the cost-effectiveness of arsenic trioxide (ATO) added to all-trans retinoic acid (ATRA) when used in first-line acute promyelocytic leukemia (APL) treatment. MATERIALS AND METHODS: A Markov cohort model was developed with 3 states: stable disease (during first- or second-line treatment), disease event, and death. Newly diagnosed patients with low- to intermediate-risk APL were included and each month could remain in their current health state or move to another. Treatment consisted of ATO + ATRA, ATRA + idarubicin (IDA), or ATRA + cytarabine (AraC) + additional chemotherapy. After an initial disease event, patients discontinued first-line therapy and switched to a second-line ATO regimen. Efficacy and safety data were obtained from published trials; quality of life/utility estimates were obtained from the literature; costs were obtained from US data sources. Costs and outcomes over time were used to calculate incremental cost-effectiveness ratios (ICERs). Deterministic and probabilistic sensitivity analyses were conducted. RESULTS: Compared to ATRA + AraC + additional chemotherapy, ATRA + IDA treatment had ICERs of $2933 per life-year (LY) saved and $3122 per quality-adjusted life-year (QALY) gained. Compared to the ATRA + IDA regimen, first-line ATO + ATRA treatment had ICERs of $4512 per LY saved and $5614 per QALY gained. Results were sensitive to changes in pharmacy costs of the ATO + ATRA regimen during consolidation. CONCLUSION: The ATO + ATRA regimen is highly cost-effective compared to ATRA + AraC + additional chemotherapy or ATRA + IDA in the treatment of newly diagnosed low- to intermediate-risk APL patients.

Budgetary impact of treating acute promyelocytic leukemia patients with first-line arsenic trioxide and retinoic acid from an Italian payer perspective.

The objective of this study was to estimate the net cost of arsenic trioxide (ATO) added to all-trans retinoic acid (ATRA) compared to ATRA plus chemotherapy when used in first-line acute promyelocytic leukemia (APL) treatment for low to intermediate risk patients from the perspective of the overall Italian healthcare systemA Markov model was developed with 3 health states: stable disease, disease event and death. Each month, patients could move from stable to disease event or die from either state. After a disease event, patients discontinued initial treatment and switched to the other regimen as second-line therapy. Treatment regimens, efficacy and adverse events were derived from published sources and expert opinion; unit costs were collected from standard Italian sources. Clinical outcomes and costs for pre-ATO and post-ATO scenarios were combined with population and product utilization information to calculate the total budgetary impact using a 3-year time horizon; one-way sensitivity analyses were conducted. Three-year cumulative pharmacy costs for ATO+ATRA were €46,700 per-patient versus €6,500 for ATRA+chemotherapy; however, medical costs for ATO+ATRA were €12,300 per-patient versus €30,200 for ATRA+chemotherapy. The total budgetary impact was estimated to be an additional €127,300, €312,500 and €477,800 in the first, second and third years, respectively. The model was most sensitive to changes in the cost of the ATO+ATRA regimen during the consolidation phase. Budgetary impact models are valuable to payers making formulary decisions regarding the access and affordability of new medicines. The cost of treatment analysis showed that pharmacy costs for ATO+ATRA were higher than for ATRA+chemotherapy, while all other evaluated costs were lower for ATO+ATRA treated patients. The average budgetary impact was €305,900 per year overall, representing a 3.5% increase. Further research is needed to determine the cost-effectiveness of ATO+ATRA compared to the current first-line standard of care in APL.

Economic evaluation of arsenic trioxide for treatment of newly diagnosed acute promyelocytic leukaemia in Canada.

To assess, from a Canadian perspective, the economic impact of arsenic trioxide (ATO) + all-trans retinoic acid (ATRA) for treating newly diagnosed acute promyelocytic leukaemia (APL), the cost-effectiveness of ATO + ATRA compared to ATRA + idarubicin (IDA) was assessed over a lifetime horizon using a time-dependent Markov model. The model considers four health states: complete remission, treatment failure or relapse, post-failure, and death. Markov cycle length was 1 month for the first 48 months and 1 year thereafter. Efficacy outcomes in terms of event-free survival and overall survival were taken from a head-to-head clinical trial. Costs were associated with drug and administration, adverse events (AEs), treatment of relapses, follow-up visits, and productivity losses. Utilities and disutilities associated with health states and AEs were derived from the literature. Compared to ATRA + IDA, ATRA + ATO is associated with incremental cost-effectiveness ratios (ICERs) of $CAD50,193/quality-adjusted life years (QALY) and $CAD50,338/QALY from a Canadian Ministry of Health (MoH) and societal perspectives, respectively. Results of the one-way sensitivity analysis show that ICER varied from $CAD23,045 to $CAD60,759/QALY (MoH perspective) and from $CAD23,120 to $CAD60,905/QALY (societal perspective). ATO in the first-line therapy for patients with APL can be considered a more cost-effective strategy than standard treatment from a Canadian perspective.

Economic evaluation of arsenic trioxide compared to all-trans retinoic acid + conventional chemotherapy for treatment of relapsed acute promyelocytic leukemia in Canada.

OBJECTIVES: Acute promyelocytic leukemia (APL) is an uncommon type of acute leukemia characterized by high early mortality. Current first-line treatments include all-trans retinoic acid (ATRA), anthracyclines, and other conventional chemotherapies (CTs). Although APL is generally associated with a good prognosis, about 20% of patients who achieve remission subsequently relapse and are resistant to the previously administrated treatment. The objective of this study was to assess, from a Canadian perspective, the economic impact of arsenic trioxide (ATO) compared to ATRA+CT for treatment of patients with relapsed/refractory APL. METHODS: The cost-effectiveness of ATO compared to ATRA+CT for treating patients with relapsed/refractory APL was assessed over a lifetime horizon using a Markov model. The model considers five health states: induction, second remission, treatment failure or relapse, postfailure, and death. Markov cycle length was 1 month for the first 24 months and 1 yr thereafter. The model also takes into account the incidence of grade 3-4 adverse events reported in clinical trials. Analyses were conducted from a Canadian Ministry of Health (MoH) and a societal perspective. RESULTS: Compared to ATRA+CT, ATO was associated with incremental cost-effectiveness ratios of $ 20,551/quality-adjusted life year (QALY) from a MoH perspective and $ 22,219/QALY from a societal perspective. Results of the probabilistic sensitivity analysis indicated that ATO is a cost-effective strategy in 99.27% and 98.98% of the simulations from a MoH and a societal perspective, respectively. CONCLUSIONS: This economic evaluation demonstrates that ATO is a cost-effective strategy compared to ATRA+CT for treatment of patients with relapsed/refractory APL in Canada.

Variation of D-dimer values as assessment of pulmonary thromboembolism during adulticide treatment of heartworm disease in dogs.

Dirofilaria immitis adult worms lodged in the pulmonary arteries are the causative agent of heartworm disease, characterized by endarteritis and obstruction of the blood flow. Dying worms form embolic fragments which trigger thrombosis. Thus, pulmonary thromboembolism is an inevitable consequence of successful adulticide therapy. Clinical signs of pulmonary thromboembolisms are highly variable and non-specific, and its diagnosis is often difficult to obtain. The D-dimer assay is considered the marker of choice for dogs with a suspicion of pulmonary thromboembolism. The aim of the present study was to evaluate the variation of D-dimer and platelets in 15 heartworm-infected dogs during the adulticide treatment with ivermectin, doxycycline and melarsomine. Nine dogs were considered to have a low parasite burden and 6 had a high burden. Measurements were carried out on days 0, 60, and afterwards weekly on days 67, 75, 82, 91, 98, 106, 113, 120, and finally on day 271 after treatment. 40% of dogs showed pathological concentrations of D-dimer and 40% showed slight or mild thrombocytopenia on day 0. The levels of D-dimer decreased by day 60, probably due to the joint action of the ivermectin, doxycycline and exercise restriction. All dogs with high parasite burden showed elevated values of D-dimer on several occasions during the treatment, reaching the highest values the first and second week after the injections of melarsomine. Only 33.3% of the dogs with low parasite burden showed elevated D-dimer levels at some point during the treatment, and all of them showed undetectable levels from the third week after the first injection of melarsomine. On day 271, all dogs showed undetectable levels of D-dimer. There was no correlation between thrombocytopenia and levels of D-dimer during the treatment. The evaluation of serum D-dimer appears to be a supportive test in the assessment and monitoring of pulmonary thromboembolism in dogs with heartworm disease during the adulticide treatment.

Application and assessment of Chinese arsenic drugs in treating malignant hematopathy in China.

Chinese arsenic drugs have been applied in Chinese medicine for several centuries. Beginning from 1970s, arsenic containing drugs have been generally used for the treatment of malignant hematologic diseases including acute promyelocytic leukemia, myelodysplastic syndrome, and multiple myeloma. No matter what ingredients of arsenic drugs were applied, either arsenic trioxide, arsenic disulfide, or arsenic containing Chinese herbal compositions including Qinghuang Powder and Realgar-Indigo naturalis formula, they all provided the distinct approaches for the management of malignant hematologic diseases, and good clinical efficacy was obtained with mild adverse reactions. Moreover, the mechanisms of action have been continually elucidated.

Assessment of the effectiveness of low-level laser therapy on the hands of patients with rheumatoid arthritis: a randomized double-blind controlled trial.

Assess the effectiveness of low-level laser therapy on pain reduction and improvement in function in the hands of patients with rheumatoid arthritis. A randomized double-blind controlled trial was carried out on 82 patients with rheumatoid arthritis. The experimental group was submitted to the application of laser therapy, whereas the control group received a placebo laser. Aluminum gallium arsenide laser was used, at a wavelength of 785 nm, dose of 3 J/cm(2) and mean power of 70 mW. The groups were homogenous at the beginning of the study with regard to the main variables (p > 0.05). There were no statistically significant differences between groups in most of the measurements taken at the end of the intervention including the primary variables; the following variables were the exceptions: favoring the experimental group-inflammation of the interphalangeal joint of the right thumb (p = 0.012) and perimetry of the interphalangeal joint of the left thumb (p = 0.013); and favoring the control group-flexion of the proximal interphalangeal joint of the right fifth finger (p = 0.021), perimetry of the third proximal interphalangeal joint of the right hand (p = 0.044), grip strength in the left hand (p = 0.010), and the work domain of the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire (p = 0.010). We conclude that low-level aluminum gallium arsenide laser therapy is not effective at the wavelength, dosage, and power studied for the treatment of hands among patients with rheumatoid arthritis.

Pathologic, cytogenetic and molecular assessment of acute promyelocytic leukemia patients treated with arsenic trioxide (As2O3).

Arsenic trioxide (As2O3) shows great promise as an effective therapy for patients with all-trans retinoic acid (ATRA)-resistant acute promyelocytic leukemia (APL). Little data is available addressing the pathology of As2O3 treated APL and whether the antileukemic mechanism of As2O3 is primarily cytolysis or through stimulation of cell differentiation. In this report, we made a morphologic, cytogenetic, and molecular evaluation of five ATRA-refractory APL patients who were treated with As2O3. Four of the five patients had morphologic responses after one or two cycles of As2O3 treatment. Of the four responders based on bone marrow morphology, two achieved molecular remission (negative RT-PCR for PML- RAR alpha fusion transcripts) by the end of the second and third cycles of As2O3 therapy. Two patients exhibited marked leukocytosis during the first cycle of As2O3, and at that time point the APL cells were largely replaced by the cells showing partial differentiation towards myelocytes with co-expression of CD11b and CD33. Nevertheless, these "myelocyte-like" cells that showed the t(15;17) translocation eventually disappeared with continuous As2O3 therapy. As2O3 treatment appears to be effective therapy for the patients with relapsed APL after the failure of conventional chemotherapy and ATRA therapy. The pathologic findings in these five cases suggest that at low doses As2O3 primarily induces differentiation of the APL cells, generating abnormal myelocytes resembling APL cells treated with ATRA, whereas at higher doses AS2O3 induces marrow necrosis.

[Current therapy of trypanosomiasis]. / Actualités thérapeutiques de la trypanosomiase.

The authors review the available products used for human african trypanosomiasis (HAT) chemotherapy: pentamidine, suramin, melarsoprol and the new compound DFMO. The administration of pentamidine at the beginning of the nervous stage, when the number of cells in the cerebrospinal fluid do not exceed 20/mn3 is a new approach for HAT treatment. At this time of the disease, patients generally are healthy and the pentamidine therapy avoids the use of the toxic melarsoprol (Arsobal). An alternative protocol for Arsobal therapy (2, 16 mg/kg/d for 10 consecutive days) has been described from pharmacokinetics data to decrease the rate of relapses and the duration of hospital care. Efficacy and tolerance of this new protocol must be evaluated by randomised clinical trials. Preliminary data of clinical trials using short-term DFMO therapy are encouraging. DFMO therapy be less expensive. From its efficacy and tolerance, DFMO is a choice chemotherapy for HAT treatment, especially in the case of resistance to usual trypanocides. Both MLD 73811 and IMOL 881 are new trypanocidal compounds, effective on Trypanosoma brucei rhodesiense and T. b. gambiense. In addition, IMOL 881 is effective on the animal trypanosomes, T. evansi and T. equiperdum. Waiting for the availability of these new products, classical trypanocides remain the basis of HAT treatment.

Basic studies on the laboratory assessment of macrofilaricides using Brugia malayi in the jird, Meriones unguiculatus. 2. Establishment and evaluation of a new method of macrofilaricide assessment.

Jird infected subcutaneously with infective stage larvae (L3) of Brugia malayi were evaluated as an animal model for assessing macrofilaricides using a method of observing the change in microfilaria (mf) density but not by recovering adult worms. The animals were treated with a test compound followed by diethylcarbamazine (DEC) at 50 mg/kg for 5 consecutive days for clearing the existing mf from the blood stream. A continuous decrease in mf density was observed when jirds were treated with flubendazole. Nevertheless, slow recovery of mf density was observed in the jirds which were given suramin or Mel W, indicating that mf productivity of female worms was continuing after DEC treatment. The results obtained by monitoring microfilaremia corresponded with those obtained by recovery of adult worms at autopsy, suggesting that the system of L3-induced B. malayi jird model is useful for testing macrofilaricides.

The effects of drugs on Onchocerca volvulus. 1. Methods of assessment, population dynamics of the parasite and the effects of diethylcarbamazine.

It is important to standardize quantitative methods for assessing the action of drugs on Onchocerca volvulus in man. There are certain disadvantages to making observations on adult worms removed from excised nodules in treated patients, but a great deal of information on drug action can be obtained by making a careful study of the concentrations of microfilariae in multiple weighed skin snips taken before treatment and at intervals after treatment.Before drug trials can be carried out intelligently by this method it is necessary to know the normal length of life of the various stages of the parasite in man. By a variety of experimental methods the life-spans of the adult worms and the microfilariae have been determined, as well as the duration of the prepatent interval.Diethylcarbamazine can be used at doses that are effectively microfilaricidal but have no action on the adult worms. This drug can therefore be used to eliminate any residual microfilariae that remain after treatment with a new drug under trial, thus permitting a more rapid assessment of the latter's action on adult worms.