Multidrug Treatment Research Articles

Effectiveness of multi-drug regimen chemotherapy treatment in osteosarcoma patients: a network meta-analysis of randomized controlled trials

BackgroundOsteosarcoma is the most common malignant bone tumour. Due to the high metastasis rate and drug resistance of this disease, multi-drug regimens are necessary to control tumour cells at various stages of the cell cycle, eliminate local or distant micrometastases, and reduce the emergence of drug-resistant cells. Many adjuvant chemotherapy protocols have shown different efficacies and controversial results. Therefore, we classified the types of drugs used for adjuvant chemotherapy and evaluated the differences between single- and multi-drug chemotherapy regimens using network meta-analysis. MethodsWe searched electronic databases, including PubMed (MEDLINE), EmBase, and the Cochrane Library, through November 2016 using the keywords “osteosarcoma”, “osteogenic sarcoma”, “chemotherapy”, and “random*” without language restrictions. The major outcome in the present analysis was progression-free survival (PFS), and the secondary outcome was overall survival (OS). We used a random effect network meta-analysis for mixed multiple treatment comparisons.ResultsWe included 23 articles assessing a total of 5742 patients in the present systematic review. The analysis of PFS indicated that the T12 protocol (including adriamycin, bleomycin, cyclophosphamide, dactinomycin, methotrexate, cisplatin) plays a more critical role in osteosarcoma treatment (surface under the cumulative ranking (SUCRA) probability 76.9%), with a better effect on prolonging the PFS of patients when combined with ifosfamide (94.1%) or vincristine (81.9%). For the analysis of OS, we separated the regimens to two groups, reflecting the disconnection. The T12 protocol plus vincristine (94.7%) or the removal of cisplatinum (89.4%) is most likely the best regimen.ConclusionsWe concluded that multi-drug regimens have a better effect on prolonging the PFS and OS of osteosarcoma patients, and the T12 protocol has a better effect on prolonging the PFS of osteosarcoma patients, particularly in combination with ifosfamide or vincristine. The OS analysis showed that the T12 protocol plus vincristine or the T12 protocol with the removal of cisplatinum might be a better regimen for improving the OS of patients. However, well-designed randomized controlled trials of chemotherapeutic protocols are still necessary.

Use of the GenoType MTBDRplus for early diagnosis of multidrug-resistant tuberculosis

The type of diagnostics methods and their duration, loss of time for the appointment of the optimal treatment are the major categories of factors that influence on multidrug resistant tuberculosis treatment effectiveness. Problem of multidrug resistant tuberculosis and improving of its laboratory diagnosis is very important in Ukraine. Inadequate and ineffective treatment is applied in cases of delayed diagnostic of multidrug resistant tuberculosis in patient. It causes further spread of drug-resistant tuberculosis and increase of mycobacterium tuberculosis drug resistance to anti-tuberculosis drugs. Therefore, rapid diagnostics of multidrug resistant tuberculosis is a requirement for timely and correct treatment strategy, and one of the urgent problems of modern phthisiology. The aim of this review was to evaluate the GenoType MTBDRplus for early diagnosis of multidrug-resistant tuberculosis diagnostic in Ukraine. Conclusions. Use of the GenoType MTBDRplus (2.0) assay for rapid multidrug resistant tuberculosis detection in Ukraine is important. With Genotype MTBDRplus test TB Complex identification and resistance detection to INH and RMP is completed in 8 hours compared to 25 days in Bactec MGIT 960 System and three months on solid LG medium. Pulmonary specimens (sputum, bronchoalveolar lavage, bronchoscopic aspirate), as well as clinical specimens from extrapulmonary sites (pleural fluid, lymph node biopsy, ascitic fluid, cerebrospinal fluid) can be used. Smear-positive patients, as well smear-negative and pulmonary cases as well extra-pulmonary, would be to benefit from using the revised version 2.0 of MTBDRplus. The sensitivity of this method is 95 to 97 % and the specificity – up to 90.7 %. It is recommended for detection of MDR TB in contact persons, for screening of multi-resistant tuberculosis patients and for detection of multi-resistant tuberculosis in TB patients with treatment failure, for determination of genotype of Mycobacterium tuberculosis in the region. Qualified bacteriologic diagnostics has the potential to interrupt the transmission chain of resistant M. tuberculosis.

Physical disability and its social and functional repercussions in patients with leprosy after discharge from multidrug therapy

Purpose: This paper analysed the clinical characteristics, social insertion and functional limitations in patients with leprosy. They were evaluated in a university hospital in southeast Brazil between 1998 and 2013. Methods: One hundred thirty six leprosy patients (aged 12–82 years) participated in a cross-sectional descriptive study after discharge from multidrug therapy treatment. Clinical and functional evaluations and characterisation of the restrictions to social involvement, through SALSA (Screening of Activity Limitation and Safety Awareness) and Participation Scales were performed. Results: The patients (79 males, 57 females) mean age was 44.67 ± 15.05 years. The major characteristics were male (79%), multibacillary (86%) and some disability (91.2%). 33.8% of the disabilities were graded 2. During the evaluation 56.5% of patients reported pain and 27.2% had used corticosteroid therapy. Ninety-five patients underwent neural decompression or tendon transfer surgery. Age bellow 64 years and pain represented a higher risk to activity limitation. According to SALSA and Participation Scores, 75% of patients had functional limitation and 52.2% social restriction. Conclusion: Despite the context of a reference hospital, it is important to highlight the late diagnostics in this study. Our findings suggest that age over 64 was a protective factor for activity limitations, which may be related with a higher impact of the disease in the young, causing more limitations on activities. There was no association between SALSA score and the presence of deformity, demonstrating adaptation to physical disabilities. The treatment with MDT eradicates M. leprae, however it does not overcome the physical deformities already placed.

Quantifying antiviral activity optimizes drug combinations against hepatitis C virus infection

With the introduction of direct-acting antivirals (DAAs), treatment against hepatitis C virus (HCV) has significantly improved. To manage and control this worldwide infectious disease better, the "best" multidrug treatment is demanded based on scientific evidence. However, there is no method available that systematically quantifies and compares the antiviral efficacy and drug-resistance profiles of drug combinations. Based on experimental anti-HCV profiles in a cell culture system, we quantified the instantaneous inhibitory potential (IIP), which is the logarithm of the reduction in viral replication events, for both single drugs and multiple-drug combinations. From the calculated IIP of 15 anti-HCV drugs from different classes [telaprevir, danoprevir, asunaprevir, simeprevir, sofosbuvir (SOF), VX-222, dasabuvir, nesbuvir, tegobuvir, daclatasvir, ledipasvir, IFN-α, IFN-λ1, cyclosporin A, and SCY-635], we found that the nucleoside polymerase inhibitor SOF had one of the largest potentials to inhibit viral replication events. We also compared intrinsic antiviral activities of a panel of drug combinations. Our quantification analysis clearly indicated an advantage of triple-DAA treatments over double-DAA treatments, with triple-DAA treatments showing enhanced antiviral activity and a significantly lower probability for drug resistance to emerge at clinically relevant drug concentrations. Our framework provides quantitative information to consider in designing multidrug strategies before costly clinical trials.

Enfermedad de hansen (lepra): Eritema nodoso leproso presentación de caso

La enfermedad de Hansen o lepra es una enfermedad infectocontagiosa de curso crónico tan antigua como la humanidad misma, que a lo largo de la historia ha marginado a todo aquel que la padece. En la actualidad con el conocimiento de su patogenia y avances en la terapéutica se tiene una visión diferente de la misma. En los siguientes párrafos se realiza una revisión bibliográfica actualizada y la presentación del caso clínico de un paciente de 44 años de edad, al cual se le diagnostico lepra lepromatosa con desarrollo de eritema nodoso leproso quien recibió manejo poliquimioterapéutico con adecuada evolución.

Low pre-diagnosis attrition but high pre-treatment attrition among patients with MDR-TB: An operational research from Chennai, India

BackgroundWorldwide, there’s concern over high pre-diagnosis and pre-treatment attritions or delays in Multidrug resistant tuberculosis (MDR-TB) diagnosis and treatment pathway (DTP). We conducted this operational research among patients with presumptive MDR-TB in north and central Chennai, India to determine attrition and turnaround times (TAT) at various steps of DTP and factors associated with attrition. MethodsStudy was conducted in Revised National Tuberculosis Control Programme setting. It was a retrospective cohort study involving record review of all patients with presumptive MDR-TB (eligible for DST) in 2014. ResultsOf 628 eligible for DST, 557 (88%) underwent DST and 74 (13%) patients were diagnosed as having MDR-TB. Pre-diagnosis and pre-treatment attrition was 11% (71/628) and 38% (28/74) respectively. TAT [median (IQR)] to test from eligibility for DST and initiate DR-TB treatment from diagnosis were 14 (9,27) and 18 (13,36) days respectively. Patients with smear negative TB and detected in first quarter of 2014 were less likely to undergo DST. Patients in first quarter of 2014 had significantly lower risk of pre-treatment attrition. ConclusionThere was high uptake of DST. However, urgent attention is required to reduce pre-treatment attrition, improve TAT to test from eligibility for DST and improve DST among patients with smear-negative TB.

Vacuum Sealing Drainage Treatment of Multi-Drug–Resistant Enterobacter Cloacae Wound Infection in a Diabetic Patient: A Case Report and Review of the Literature

Diabetic foot ulcers differ from non-diabetic trauma, as diabetic patients have dysfunctional wound healing owing to changes in the microcirculation. Herein, we report the case of a 48-year-old man with a 4-year history of uncontrolled type 2 diabetes. The patient had developed a 3-cm-wide ulcer deep to the phalanx on the big toe of the right foot 3 weeks ago, and the ulcer became infected with multi-drug–resistant Enterobacter cloacae 1 week later. We performed thorough wound debridement combined with Vacuum Sealing Drainage (VSD) and intravenous immunoglobulin administration without antibiotic therapy. This treatment strategy reduced the size of the ulcer. Three weeks later, antibiotic-susceptible Staphylococcus aureus was cultured from the wound tissue instead of Enterobacter cloacae, and so, the patient was administered antibiotics. The patient recovered well after this simple procedure followed by antibiotic therapy.

Safety and Efficacy of First-Line Treatments for Chemotherapy-Naive Metastatic Castration-Resistant Prostate Cancer: A Systematic Review and Indirect Comparison.

Recently, several drugs have been introduced for the first-line treatment of chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC), but few studies have compared treatment outcomes directly. This indirect comparison among 10 clinical trials (n = 4870 patients) retrieved from PubMed, Web of Science, Cochrane Collaboration, and ClinicalTrails.gov was performed to assess the safety and efficacy of docetaxel, cabazitaxel, abiraterone, enzalutamide, and sipuleucel-T for the initial treatment of mCRPC. No significant differences in primary outcome (overall survival) were found among initial treatments. However, docetaxel had the highest probability (37.53%) of being the most effective, but at the cost of more adverse events, while enzalutamide was associated with the best secondary outcomes (prostate-specific antigen response, progression-free survival, quality of life, and adverse event profile). Thus, docetaxel is recommended as the first agent used for the chemotherapy of mCRPC, while enzalutamide is recommended as the first nonchemotherapy treatment. Additional clinical trials are needed to confirm these findings and establish the optimal order for multidrug treatment of mCRPC.

Historical Overview of Leprosy Control in Cuba.

INTRODUCTION Leprosy, an infectious disease caused by Mycobacterium leprae, affects the nervous system, skin, internal organs, extremities and mucous membranes. Biological, social and environmental factors influence its occurrence and transmission. The first effective treatments appeared in 1930 with the development of dapsone, a sulfone. The main components of a control and elimination strategy are early case detection and timely administration of multidrug therapy. OBJECTIVES Review the history of leprosy control in Cuba, emphasizing particularly results of the National Leprosy Control Program, its modifications and influence on leprosy control. EVIDENCE ACQUISITION The historiological method was applied using document review, complemented by interviews with experts on leprosy and its control. Archived documents, medical records, disease prevalence censuses conducted since 1942, and incidence and prevalence statistics for 1960-2015 from the Ministry of Public Health's National Statistics Division were reviewed. Reports and scientific literature published on the Program and the history of leprosy in Cuba were also reviewed. DEVELOPMENT Leprosy has been documented in Cuba since 1613. In 1938, the Leprosy Foundation was created with ten dispensaries nationwide for diagnosis and treatment. The first National Leprosy Control Program was established in 1962, implemented in 1963 and revised five times. In 1972, leper colonies were closed and treatment became ambulatory. In 1977, rifampicin was introduced. In 1988, the Program instituted controlled, decentralized, community-based multidrug treatment and established the criteria for considering a patient cured. In 2003, it included actions aimed at early diagnosis and prophylactic treatment of contacts. Since 2008, it prioritizes actions directed toward the population at risk, maintaining five-year followup with dermatological and neurological examination. Primary health care carries out diagnostic and treatment activities. The lowest leprosy incidence of 1.6 per 100,000 population was achieved in 2006. Since 2002, prevalence has remained steady at 0.2 per 10,000 population. Leprosy ceased to be considered a public health problem in Cuba as of 1993. In 1990-2015, 1.6% of new leprosy patients were aged <15 years. At present, late diagnosis of cases exceeds 20%, which leads to a high percentage of grade 2 disability in such patients. Spontaneous physician visits by already symptomatic patients surpassed 70% of cases diagnosed in 2010-2015. CONCLUSIONS Actions undertaken after initial detection of leprosy in Cuba failed to control it. Effective control began in 1963, with the implementation of the National Leprosy Control Program, whose systematic actions have had an impact on trends in leprosy, reflected in WHO's 1993 declaration that leprosy was no longer a public health problem in Cuba. KEYWORDS Leprosy, Mycobacterium leprae, history of medicine, epidemiology, communicable disease control, Cuba.

Abstract B46: Tetra-O-methyl nordihydroguaiaretic acid broadly suppresses cancer metabolism and synergistically induces strong anticancer activity in combination with Etoposide, Rapamycin and UCN-01

Abstract We have been developing an anticancer drug, Tetra-O-methyl nordihydroguaiaretic acid (M4N), for many years. M4N is currently in Phase I/II clinical trials in patients with various advanced cancer. The results of these clinical trials so far indicate that M4N has a certain degree of anticancer activity, but was unable to induce remission in any of these patients with advanced cancers. One of the most frequently attempted strategy to increase anticancer efficacy of chemotherapy drugs is combination treatment with one or more appropriately selected drugs. An important finding from the clinical trials with M4N is that the toxicity of the drug was very low. Patients were able to tolerate high doses of M4N with minimal side-effects, which make this drug very suitable for being use in multidrug treatments (for instance the LD50 of M4N for mice is greater than 1000mg/kg while that of NDGA, a parental compound for M4N, is only 75mg/kg). In this study the ability of M4N to induce rapid cell death in combination with Etoposide, Rapamycin, or UCN-01 was examined in LNCaP cells, both in cell culture and animal experiments. Mice treated with M4N drug combinations with either Etoposide or Rapamycin showed no evidence of tumor and had a 100% survival rate 100 days after tumor implantation. By comparison all other vehicles or single drug treated mice failed to survive longer than 30 days after implantation. This synergistic improvement of anticancer effect was also confirmed in more than 20 cancer cell lines including several pancreatic cell lines (AsPC-1, CAK24, Panc1.98, and Panc215). In LNCaP cells, M4N was found to reduce cellular ATP content, and suppress NDUFS1 expression while inducing hyperpolarization of mitochondrial membrane potential. M4N-treated cells lacked autophagy with reduced expression of BNIP3 and ATG5. To understand the mechanisms of this anticancer activity of M4N, the effect of this drug on three cancer cell lines (LNCaP prostatic, AsPC-1 pancreatic, and L428 leukemic cells) was further examined via transcriptome and metabolomics analyses. Metabolomic results showed that there were reductions of 26 metabolites essential for energy generation and/or production of cellular components in common with these three cell lines following 8 hours of M4N treatment. Deep RNA sequencing analysis demonstrated that there were sixteen genes whose expressions were found to be modulated following 6 hours of M4N treatment similarly in these three cell lines. Six out of these 16 genes were functionally related to the 26 metabolites described above. One of these up-regulated genes encodes for CHAC1, a key enzyme affecting the stress pathways through its degradation of glutathione. In fact M4N was found to suppress glutathione content and induce reactive oxygen species production. The data overall indicate that M4N has profound specific negative impacts on a wide range of cancer metabolisms supporting the use of M4N combination treatments for cancers of various origins including pancreas. Citation Format: Kotohiko Kimura, Ru Chih C. Huang.{Authors}. Tetra-O-methyl nordihydroguaiaretic acid broadly suppresses cancer metabolism and synergistically induces strong anticancer activity in combination with Etoposide, Rapamycin and UCN-01. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B46.

Effect of Tea Polyphenol Compounds on Anticancer Drugs in Terms of Anti-Tumor Activity, Toxicology, and Pharmacokinetics.

Multidrug resistance and various adverse side effects have long been major problems in cancer chemotherapy. Recently, chemotherapy has gradually transitioned from mono-substance therapy to multidrug therapy. As a result, the drug cocktail strategy has gained more recognition and wider use. It is believed that properly-formulated drug combinations have greater therapeutic efficacy than single drugs. Tea is a popular beverage consumed by cancer patients and the general public for its perceived health benefits. The major bioactive molecules in green tea are catechins, a class of flavanols. The combination of green tea extract or green tea catechins and anticancer compounds has been paid more attention in cancer treatment. Previous studies demonstrated that the combination of chemotherapeutic drugs and green tea extract or tea polyphenols could synergistically enhance treatment efficacy and reduce the adverse side effects of anticancer drugs in cancer patients. In this review, we summarize the experimental evidence regarding the effects of green tea-derived polyphenols in conjunction with chemotherapeutic drugs on anti-tumor activity, toxicology, and pharmacokinetics. We believe that the combination of multidrug cancer treatment with green tea catechins may improve treatment efficacy and diminish negative side effects.

Leukemic Stem Cells Identities: A Philosophical Analysis

What are leukemic stem cells (LSCs)? This is a biological, a semantic, and a philosophical question. Leukemic stem cells raise a number of questions for onco-hematologists in particular when it comes to their clinical relevance. What are their functions in the initiation and in the progression of the disease? How to identify them? How to target them without damaging the non-malignant hematopoietic stem cells (HSCs)? Given that LSCs come from HSCs or progenitors, a semantic question arises: should we rather call them leukemic initiating cells? or leukemic propagating cells? As a philosopher, I approach all these biological and semantic issues with a slightly different perspective. Instead of asking what are LSCs, I will start by asking what kind of property is stemness.In previous work, I performed an analysis of the scientific literature on stem cells (including cancer stem cells) and framed a classification of their possible identities (Laplane, HUP 2016; reviewed in Clevers, Nature 2016):Categorical: stemness is a purely intrinsic property (e.g. of categorical property: the atomic number of chemical elements).Dispositional: stemness is an intrinsic property whose expression depends on extrinsic stimuli from the niche (e.g. of dispositional property: fragility).Relational: stemness is an extrinsic property that depends on a relationship between the cell and its environment; the microenvironment can induce stemness (e.g. of relational property: being the sister of someone).Systemic: stemness is an extrinsic property, maintained and controlled at the level of the system (e.g. of systemic properties: soccer positions that depend on the system of play)Here, I applied this framework to LSCs, in particular in acute myeloid leukemia. This analysis of the identity of stemness matters for onco-hematology because we cannot get rid of categorical, disposition, relational, and systemic properties in the same way. Thus, different therapeutic strategies will have different efficacy depending on the identity of LSCs. For example, targeting LSCs will be much more efficient if they are categorical or dispositional. Targeting the stem cell niche will be more efficient if they are dispositional or relational. But both strategies will lack efficiency if they are systemic. In such cases multi-drug treatments will predictably be more appropriate than targeted therapies.We think about properties as having fixed identities. This is how we study, learn, teach, and investigate biology, and more generally this is how we think. This typological thinking, inherited from Aristotle and Plato, applies well to normal hematopoiesis where most if not all reports describe stemness as a dispositional property. However, the progression of hematological malignancies, from clonal hematopoiesis and pre-malignant stages to chronic and acute leukemia, questions the relevance of this typological thinking in cancer. A first question is whether HSCs, pre-LSCs, and LSCs have the same identity. A second one is whether LSCs of different hematological malignancies and the LSCs in one patient all have the same identity. I will discuss cases of genetic and epigenetic alterations that suggest possible switches in stemness identity and their consequences for therapies.To conclude, I used a classical philosophical method developed in three steps: i- analysis of the scientific literature, ii- production of conceptual distinctions, iii- analysis of their consequences. I suggested the distinction between four stemness identities (categorical, dispositional, relational, systemic). HSCs fits the dispositional identity, suggesting that both LSCs-targeting and niche-targeting therapies could be efficient (provided that we can identity and target them properly). However, the identity of LSCs can differ from that of HSCs. Moreover, in contrast with HSCs that have one unique and stable identity, LSCs can be categorical, dispositional, relational, or systemic, and they can switch from one to another identity following particular genetic and epigenetic insults. This drastically complicates the therapeutic approaches and highlights the need to develop multiple therapies.ReferencesLaplane L, Cancer Stem Cells: Philosophy and Therapies. Harvard University Press, Cambridge (MA), 2016.Clevers H, Cancer Therapy: Defining Stemness. Nature 2016; 534(7606): 176-177. DisclosuresNo relevant conflicts of interest to declare.

Epigallocatechin Gallate Remodels Overexpressed Functional Amyloids in Pseudomonas aeruginosa and Increases Biofilm Susceptibility to Antibiotic Treatment

Epigallocatechin-3-gallate (EGCG) is the major polyphenol in green tea. It has antimicrobial properties and disrupts the ordered structure of amyloid fibrils involved in human disease. The antimicrobial effect of EGCG against the opportunistic pathogen Pseudomonas aeruginosa has been shown to involve disruption of quorum sensing (QS). Functional amyloid fibrils in P. aeruginosa (Fap) are able to bind and retain quorum-sensing molecules, suggesting that EGCG interferes with QS through structural remodeling of amyloid fibrils. Here we show that EGCG inhibits the ability of Fap to form fibrils; instead, EGCG stabilizes protein oligomers. Existing fibrils are remodeled by EGCG into non-amyloid aggregates. This fibril remodeling increases the binding of pyocyanin, demonstrating a mechanism by which EGCG can affect the QS function of functional amyloid. EGCG reduced the amyloid-specific fluorescent thioflavin T signal in P. aeruginosa biofilms at concentrations known to exert an antimicrobial effect. Nanoindentation studies showed that EGCG reduced the stiffness of biofilm containing Fap fibrils but not in biofilm with little Fap. In a combination treatment with EGCG and tobramycin, EGCG had a moderate effect on the minimum bactericidal eradication concentration against wild-type P. aeruginosa biofilms, whereas EGCG had a more pronounced effect when Fap was overexpressed. Our results provide a direct molecular explanation for the ability of EGCG to disrupt P. aeruginosa QS and modify its biofilm and strengthens the case for EGCG as a candidate in multidrug treatment of persistent biofilm infections.

Investigation into the Solid and Solution Properties of Known and Novel Polymorphs of the Antimicrobial Molecule Clofazimine

Clofazimine is an anti-mycobacterial agent used as part of a multidrug treatment for leprosy. Recently clofazimine has shown promising activity against multidrug resistant tuberculosis. Clofazimine has been previously known to exist in two different crystal forms, or polymorphs, which are triclinic (F I) and monoclinic (F II) in crystal structure. The thermodynamic relationship between, and the solubility of, these different crystal structures of clofazimine has not previously been characterized. In this work, their solid and solution properties are studied, and as a result, two novel polymorphs of clofazimine (an orthorhombic crystal polymorph and a high temperature polymorph with a monoclinic structure) are reported. The properties of these new solid forms are compared and contrasted with those of the two previously reported polymorphs using thermal, spectroscopic, and microscopic techniques. Molecular modeling studies were also carried out to predict the relative thermodynamic relationship and the crys...

Successful co-encapsulation of benzoyl peroxide and chloramphenicol in liposomes by a novel manufacturing method - dual asymmetric centrifugation

Encapsulation of more than one active pharmaceutical ingredient into nanocarriers such as liposomes is an attractive approach to achieve a synergic drug effect and less complicated dosing schedules in multi-drug treatment regimes. Liposomal drug delivery in acne treatment may improve drug efficiency by targeted delivery to pilosebaceous units, reduce adverse effects and improve patient compliance. We therefore aimed to co-encapsulate benzoyl peroxide (BPO) and chloramphenicol (CAM) into liposomes using the novel liposome processing method – dual asymmetric centrifugation (DAC). Liposomes were formed from soybean lecithin, propylene glycol and distilled water (2:1:2w/v/v ratio), forming a viscous liposome dispersion. Liposomes containing both drugs (BPO-CAM-Lip), single drug (BPO-Lip and CAM-Lip), and empty liposomes were prepared. Drug entrapment of BPO and CAM was determined by a newly developed HPLC method for simultaneous detection and quantification of both drugs. Encapsulation of around 50% for BPO and 60% for CAM respectively was obtained in both single-drug encapsulated formulations (BPO-Lip and CAM-Lip) and co-encapsulated formulations (BPO-CAM-Lip). Liposome sizes were comparable for all liposome formulations, ranging from 130 to 150nm mean diameter, with a polydispersity index <0.2 for all formulations. CAM exhibited a sustained release from all liposomal formulations, whereas BPO appeared retained within the liposomes. BPO retention could be attributed to its poor solubility. However, HaCaT cell toxicity was found dependent on BPO released from the liposomes. In the higher concentration range (4%v/v), liposomal formulations were less cytotoxic than the corresponding drug solutions used as reference. We have demonstrated that DAC is a fast, easy, suitable method for encapsulation of more than one drug within the same liposomes.

Achieving remission of proteinuria in childhood CKD.

A multidrug treatment strategy that targets urinary proteins with an angiotensin-converting enzyme (ACE) inhibitor and angiotensin receptor blocker (ARB) up-titrated to the respective maximum tolerated dose combined with intensified blood pressure (BP) control has been found to prevent renal function loss in adults with proteinuric nephropathies. Herein, we investigated the effects of this treatment protocol in the pediatric patient population. From May 2002 to September 2014 we included in this observational, longitudinal, cohort study 20 consecutive children with chronic nephropathies and 24-h proteinuria of >200mg who had received ramipril and losartan up-titrated to the respective maximum approved and tolerated doses [mean (standard deviation) dose:2.48 (1.37)mg/m2 and 0.61(0.46)mg/kg daily, respectively]. The primary efficacy endpoint was a >50% reduction in 24-h proteinuria to <200mg (remission). Secondary outcomes included changes in proteinuria, serum albumin, BP, and glomerular filtration rate (GFR). Mean (± standard deviation) patient age at inclusion was 13.8 ± 2.8years, and the median [interquartile range (IQR)] serum creatinine level and proteinuria were 0.7(0.6-1.0) mg/dl and 690 (379-1270) mg/24h or 435 (252-711) mg/m2/24h, respectively. Proteinuria significantly decreased by month 6 of follow-up, and serum albumin levels increased over a median follow-up period of 78 (IQR 39-105) months. In the nine children who achieved remission, proteinuria reduction persisted throughout the whole follow-up without rebounds. The GFR improved in those children who achieved remission and worsened in those who did not. The mean GFR slopes differed significantly between these two groups (p < 0.05), being positive in those children with remission and negative in those without remission (+0.023 ± 0.15 vs.-0.014 ± 0.23ml/min/1.73m2/month, respectively), whereas BP control was similar between the two groups. Hyperkalemia was observed in two children. Combination therapy with maximum approved doses of ACE inhibitors and ARBs is a safe strategy which may achieve proteinuria remission with kidney function stabilization or even improvement in a substantial proportion of children with proteinuric nephropathies.

Executive Summary: Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis.

The American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America jointly sponsored the development of this guideline for the treatment of drug-susceptible tuberculosis, which is also endorsed by the European Respiratory Society and the US National Tuberculosis Controllers Association. Representatives from the American Academy of Pediatrics, the Canadian Thoracic Society, the International Union Against Tuberculosis and Lung Disease, and the World Health Organization also participated in the development of the guideline. This guideline provides recommendations on the clinical and public health management of tuberculosis in children and adults in settings in which mycobacterial cultures, molecular and phenotypic drug susceptibility tests, and radiographic studies, among other diagnostic tools, are available on a routine basis. For all recommendations, literature reviews were performed, followed by discussion by an expert committee according to the Grading of Recommendations, Assessment, Development and Evaluation methodology. Given the public health implications of prompt diagnosis and effective management of tuberculosis, empiric multidrug treatment is initiated in almost all situations in which active tuberculosis is suspected. Additional characteristics such as presence of comorbidities, severity of disease, and response to treatment influence management decisions. Specific recommendations on the use of case management strategies (including directly observed therapy), regimen and dosing selection in adults and children (daily vs intermittent), treatment of tuberculosis in the presence of HIV infection (duration of tuberculosis treatment and timing of initiation of antiretroviral therapy), as well as treatment of extrapulmonary disease (central nervous system, pericardial among other sites) are provided. The development of more potent and better-tolerated drug regimens, optimization of drug exposure for the component drugs, optimal management of tuberculosis in special populations, identification of accurate biomarkers of treatment effect, and the assessment of new strategies for implementing regimens in the field remain key priority areas for research. See the full-text online version of the document for detailed discussion of the management of tuberculosis and recommendations for practice.

Clinical Characteristics, Treatment Outcomes, and Resistance Mutations Associated with Macrolide-Resistant Mycobacterium avium Complex Lung Disease.

Macrolide antibiotics are key components of the multidrug treatment regimen for treating lung disease (LD) due to Mycobacterium avium complex (MAC). Despite the emergence of macrolide resistance, limited data are available on macrolide-resistant MAC-LD. This study evaluated the clinical features and treatment outcomes of patients with macrolide-resistant MAC-LD and the molecular characteristics of the macrolide-resistant isolates. A retrospective review of the medical records of 34 patients with macrolide-resistant MAC-LD who were diagnosed between January 2002 and December 2014 was performed, along with genetic analysis of 28 clinical isolates. Nineteen (56%) patients had the fibrocavitary form of MAC-LD, and 15 (44%) had the nodular bronchiectatic form. M. intracellulare was the etiologic organism in 21 (62%) patients. Approximately two-thirds (22/34 [65%]) of the patients had been treated with currently recommended multidrug regimens that included macrolide, ethambutol, and rifamycin prior to the emergence of macrolide resistance, and none had been treated with macrolide monotherapy. The median duration of treatment after the detection of macrolide resistance was 23.0 months (interquartile range, 16.8 to 45.3 months). Treatment outcomes were poor after the development of macrolide resistance, with favorable treatment outcomes achieved in only five (15%) patients, including two patients who underwent surgical resection. One-, 3-, and 5-year mortality rates were 9, 24, and 47%, respectively. Molecular analysis of 28 clinical isolates revealed that 96% (27/28) had point mutations at position 2058 or 2059 of the 23S rRNA gene. Our analyses indicate that more effective therapy is needed to treat macrolide-resistant MAC-LD and prevent its development.

Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis.

The American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America jointly sponsored the development of this guideline for the treatment of drug-susceptible tuberculosis, which is also endorsed by the European Respiratory Society and the US National Tuberculosis Controllers Association. Representatives from the American Academy of Pediatrics, the Canadian Thoracic Society, the International Union Against Tuberculosis and Lung Disease, and the World Health Organization also participated in the development of the guideline. This guideline provides recommendations on the clinical and public health management of tuberculosis in children and adults in settings in which mycobacterial cultures, molecular and phenotypic drug susceptibility tests, and radiographic studies, among other diagnostic tools, are available on a routine basis. For all recommendations, literature reviews were performed, followed by discussion by an expert committee according to the Grading of Recommendations, Assessment, Development and Evaluation methodology. Given the public health implications of prompt diagnosis and effective management of tuberculosis, empiric multidrug treatment is initiated in almost all situations in which active tuberculosis is suspected. Additional characteristics such as presence of comorbidities, severity of disease, and response to treatment influence management decisions. Specific recommendations on the use of case management strategies (including directly observed therapy), regimen and dosing selection in adults and children (daily vs intermittent), treatment of tuberculosis in the presence of HIV infection (duration of tuberculosis treatment and timing of initiation of antiretroviral therapy), as well as treatment of extrapulmonary disease (central nervous system, pericardial among other sites) are provided. The development of more potent and better-tolerated drug regimens, optimization of drug exposure for the component drugs, optimal management of tuberculosis in special populations, identification of accurate biomarkers of treatment effect, and the assessment of new strategies for implementing regimens in the field remain key priority areas for research. See the full-text online version of the document for detailed discussion of the management of tuberculosis and recommendations for practice.

Addressing drug-drug and drug-food interactions through personalized empowerment services for healthcare.

Personalized healthcare systems support the provision of timely and appropriate information regarding healthcare options and treatment alternatives. Especially for patients that receive multi-drug treatments a key issue is the minimization of the risk of adverse effects due to drug-drug interactions (DDIs). DDIs may be the result of doctor prescribed drugs but also due to self-medication of conventional drugs, alternative medicines, food habits, alcohol or smoking. It is therefore crucial for personalized health systems, apart from assisting physicians for optimal prescription practices, to also provide appropriate information for individual users for drug-drug interactions or similar information regarding risks for modulation of the ensuing treatment. In this manuscript we describe a DDI service including drug-food, drug-herb and other lifestyle-related factors, developed in the context of a personalized patient empowerment platform. The solution enables guidance to patients for their medication on how to reduce the risk of unwanted drug interactions and side effects in a seamless and transparent way. We present and analyze the implemented services and provide examples on using an alerting service to identify potential DDIs in two different chronic diseases, congestive heart failure and osteoarthritis.