Disease and pharmacologic risk factors for first and subsequent episodes of equine laminitis: A cohort study of free-text electronic medical records.

Prev Vet Med. 2017 Jan 01;136:11-18

Authors: Welsh CE, Duz M, Parkin TD, Marshall JF

Abstract
Electronic medical records from first opinion equine veterinary practice may represent a unique resource for epidemiologic research. The appropriateness of this resource for risk factor analyses was explored as part of an investigation into clinical and pharmacologic risk factors for laminitis. Amalgamated medical records from seven UK practices were subjected to text mining to identify laminitis episodes, systemic or intra-synovial corticosteroid prescription, diseases known to affect laminitis risk and clinical signs or syndromes likely to lead to corticosteroid use. Cox proportional hazard models and Prentice, Williams, Peterson models for repeated events were used to estimate associations with time to first, or subsequent laminitis episodes, respectively. Over seventy percent of horses that were diagnosed with laminitis suffered at least one recurrence. Risk factors for first and subsequent laminitis episodes were found to vary. Corticosteroid use (prednisolone only) was only significantly associated with subsequent, and not initial laminitis episodes. Electronic medical record use for such analyses is plausible and offers important advantages over more traditional data sources. It does, however, pose challenges and limitations that must be taken into account, and requires a conceptual change to disease diagnosis which should be considered carefully.

PMID: 28010903 [PubMed - in process]

Novel Treatments for Rare Cancers: The U.S. Orphan Drug Act Is Delivering-A Cross-Sectional Analysis.

Oncologist. 2016 Apr;21(4):487-93

Authors: Stockklausner C, Lampert A, Hoffmann GF, Ries M

Abstract
BACKGROUND: Rare cancers are a heterogeneous group of conditions with highly unmet medical needs. Although infrequent in individuals, rare cancers affect millions of people who deserve effective treatments. Therefore, we systematically analyzed the impact of the U.S. Orphan Drug Act of 1983 on delivery of novel treatments for rare cancers.
METHODS: Quantitative cross-sectional analysis was conducted on the U.S. Food and Drug Administration Orphan Drug Product database according to Strengthening the Reporting of Observational Studies in Epidemiology Statement criteria between 1983 and 2015.
RESULTS: Since 1983, a total of 177 approvals have originated from 1,391 orphan drug designations to treat rare cancers, which represents 36% of all approvals within the U.S. orphan drug act (n = 492). Two compounds (1%) to treat rare cancer were withdrawn after approval. Median time from designation to approval was 2.49 years (interquartile range 1.13-4.64) and decreased significantly over time (p < .001, linear regression). Over the last decade, rare cancer treatments have been transformed from nonspecific cytotoxic agents toward targeted therapies, such as protein kinase inhibitors and monoclonal antibodies, representing the largest groups of innovative rare cancer treatments today. Most compounds were approved to treat solid tumors and hematological malignancies.
CONCLUSION: The U.S. Orphan Drug Act and associated incentives, such as 7 years of marketing exclusivity, have fostered delivery of novel treatments for rare cancers. More than one-third of all orphan drug approvals address needs of patients suffering from rare cancers. Over the last decade, the understanding of tumorigenesis and genetic driver mutations in different tumor entities has produced innovative treatments, of which many were first approved within the U.S. Orphan Drug Act.
IMPLICATIONS FOR PRACTICE: Over the last 30 years, the U.S. Orphan Drug Act successfully delivered numerous novel treatments for rare cancers, of which some were subsequently used in other, nonorphan indications. The understanding of molecular mechanisms of diseases is directly connected to the search for novel therapies. The constant pursuit to translate basic research findings into clinical practice is a crucial prerequisite to address unmet medical needs in rare cancers, as in other rare diseases. Oncological drug development proves to be a major player in overall orphan drug research, displayed by more than one-third of all U.S. Food and Drug Administration-approved orphan drugs with oncological indications.

PMID: 27022038 [PubMed - indexed for MEDLINE]

[Pathophysiology of systemic sclerosis].

Med Sci (Paris). 2016 Feb;32(2):183-91

Authors: Allanore Y

Abstract
Systemic sclerosis (SSc) is an orphan disease affecting the connective tissue. The cause of SSc remains unknown but is likely to involve environmental factors in a genetically primed individual with SSc belonging to the multigenic disorders. Pathogenesis is dominated by early microvascular changes targeting endothelial cells and with the release of several mediators promoting an inflammatory response and vascular remodelling. Several lines of evidence position autoimmunity as a key perpetuating event with activation of both innate and adaptive immunity and with the production of distinct autoantibodies. The cascade ultimates with the fibrosis defined by accumulation of extra-cellular matrix through an imbalance between synthesis and degradation of several components and mesenchymal cell activation and differentiation controlled by a large number of autocrine and paracrine factors.

PMID: 26936176 [PubMed - indexed for MEDLINE]

The functional mechanisms and clinical application of read-through drugs.

Yi Chuan. 2016 Jul 20;38(7):623-633

Authors: Yang F, Zaiyue S, Mingmin G

Abstract
According to previous reports, nearly one in 10 genetic diseases are caused by nonsense mutations around the world. Nonsense mutations lead to premature transcription terminations in cells, which in turn generate non-functional, truncated proteins. In recent years, read-through drugs are playing increasing prominent roles in the researches related to genetic diseases caused by nonsense mutations. However, due to the fact that the mechanisms lying behind translation termination still remain to be elucidated, the mechanistic research and clinical application of read-through drugs are facing new challenges. This review mainly discusses about the pathogenesis of genetic diseases caused by nonsense mutations, and then introduces the current clinical application of read-through drugs. Finally, we display some problems that remain to be solved and propose some possible coping strategies.

PMID: 27733335 [PubMed - indexed for MEDLINE]

RNA Structural Determinants of Optimal Codons Revealed by MAGE-Seq.

Cell Syst. 2016 Dec 21;3(6):563-571.e6

Authors: Kelsic ED, Chung H, Cohen N, Park J, Wang HH, Kishony R

Abstract
Synonymous codon choices at the beginning of genes optimize 5' RNA structures for enhanced translation initiation, but less is known about mechanisms that drive codon optimization downstream within the gene. To understand what determines codon choices across a gene, we generated 12,726 in situ codon mutants in the Escherichia coli essential gene infA and measured their fitness by combining multiplex automated genome engineering mutagenesis with amplicon deep sequencing (MAGE-seq). Correlating predicted 5' RNA structure with fitness revealed that codons even far from the start of the gene are deleterious if they disrupt the native 5' RNA conformation. These long-range structural interactions generate context-dependent rules that constrain codon choices beyond intrinsic codon preferences. Genome-wide RNA folding predictions confirm that natural codon choices far from the start codon are optimized in part to prevent disruption of native structures near the 5' UTR. Our results shed light on natural codon distributions and should improve engineering of gene expression for synthetic biology applications.

PMID: 28009265 [PubMed]

Principles of Systems Biology, No. 12.

Cell Syst. 2016 Dec 21;3(6):504-506

Authors:

Abstract
This month: Plants take center stage with fascinating insights into disease susceptibility and engineered pathways for photosynthesis. Also, a wearable stethoscope, new noncanonical miRNA targeting rules, Hsf1, and transcription.

PMID: 28009259 [PubMed]

Interneuronal mechanisms of hippocampal theta oscillation in a full-scale model of the rodent CA1 circuit.

Elife. 2016 Dec 23;5:

Authors: Bezaire MJ, Raikov I, Burk K, Vyas D, Soltesz I

Abstract
The hippocampal theta rhythm plays important roles in information processing; however, the mechanisms of its generation are not well understood. We developed a data-driven, supercomputer-based, full-scale (1:1) model of the rodent CA1 area and studied its interneurons during theta oscillations. Theta rhythm with phase-locked gamma oscillations and phase-preferential discharges of distinct interneuronal types spontaneously emerged from the isolated CA1 circuit without rhythmic inputs. Perturbation experiments identified parvalbumin-expressing interneurons and neurogliaform cells, as well as interneuronal diversity itself, as important factors in theta generation. These simulations reveal new insights into the spatiotemporal organization of the CA1 circuit during theta oscillations.

PMID: 28009257 [PubMed - as supplied by publisher]

Impact of late presentation of HIV infection on short-, mid- and long-term mortality and causes of death in a multicenter national cohort: 2004-2013.

J Infect. 2016 May;72(5):587-96

Authors: Sobrino-Vegas P, Moreno S, Rubio R, Viciana P, Bernardino JI, Blanco JR, Bernal E, Asensi V, Pulido F, del Amo J, Hernando V, Cohorte de la Red de Investigación en Sida, Spain

Abstract
OBJECTIVES: To analyze the impact of late presentation (LP) on overall mortality and causes of death and describe LP trends and risk factors (2004-2013).
METHODS: Cox models and logistic regression were used to analyze data from a nation-wide cohort in Spain. LP is defined as being diagnosed when CD4 < 350 cells/ml or AIDS.
RESULTS: Of 7165 new HIV diagnoses, 46.9% (CI95%:45.7-48.0) were LP, 240 patients died. First-year mortality was the highest (aHRLP.vs.nLP = 10.3[CI95%:5.5-19.3]); between 1 and 4 years post-diagnosis, aHRLP.vs.nLP = 1.9(1.2-3.0); and >4 years, aHRLP.vs.nLP = 1.5(0.7-3.1). First-year's main cause of death was HIV/AIDS (73%); and malignancies among those surviving >4 years (32%). HIV/AIDS-related deaths were more likely in LP (59.2% vs. 25.0%; p < 0.001). LP declined from 55.9% (2004-05) to 39.4% (2012-13), and reduced in 46.1% in men who have sex with men (MSM) and 37.6% in heterosexual men, but increased in 22.6% in heterosexual women. Factors associated with LP: sex (ORMEN.vs.WOMEN = 1.4[1.2-1.7]); age (OR31-40.vs.<30 = 1.6[1.4-1.8], OR41-50.vs.<30 = 2.2[1.8-2.6], OR>50.vs.<30 = 3.6[2.9-4.4]); behavior (ORInjectedDrugUse.vs.MSM = 2.8[2.0-3.8]; ORHeterosexual.vs.MSM = 2.2[1.7-3.0]); education (ORPrimaryEducation.vs.University = 1.5[1.1-2.0], ORLowerSecondary.vs.University = 1.3[1.1-1.5]); and geographical origin (ORSub-Saharan.vs.Spain = 1.6[1.3-2.0], ORLatin-American.vs.Spain = 1.4[1.2-1.8]).
CONCLUSIONS: LP is associated with higher mortality, especially short-term- and HIV/AIDS-related mortality. Mid-term-, but not long-term mortality, remained also higher in LP than nLP. LP decreased in MSM and heterosexual men, not in heterosexual women. The groups most affected by LP are low educated, non-Spanish and heterosexual women.

PMID: 26920789 [PubMed - indexed for MEDLINE]

FLP-4 neuropeptide and its receptor in a neuronal circuit regulate preference choice through functions of ASH-2 trithorax complex in Caenorhabditis elegans.

Sci Rep. 2016 Feb 18;6:21485

Authors: Yu Y, Zhi L, Guan X, Wang D, Wang D

Abstract
Preference choice on food is an important response strategy for animals living in the environment. Using assay system of preference choice on bacterial foods, OP50 and PA14, we identified the involvement of ADL sensory neurons in the control of preference choice in Caenorhabditis elegans. Both genetically silencing and ChR2-mediated activation of ADL sensory neurons significantly affected preference choice. ADL regulated preference choice by inhibiting function of G protein-coupled receptor (GPCR)/SRH-220. ADL sensory neurons might regulate preference choice through peptidergic signals of FLP-4 and NLP-10, and function of FLP-4 or NLP-10 in regulating preference choice was regulated by SRH-220. FLP-4 released from ADL sensory neurons further regulated preference choice through its receptor of NPR-4 in AIB interneurons. In AIB interneurons, NPR-4 was involved in the control of preference choice by activating the functions of ASH-2 trithorax complex consisting of SET-2, ASH-2, and WDR-5, implying the crucial role of molecular machinery of trimethylation of histone H3K4 in the preference choice control. The identified novel neuronal circuit and the underlying molecular mechanisms will strengthen our understanding neuronal basis of preference choice in animals.

PMID: 26887501 [PubMed - indexed for MEDLINE]

10 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"cystic fibrosis"

These pubmed results were generated on 2016/12/23

PubMed comprises more than 24 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Drug Repositioning for Alzheimer's Disease Based on Systematic 'omics' Data Mining.

PLoS One. 2016;11(12):e0168812

Authors: Zhang M, Schmitt-Ulms G, Sato C, Xi Z, Zhang Y, Zhou Y, St George-Hyslop P, Rogaeva E

Abstract
Traditional drug development for Alzheimer's disease (AD) is costly, time consuming and burdened by a very low success rate. An alternative strategy is drug repositioning, redirecting existing drugs for another disease. The large amount of biological data accumulated to date warrants a comprehensive investigation to better understand AD pathogenesis and facilitate the process of anti-AD drug repositioning. Hence, we generated a list of anti-AD protein targets by analyzing the most recent publically available 'omics' data, including genomics, epigenomics, proteomics and metabolomics data. The information related to AD pathogenesis was obtained from the OMIM and PubMed databases. Drug-target data was extracted from the DrugBank and Therapeutic Target Database. We generated a list of 524 AD-related proteins, 18 of which are targets for 75 existing drugs-novel candidates for repurposing as anti-AD treatments. We developed a ranking algorithm to prioritize the anti-AD targets, which revealed CD33 and MIF as the strongest candidates with seven existing drugs. We also found 7 drugs inhibiting a known anti-AD target (acetylcholinesterase) that may be repurposed for treating the cognitive symptoms of AD. The CAD protein and 8 proteins implicated by two 'omics' approaches (ABCA7, APOE, BIN1, PICALM, CELF1, INPP5D, SPON1, and SOD3) might also be promising targets for anti-AD drug development. Our systematic 'omics' mining suggested drugs with novel anti-AD indications, including drugs modulating the immune system or reducing neuroinflammation that are particularly promising for AD intervention. Furthermore, the list of 524 AD-related proteins could be useful not only as potential anti-AD targets but also considered for AD biomarker development.

PMID: 28005991 [PubMed - in process]

Transcriptome analyses identify key cellular factors associated with HIV-1 associated neuropathogenesis in infected men.

AIDS. 2016 Dec 21;:

Authors: Venkatachari NJ, Jain S, Walker L, Bivalkar-Mehla S, Chattopadhyay A, Bar-Joseph Z, Rinaldo C, Ragin A, Seaberg E, Levine A, Becker J, Martin E, Sacktor N, Ayyavoo V

Abstract
OBJECTIVE: HIV-1 viral proteins and host inflammatory factors have a direct role in neuronal toxicity in in vitro, however, the contribution of these factors in vivo in HIV-1 associated neurocognitive disorder (HAND) is not fully understood. We applied novel Systems Biology approaches to identify specific cellular and viral factors and their related pathways that are associated with different stages of HAND.
DESIGN: A cross-sectional study of individuals enrolled in the Multicenter AIDS Cohort Study (MACS) including HIV-1 seronegative (N = 36) and HIV-1 seropositive individuals without neurocognitive symptoms (N = 16), or with mild neurocognitive disorder (MND) (N = 8) or HIV-associated dementia (HAD) (N = 16).
METHODS: A systematic evaluation of global transcriptome of peripheral blood mononuclear cells (PBMCs) obtained from HIV-1 seronegative individuals and from HIV-1 positive men without neurocognitive symptoms, or MND or HAD was performed.
RESULTS: MND and HAD were associated with specific changes in mRNA transcripts and miRNAs in PBMCs. Comparison of upstream regulators and TimePath analyses identified specific cellular factors associated with MND and HAD, while HIV-1 viral proteins played a greater role in HAD. Additionally, expression of specific microRNAs - miR-let-7a, miR-124, miR-15a and others were found to correlate with mRNA gene expression and may have a potential protective role in asymptomatic HIV-1 seropositive individuals by regulating cellular signal transduction pathways downstream of chemokines and cytokines.
CONCLUSIONS: These results identify signature transcriptome changes in PBMCs associated with stages of HAND and shed light on the potential contribution of host cellular factors and viral proteins in HAND development.

PMID: 28005686 [PubMed - as supplied by publisher]

Data-intensive drug development in the information age: applications of Systems Biology/Pharmacology/Toxicology.

J Toxicol Sci. 2016;41(Special):SP15-SP25

Authors: Kiyosawa N, Manabe S

Abstract
Pharmaceutical companies continuously face challenges to deliver new drugs with true medical value. R&D productivity of drug development projects depends on 1) the value of the drug concept and 2) data and in-depth knowledge that are used rationally to evaluate the drug concept's validity. A model-based data-intensive drug development approach is a key competitive factor used by innovative pharmaceutical companies to reduce information bias and rationally demonstrate the value of drug concepts. Owing to the accumulation of publicly available biomedical information, our understanding of the pathophysiological mechanisms of diseases has developed considerably; it is the basis for identifying the right drug target and creating a drug concept with true medical value. Our understanding of the pathophysiological mechanisms of disease animal models can also be improved; it can thus support rational extrapolation of animal experiment results to clinical settings. The Systems Biology approach, which leverages publicly available transcriptome data, is useful for these purposes. Furthermore, applying Systems Pharmacology enables dynamic simulation of drug responses, from which key research questions to be addressed in the subsequent studies can be adequately informed. Application of Systems Biology/Pharmacology to toxicology research, namely Systems Toxicology, should considerably improve the predictability of drug-induced toxicities in clinical situations that are difficult to predict from conventional preclinical toxicology studies. Systems Biology/Pharmacology/Toxicology models can be continuously improved using iterative learn-confirm processes throughout preclinical and clinical drug discovery and development processes. Successful implementation of data-intensive drug development approaches requires cultivation of an adequate R&D culture to appreciate this approach.

PMID: 28003636 [PubMed - in process]

Building an Evaluation Scale using Item Response Theory.

Proc Conf Empir Methods Nat Lang Process. 2016 Nov;2016:648-657

Authors: Lalor JP, Wu H, Yu H

Abstract
Evaluation of NLP methods requires testing against a previously vetted gold-standard test set and reporting standard metrics (accuracy/precision/recall/F1). The current assumption is that all items in a given test set are equal with regards to difficulty and discriminating power. We propose Item Response Theory (IRT) from psychometrics as an alternative means for gold-standard test-set generation and NLP system evaluation. IRT is able to describe characteristics of individual items - their difficulty and discriminating power - and can account for these characteristics in its estimation of human intelligence or ability for an NLP task. In this paper, we demonstrate IRT by generating a gold-standard test set for Recognizing Textual Entailment. By collecting a large number of human responses and fitting our IRT model, we show that our IRT model compares NLP systems with the performance in a human population and is able to provide more insight into system performance than standard evaluation metrics. We show that a high accuracy score does not always imply a high IRT score, which depends on the item characteristics and the response pattern.

PMID: 28004039 [PubMed]

Natural Language Processing for Cohort Discovery in a Discharge Prediction Model for the Neonatal ICU.

Appl Clin Inform. 2016;7(1):101-15

Authors: Temple MW, Lehmann CU, Fabbri D

Abstract
OBJECTIVES: Discharging patients from the Neonatal Intensive Care Unit (NICU) can be delayed for non-medical reasons including the procurement of home medical equipment, parental education, and the need for children's services. We previously created a model to identify patients that will be medically ready for discharge in the subsequent 2-10 days. In this study we use Natural Language Processing to improve upon that model and discern why the model performed poorly on certain patients.
METHODS: We retrospectively examined the text of the Assessment and Plan section from daily progress notes of 4,693 patients (103,206 patient-days) from the NICU of a large, academic children's hospital. A matrix was constructed using words from NICU notes (single words and bigrams) to train a supervised machine learning algorithm to determine the most important words differentiating poorly performing patients compared to well performing patients in our original discharge prediction model.
RESULTS: NLP using a bag of words (BOW) analysis revealed several cohorts that performed poorly in our original model. These included patients with surgical diagnoses, pulmonary hypertension, retinopathy of prematurity, and psychosocial issues.
DISCUSSION: The BOW approach aided in cohort discovery and will allow further refinement of our original discharge model prediction. Adequately identifying patients discharged home on g-tube feeds alone could improve the AUC of our original model by 0.02. Additionally, this approach identified social issues as a major cause for delayed discharge.
CONCLUSION: A BOW analysis provides a method to improve and refine our NICU discharge prediction model and could potentially avoid over 900 (0.9%) hospital days.

PMID: 27081410 [PubMed - indexed for MEDLINE]

8 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"cystic fibrosis"

These pubmed results were generated on 2016/12/22

PubMed comprises more than 24 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

The wide spectrum of cerebrotendinous xanthomatosis: Case report of a rare but treatable disease.

Clin Neurol Neurosurg. 2016 Apr;143:1-3

Authors: Rosafio F, Cavallieri F, Guaraldi P, Taroni F, Nichelli PF, Mandrioli J

Abstract
Cerebrotendinous xanthomatosis (CTX) is an autosomal-recessive disorder of lipid storage caused by mutations in the CYP27A1 gene, coding for a sterol 27-hydroxylase, leading to increased deposition of cholesterol in multiple tissues. CTX is characterized by the association of early non-neurological manifestations and adult-onset neurological dysfunctions (spastic ataxia, dementia, psychiatric disorders, peripheral neuropathy). Early and long-term treatment with chenodeoxycholic acid (CDCA) can slow down neurological symptoms progression, but diagnosis usually has a delay of several years. We report two Italian siblings having quite different phenotypes associated to a G-to-A transition in the c-1263 terminal causing a splicing alteration. This mutation has not been described before in Italy, and has been reported once in Japan. This case widens the clinical and genetic spectrum of Cerebrotendinous Xantomatosis in Italy and would like to suggest the importance of genetic testing in patients with autosomal recessive spastic paraparesis associated with typical non-neurological symptoms.

PMID: 26874936 [PubMed - indexed for MEDLINE]

Review of Toxic Epidermal Necrolysis.

Int J Mol Sci. 2016 Dec 18;17(12):

Authors: Harris V, Jackson C, Cooper A

Abstract
Toxic epidermal necrolysis (TEN) is a rare but life threatening mucocutaneous reaction to drugs or their metabolites. It is characterised by widespread keratinocyte apoptosis and sloughing of the skin, erosions of the mucous membranes, painful blistering, and severe systemic disturbance. The pathophysiology of TEN is incompletely understood. Historically, it has been regarded as a drug-induced immune reaction initiated by cytotoxic lymphocytes via a human leukocyte antigen (HLA)-restricted pathway. Several mediators have been identified as contributors to the cell death seen in TEN, including; granulysin, soluble Fas ligand, perforin/granzyme, tumour necrosis factor-α (TNF-α), and TNF-related apoptosis-inducing ligand. Currently, granulysin is accepted as the most important mediator of T cell proliferation. There is uncertainty around the accepted management of TEN. The lack of definitive management guidelines for TEN is explained in part by the rarity of the disease and its high mortality rate, which makes it difficult to conduct randomised control trials on emerging therapies. Developments have been made in pharmacogenomics, with numerous HLA alleles identified; however, these have largely been ethnically specific. These associations have translated into screening recommendations for Han Chinese.

PMID: 27999358 [PubMed - in process]

Identification of potential drug targets based on a computational biology algorithm for venous thromboembolism.

Int J Mol Med. 2016 Dec 14;:

Authors: Xie R, Li L, Chen L, Li W, Chen B, Jiang J, Huang H, Li Y, He Y, Lv J, He W

Abstract
Venous thromboembolism (VTE) is a common, fatal and frequently recurrent disease. Changes in the activity of different coagulation factors serve as a pathophysiological basis for the recurrent risk of VTE. Systems biology approaches provide a better understanding of the pathological mechanisms responsible for recurrent VTE. In this study, a novel computational method was presented to identify the recurrent risk modules (RRMs) based on the integration of expression profiles and human signaling network, which hold promise for achieving new and deeper insights into the mechanisms responsible for VTE. The results revealed that the RRMs had good classification performance to discriminate patients with recurrent VTE. The functional annotation analysis demonstrated that the RRMs played a crucial role in the pathogenesis of VTE. Furthermore, a variety of approved drug targets in the RRM M5 were related to VTE. Thus, the M5 may be applied to select potential drug targets for combination therapy and the extended treatment of VTE.

PMID: 28000840 [PubMed - as supplied by publisher]

Application of multi-target phytotherapeutic concept in malaria drug discovery: a systems biology approach in biomarker identification.

Biomark Res. 2016;4:25

Authors: Tarkang PA, Appiah-Opong R, Ofori MF, Ayong LS, Nyarko AK

Abstract
There is an urgent need for new anti-malaria drugs with broad therapeutic potential and novel mode of action, for effective treatment and to overcome emerging drug resistance. Plant-derived anti-malarials remain a significant source of bioactive molecules in this regard. The multicomponent formulation forms the basis of phytotherapy. Mechanistic reasons for the poly-pharmacological effects of plants constitute increased bioavailability, interference with cellular transport processes, activation of pro-drugs/deactivation of active compounds to inactive metabolites and action of synergistic partners at different points of the same signaling cascade. These effects are known as the multi-target concept. However, due to the intrinsic complexity of natural products-based drug discovery, there is need to rethink the approaches toward understanding their therapeutic effect. This review discusses the multi-target phytotherapeutic concept and its application in biomarker identification using the modified reverse pharmacology - systems biology approach. Considerations include the generation of a product library, high throughput screening (HTS) techniques for efficacy and interaction assessment, High Performance Liquid Chromatography (HPLC)-based anti-malarial profiling and animal pharmacology. This approach is an integrated interdisciplinary implementation of tailored technology platforms coupled to miniaturized biological assays, to track and characterize the multi-target bioactive components of botanicals as well as identify potential biomarkers. While preserving biodiversity, this will serve as a primary step towards the development of standardized phytomedicines, as well as facilitate lead discovery for chemical prioritization and downstream clinical development.

PMID: 27999673 [PubMed]