Drug repositioning is the process of finding new therapeutic uses for existing, approved drugs-a process thathas value when considering the exorbitant costs of novel drug development. Several ...computational strategies exist as a way to predict these alternative applications. In this study, we used datasets on: (1) human biological drug targets and (2) disease-associated genes and, based on a direct functional interaction between them, searched for potential opportunities for drug repositioning. From the set of 1125 unique drug targets and their 88 490 interactions with disease-associated genes, 30 drug targets were analyzed and (3) discussed in detail for the purpose of this article. The current indications of the drugs thattarget them were validated through the interactions, and new opportunities for repositioning were predicted. Among the set of drugs for potential repositioning werebenzodiazepines for the treatment of autism spectrum disorders; nortriptyline for the treatment of melanoma, glioma and other cancers; and vitamin B6 in prevention of spontaneous abortions and cleft palate birth defects. Special emphasis was also placed on those new potential indications that pertained to orphan diseases-these are diseases whose rarity means that development of novel treatment is not financially viable. This computational drug repositioning approach uses existing information on drugs and drug targets, and insights into the genetic basis of disease, as a means to systematically generate the most probable new uses for the drugs on offer, and in this way harness their true therapeutic power.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Populations worldwide currently face several public health challenges, including growing prevalence of infections and the emergence of new pathogenic organisms. The cost and risk associated ...with drug development make the development of new drugs for several diseases, especially orphan or rare diseases, unappealing to the pharmaceutical industry. Proof of drug safety and efficacy is required before market approval, and rigorous testing makes the drug development process slow, expensive and frequently result in failure. This failure is often because of the use of irrelevant targets identified in the early steps of the drug discovery process, suggesting that target identification and validation are cornerstones for the success of drug discovery and development. Here, we present a large-scale data-driven integrative computational framework to extract essential targets and processes from an existing disease-associated data set and enhance target selection by leveraging drug-target-disease association at the systems level. We applied this framework to tuberculosis and Ebola virus diseases combining heterogeneous data from multiple sources, including protein-protein functional interaction, functional annotation and pharmaceutical data sets. Results obtained demonstrate the effectiveness of the pipeline, leading to the extraction of essential drug targets and to the rational use of existing approved drugs. This provides an opportunity to move toward optimal target-based strategies for screening available drugs and for drug discovery. There is potential for this model to bridge the gap in the production of orphan disease therapies, offering a systematic approach to predict new uses for existing drugs, thereby harnessing their full therapeutic potential.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
There is extensive experimental evidence to support the investigation of treatment with mild hypothermia after birth asphyxia. However, clinical studies have been delayed by the difficulty in ...predicting long-term outcome very soon after birth and by concern about adverse effects of hypothermia.
The objectives of this study were to determine whether it is feasible to select infants with a bad neurological prognosis and to begin hypothermic therapy within 6 hours of birth, and to observe the effect of this therapy on relevant physiologic variables.
Sixteen newborn infants with clinical features of birth asphyxia (median cord blood pH: 6.74; range: 6.58-7.08) were assessed by amplitude integrated electroencephalography (aEEG), and mild whole body hypothermia was instituted within 6 hours of birth in the 10 infants with an aEEG prognostic of a bad outcome. Rectal temperature was maintained at 33.2 +/- (standard deviation).6 degrees C for 48 hours. Rectal and tympanic membrane temperature, blood pressure, heart rate, blood gases, blood lactate, full blood count, blood electrolytes, high and low shear rate viscosity, and coagulation studies were monitored during and after cooling. A preliminary assessment of neurological outcome was made by repeated magnetic resonance imaging (MRI) and neurological examination.
All infants selected to receive hypothermia developed convulsions and a severe encephalopathy. During 48 hours of hypothermia infants had prolonged metabolic acidosis (median pH: 7.30; base excess: -6.3 mmol x L(-1), a high blood lactate (median lactate: 5.3 mmol x L(-1)) and low blood potassium levels (median value: 3.9 mmol x L(-1)) x Hypothermia was associated with lower heart rate and higher mean blood pressure. However, these changes did not seem to be clinically relevant and no significant complication of hypothermia was encountered. Blood viscosity and coagulation studies were similar during and after cooling. Unusual MRI findings were noted in 3 infants: transverse sinus thrombosis with subsequent small cerebellar infarct; probable thrombosis in the straight sinus; and hemorrhagic cerebral infarction. Six of the 10 cooled infants had minor abnormalities only or normal follow-up neurological examination; 3 infants died and 1 had major abnormalities. None of the 6 infants with a normal aEEG developed severe neonatal encephalopathy or neurological sequel.
After birth asphyxia infants can be objectively selected by aEEG and hypothermia started within 6 hours of birth in infants at high risk of developing severe neonatal encephalopathy. Prolonged mild hypothermia to 33 degrees C to 34 degrees C is associated with minor physiologic abnormalities. Further studies of both the safety and efficacy of mild hypothermia, including further neuroimaging studies, are warranted.
The biochemical characteristics of white matter damage (WMD) in preterm infants were assessed using magnetic resonance spectroscopy (MRS). The authors hypothesized that preterm infants with WMD at ...term had a persisting cerebral lactic alkalosis and reduced N-acetyl aspartate (NAA)/creatine plus phosphocreatine (Cr), similar to that previously documented in term infants weeks after perinatal hypoxia–ischemia (HI). Thirty infants (gestational age 27.9 ± 3.1 weeks, birth weight 1122 ± 445 g) were studied at postnatal age of 9.8 ± 4.1 weeks (corrected age 40.3 ± 3.9 weeks). Infants were grouped according to the presence or absence of WMD on magnetic resonance (MR) images. The peak area ratios of lactate/Cr, NAA/Cr, myo-inositol/Cr, and choline (Cho)/Cr were measured from an 8-cm3 voxel in the posterior periventricular white matter (WM) using proton MRS. Intracellular pH (pHi) was calculated using phosphorus MRS. Eighteen infants had normal WM on MR imaging; 12 had WMD. For infants with WMD, lactate/Cr and myo-inositol/Cr were related (P < 0.01); lactate/Cr and pHi were not (P = 0.8). In the WMD group, mean lactate/Cr and myo-inositol/Cr were higher (P < 0.001, P < 0.05, respectively) than the normal WM group. There was no difference in the NAA/Cr, Cho/Cr, or pHi between the two groups, although pHi was not measured in all infants. These findings suggest that WMD in the preterm infant at term has a different biochemical profile compared with the term infant after perinatal HI.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
The biochemical characteristics of white matter damage (WMD) in preterm infants were assessed using magnetic resonance spectroscopy (MRS). The authors hypothesized that preterm infants with WMD at ...term had a persisting cerebral lactic alkalosis and reduced N-acetyl aspartate (NAA)/creatine plus phosphocreatine (Cr), similar to that previously documented in term infants weeks after perinatal hypoxia–ischemia (HI). Thirty infants (gestational age 27.9 ± 3.1 weeks, birth weight 1122 ± 445 g) were studied at postnatal age of 9.8 ± 4.1 weeks (corrected age 40.3 ± 3.9 weeks). Infants were grouped according to the presence or absence of WMD on magnetic resonance (MR) images. The peak area ratios of lactate/Cr, NAA/Cr, myo-inositol/Cr, and choline (Cho)/Cr were measured from an 8-cm
3
voxel in the posterior periventricular white matter (WM) using proton MRS. Intracellular pH (pH
i
) was calculated using phosphorus MRS. Eighteen infants had normal WM on MR imaging; 12 had WMD. For infants with WMD, lactate/Cr and myo-inositol/Cr were related ( P < 0.01); lactate/Cr and pH
i
were not ( P = 0.8). In the WMD group, mean lactate/Cr and myo-inositol/Cr were higher ( P < 0.001, P < 0.05, respectively) than the normal WM group. There was no difference in the NAA/Cr, Cho/Cr, or pH
i
between the two groups, although pH
i
was not measured in all infants. These findings suggest that WMD in the preterm infant at term has a different biochemical profile compared with the term infant after perinatal HI.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
SummaryThe biochemical characteristics of white matter damage (WMD) in preterm infants were assessed using magnetic resonance spectroscopy (MRS). The authors hypothesized that preterm infants with ...WMD at term had a persisting cerebral lactic alkalosis and reduced N-acetyl aspartate (NAA)/creatine plus phosphocreatine (Cr), similar to that previously documented in term infants weeks after perinatal hypoxia-ischemia (HI). Thirty infants (gestational age 27.9 +/- 3.1 weeks, birth weight 1122 +/- 445 g) were studied at postnatal age of 9.8 +/- 4.1 weeks (corrected age 40.3 +/- 3.9 weeks). Infants were grouped according to the presence or absence of WMD on magnetic resonance (MR) images. The peak area ratios of lactate/Cr, NAA/Cr, myo-inositol/Cr, and choline (Cho)/Cr were measured from an 8-cm super(3) voxel in the posterior periventricular white matter (WM) using proton MRS. Intracellular pH (pH sub(i)) was calculated using phosphorus MRS. Eighteen infants had normal WM on MR imaging; 12 had WMD. For infants with WMD, lactate/Cr and myo-inositol/Cr were related (P < 0.01); lactate/Cr and pH sub(i) were not (P = 0.8). In the WMD group, mean lactate/Cr and myo-inositol/Cr were higher (P < 0.001, P < 0.05, respectively) than the normal WM group. There was no difference in the NAA/Cr, Cho/Cr, or pH sub(i) between the two groups, although pH sub(i) was not measured in all infants. These findings suggest that WMD in the preterm infant at term has a different biochemical profile compared with the term infant after perinatal HI.Journal of Cerebral Blood Flow & Metabolism (2000) 20, 1446-1456; doi:10.1097/00004647-200010000-00006
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