Xanthine-Dopamine Hybrid Molecules as Multitarget Drugs with Potential for the Treatment of Neurodegenerative Diseases.

Multitarget drugs based on a hybrid dopamine-xanthine core were designed as potential drug candidates for the treatment of neurodegenerative diseases. Monoamine oxidase B (MAO-B) inhibitors with significant ancillary A2A adenosine receptor (A2AAR) antagonistic properties were further developed to exhibit additional phosphodiesterase-4 and -10 (PDE4/10) inhibition and/or dopamine D2 receptor (D2R) agonistic activity. While all of the designed compounds showed MAO-B inhibition in the nanomolar range mostly combined with submicromolar A2AAR affinity, significant enhancement of PDE-inhibitory and D2R-agonistic activity was additionally reached for some compounds through various structural modifications. The final multitarget drugs also showed promising antioxidant properties in vitro. In order to evaluate their potential neuroprotective effect, representative ligands were tested in a cellular model of toxin-induced neurotoxicity. As a result, protective effects against oxidative stress in neuroblastoma cells were observed, confirming the utility of the applied strategy. Further evaluation of the newly developed multitarget ligands in preclinical models of Alzheimer's and Parkinson's diseases is warranted.

Blockade of Asparagine Endopeptidase Inhibits Cancer Metastasis.

Asparagine endopeptidase (AEP), also called legumain, is highly expressed in various solid tumors, promoting cancer cell invasion, migration, and metastasis. It has been proposed to be a prognostic marker and therapeutic target for cancer treatment. However, an effective nonpeptide, small-molecule inhibitor against this protease has not yet been identified. Here we show that a family of xanthine derivatives selectively inhibit AEP and suppress matrix metalloproteinase (MMP) cleavage, leading to the inhibition of cancer metastasis. Through structure-activity relationship (SAR) analysis, we obtained an optimized lead compound (38u) that represses breast cancer invasion and migration. Chronic treatment of nude mice, which had been inoculated with MDA-MB-231 cells, with inhibitor 38u via oral administration robustly inhibits breast cancer lung metastasis in a dose-dependent manner, associated with blockade of MMP-2 by AEP. Therefore, our study supports that 38u might act as a potent and specific AEP inhibitor useful for cancer treatment.

Design and synthesis of novel xanthine derivatives as potent and selective A2B adenosine receptor antagonists for the treatment of chronic inflammatory airway diseases.

Adenosine induces bronchial hyperresponsiveness and inflammation in asthmatics through activation of A2B adenosine receptor (A2BAdoR). Selective antagonists have been shown to attenuate airway reactivity and improve inflammatory conditions in pre-clinical studies. Hence, the identification of novel, potent and selective A2BAdoR antagonist may be beneficial for the potential treatment of asthma and Chronic Obstructive Pulmonary Disease (COPD). Towards this effort, we explored several prop-2-ynylated C8-aryl or heteroaryl substitutions on xanthine chemotype and found that 1-prop-2-ynyl-1H-pyrazol-4-yl moiety was better tolerated at the C8 position. Compound 59, exhibited binding affinity (Ki) of 62 nM but was non-selective for A2BAdoR over other AdoRs. Incorporation of substituted phenyl on the terminal acetylene increased the binding affinity (Ki) significantly to <10 nM. Various substitutions on terminal phenyl group and different alkyl substitutions on N-1 and N-3 were explored to improve the potency, selectivity for A2BAdoR and the solubility. In general, compounds with meta-substituted phenyl provided better selectivity for A2BAdoR compared to that of para-substituted analogs. Substitutions such as basic amines like pyrrolidine, piperidine, piperazine or cycloalkyls with polar group were tried on terminal acetylene, keeping in mind the poor solubility of xanthine analogs in general. However, these substitutions led to a decrease in affinity compared to compound 59. Subsequent SAR optimization resulted in identification of compound 46 with high human A2BAdoR affinity (Ki = 13 nM), selectivity against other AdoR subtypes and with good pharmacokinetic properties. It was found to be a potent functional A2BAdoR antagonist with a Ki of 8 nM in cAMP assay in hA2B-HEK293 cells and an IC50 of 107 nM in IL6 assay in NIH-3T3 cells. Docking study was performed to rationalize the observed affinity data. Structure-activity relationship (SAR) studies also led to identification of compound 36 as a potent A2BAdoR antagonist with Ki of 1.8 nM in cAMP assay and good aqueous solubility of 529 µM at neutral pH. Compound 46 was further tested for in vivo efficacy and found to be efficacious in ovalbumin-induced allergic asthma model in mice.

Analysis of prescription pattern and guideline adherence in the management of asthma among medical institutions and physician specialties in Taiwan between 2000 and 2010.

PURPOSE: The aim of this study was to evaluate prescription patterns of antiasthmatic medications in ambulatory care, guideline adherence by physician specialties and medical institutions, and the rate of hospitalization and emergency department visits due to asthma exacerbation. METHODS: The ambulatory visits between 2000 and 2010 from the Taiwan Longitudinal Health Insurance Database 2000 were analyzed for prescription trends. Seven classes of antiasthmatic medications were identified for prescription trend analysis. Prescription patterns of different medical institutions and physician specialties were further evaluated. FINDINGS: We studied 4495 patients with newly diagnosed asthma in 2000. Estimates indicated an increased use in fixed-dose combination of inhaled corticosteroids and long-acting ß2-agonists (3.6% in 2002 to 28.8% in 2010) with decreased use of inhaled corticosteroids (14.5% in 2001 to 7.3% in 2010). Xanthine was still the most frequently used medication for asthmatic patients (60.2% in 2001 and 45.2% in 2010). Another marked increase was the use of leukotriene receptor antagonists (2.6% in 2001 to 6.0% in 2010). In the studied population, the rate of hospital admission or emergency department visit moderately decreased from 1.42% to 0.59% during 10 years. Physicians in medical centers and regional hospitals, as well as asthma specialists, dominated the increased use of fixed-dose combinations of inhaled corticosteroids and long-acting ß2-agonists and leukotriene receptor antagonists. IMPLICATIONS: Physicians in academic medical centers and asthma specialists achieved better adherence to the core recommendations of the international guidelines for asthma management. The reasons for guideline nonadherence among physicians in district hospitals and primary care clinics deserve health care professionals' attention and require further investigation.

Synthesis and biological evaluation of xanthine derivatives on dipeptidyl peptidase 4.

A series of xanthine derivatives in which a methylene was inserted at position 8 of xanthine scaffold was synthesized and evaluated as inhibitors of dipeptidyl peptidase 4 (DPP-4) for the treatment of type 2 diabetes. As the results of structure-activity relationship (SAR) study of the series, the compounds with 4-methyl-quinazoline-2-yl-methyl group at N-1 position and 2-aminoethylaminomethyl group gave better activities. Compounds H4 and H9 showed good DPP-4 inhibition and more than 100-fold selectivity over DPP-7 and DPP-8.

Carotid chemoreceptor development and neonatal apnea.

The premature transition from fetal to neonatal life is accompanied by an immature respiratory neural control system. Most preterm infants exhibit recurrent apnea, resulting in repetitive oscillations in O(2) saturation (intermittent hypoxia, IH). Numerous factors are likely to play a role in the etiology of apnea including inputs from the carotid chemoreceptors. Despite major advances in our understanding of carotid chemoreceptor function in the early neonatal period, however, their contribution to the initiation of an apneic event and its eventual termination are still largely speculative. Recent findings have provided a detailed account of the postnatal changes in the incidence of hypoxemic events associated with apnea, and there is anecdotal evidence for a positive correlation with carotid chemoreceptor maturation. Furthermore, studies on non-human animal models have shown that chronic IH sensitizes the carotid chemoreceptors, which has been proposed to perpetuate the occurrence of apnea. An alternative hypothesis is that sensitization of the carotid chemoreceptors could represent an important protective mechanism to defend against severe hypoxemia. The purpose of this review, therefore, is to discuss how the carotid chemoreceptors may contribute to the initiation and termination of an apneic event in the neonate and the use of xanthine therapy in the prevention of apnea.

Physiologic basis for intermittent hypoxic episodes in preterm infants.

Intermittent hypoxic episodes are typically a consequence of immature respiratory control and remain a troublesome challenge for the neonatologist. Furthermore, their frequency and magnitude are commonly underestimated by clinically employed pulse oximeter settings. In extremely low birth weight infants the incidence of intermittent hypoxia [IH] progressively increases over the first 4 weeks of postnatal life, with a subsequent plateau followed by a slow decline beginning at weeks six to eight. Over this period of unstable respiratory control, increased oxygen-sensitive peripheral chemoreceptor activity has been associated with a higher incidence of apnea of prematurity. In contrast, infants with bronchopulmonary dysplasia [chronic neonatal lung disease] exhibit decreased peripheral chemosensitivity, although the effect on respiratory stability in this population is unclear. Such episodic hypoxia/reoxygenation in early life has the potential to sustain a proinflammatory cascade with resultant multisystem, including respiratory, morbidity. Therapeutic approaches for intermittent hypoxic episodes comprise careful titration of baseline or supplemental inspired oxygen as well as xanthine therapy to prevent apnea of prematurity. Characterization of the pathophysiologic basis for such intermittent hypoxic episodes and their consequences during early life is necessary to provide an evidence-based approach to their management.

Apnea of prematurity.

Apnea of prematurity is a significant problem due to immaturity of the central neural control circuitry responsible for integrating afferent input and central rhythm. In this review, we provide an overview of the pathogenesis of apnea of prematurity--including our current understanding of the role that afferent input to the brain stem plays in synergy with the central pattern generation circuitry in the emergence of apnea of prematurity. We then discuss the interplay of apnea, bradycardia, desaturation, as well as the genesis of central, mixed, and obstructive apnea. Finally, we provide a summary of the physiological basis for current therapeutic approaches to treating apnea of prematurity, and conclude with an overview of proposed long-term consequences of the resultant intermittent hypoxic episodes.

Caffeine analogs: biomedical impact.

Caffeine, widely consumed in beverages, and many xanthine analogs have had a major impact on biomedical research. Caffeine and various analogs, the latter designed to enhance potency and selectivity toward specific biological targets, have played key roles in defining the nature and role of adenosine receptors, phosphodiesterases, and calcium release channels in physiological processes. Such xanthines and other caffeine-inspired heterocycles now provide important research tools and potential therapeutic agents for intervention in Alzheimer's disease, asthma, cancer, diabetes, and Parkinson's disease. Such compounds also have activity as analgesics, antiinflammatories, antitussives, behavioral stimulants, diuretics/natriuretics, and lipolytics. Adverse effects can include anxiety, hypertension, certain drug interactions, and withdrawal symptoms.

Controversies surrounding xanthine therapy.

The methylxanthines aminophylline, theophylline and caffeine have been used for more than 30 years to treat apnoea of prematurity. Today, they are among the most commonly prescribed drugs in neonatal medicine. Methylxanthines reduce the frequency of idiopathic apnoea and the need for mechanical ventilation by acting as non-specific inhibitors of adenosine A(1) and A(2a) receptors. However, recent and rapidly growing research into the actions of adenosine and its receptors raises concerns about the safety of methylxanthine therapy in very preterm infants. Possible adverse effects include impaired growth, lack of neuroprotection during acute hypoxic-ischaemic episodes and abnormal behaviour. An international controlled clinical trial is underway to examine the long-term efficacy and safety of methylxanthine therapy in very low birth weight babies.

Prescribing pattern of anti-seizure medications (ASMs): an evaluation of extent of xanthine co-medication.

This study was conducted to evaluate the prescribing pattern of anti-seizure medications (ASMs) at a tertiary care hospital. The extent and pattern of concurrently used medications for co-exiting illnesses was also studied. Attention was focussed in particular on co-existence of bronchial asthma with epilepsy and co-medication of ASMs with xanthines. The study was carried out at the Central Pharmacy and at the Medical Records Department. Data analysis at the central pharmacy showed 3.98% prescriptions for ASMs, with maximum number for males. More drugs were prescribed during the second decade of life and there were 2.17 drugs per prescription. The data for pattern and extent of use of ASMs along with polytherapy and concurrently used medications revealed the highest number of prescriptions for phenytoin, maximum number with single ASM, and phenytoin with phenobarbitone as most frequently prescribed combination. Co-administration of ASMs with respiratory medications was found in 2.47%, with 38.8% prescriptions having xanthines prescribed in them. Xanthines, the well known CNS stimulants, a property attributed to their adenosine receptor antagonistic activity, are considered potential seizurogenic agents. The results of the present preliminary survey show an indirect evidence for co-existence of epilepsy with asthma along with the extent of co-medication of ASMs with xanthines. Results indicate the need for further studies to evaluate the consequences of co-medication of ASMs with xanthines.

[Xanthine derivative compounds potential activity in inflammatory process]. / Compusi cu structura xantinica potential activi în procesul inflamator.

We studied the potentially anti-inflammatory action of some new xanthine compounds, theophylline derivatives with 7-[2-hydroxy-3-(4-acetamido)-phenoxy-propyl]-8-R-1,3-dimethyl-xanthine and 8-R-1,3-bis-(1,3-dimethyl-xanthin-7yl)-2-hydroxy-propane structure substituted in 7 and 8 position. Almost all studied compounds reduced the inflammatory edema, the effect being comparable or highest theophylline. The antiinflammatory effect of theophylline intensified with the introduction in 7 position the theophylinyl radical and in 8 position the bromo, nitro, pirolidinyl, piperidinyl, morfolinyl, imidazolyl, 3,5-dimethyl-pirazolyl, 3-methyl-5-oxo-pirazolyl radicals.

Retinopathy of prematurity in very low birth weight infants.

This study aims to determine the prevalence of and risk factors associated with retinopathy of prematurity (ROP) in very low birth weight (VLBW) infants. All premature VLBW infants, admitted into the neonatal intensive care unit of the University Hospital Kuala Lumpur, were screened from 4 weeks of life. Perinatal and neonatal data were retrieved from the infants' medical notes. Between August 1994 and July 1996, 100 infants had their eyes examined serially. Of the 15 (15%) infants with ROP, all were less than 31 weeks gestation, and only 1 infant had birth weight above 1250 g. Five (5%) infants had severe ROP; 4 infants underwent cryotherapy for stage 3 threshold disease. Infants with ROP, as compared to infants without ROP, had lower birth weight [mean (SEM) 993 (50) g versus 1205 (22) g, P < 0.001], lower gestational age [mean (SEM) 28.0 (0.4) weeks versus 30.1 (0.2) weeks, P < 0.001], higher rates of patent ductus arteriosus and chronic lung disease, greater number of radiographic examinations and episodes of late-onset suspected/confirmed sepsis, and required longer duration of supplemental oxygen, ventilation, xanthine, antibiotics and intralipid use, but were slower to establish full enteral feeds. On multivariate logistic regression analysis, birth weight < or = 1000 g [OR 2.38, 95% CI 1.25, 4.55, P = 0.009] and gestational age < or = 28 weeks [OR 2.86, 95% CI 1.47, 5.56, P = 0.002] were significant predictors of increased risk of this disease. In conclusion, ROP is strongly associated with smaller, more immature and sicker neonates. Prevention of prematurity would help reduce the incidence of this disease.

Reduced signal complexity of intracellular recordings: a precursor for epileptiform activity?

Recent studies have shown that time windowed extraction of nonlinear parameters like an effective correlation dimension from intracranially recorded EEG of epileptic patients often allows to detect and identify an unequivocal "pre-ictal phase" preceding an epileptic seizure. In another study, however, such an anticipation could not be made. These conflicting findings may indicate that observed changes in nonlinear parameters probably depend on the type of elementary mechanisms underlying epileptic processes and/or the spatial distribution of neurons primarily involved in generation of epileptiform discharges. To test the existence of such dependencies, the transition from normal to epileptiform activity (EA) of CA3-neurons in hippocampal slices was analyzed in four epilepsy models, using a time windowed computation of an effective correlation dimension. Indeed, in xanthine and penicillin models, signal complexity in intracellular recordings was reduced before manifestation of paroxysmal depolarization shifts (PDS), whereas a preceding loss of complexity was missing in low-magnesium and veratridine models. These findings indicate that interictal-like EA is predictable only in some epilepsy models.