Ideal Drugs Research Articles

New molecules as drug candidates for the treatment of upper and lower GI tract ulcers.

Ulcers in the stomach, duodenum, ileum/jejunum and colon may look alike grossly and microscopically, but they have very different etiologies and pathogenesis. Unfortunately, there is virtually no etiologic treatment for any of these lesions which are also accompanied by limited or extensive inflammation. This article reviews four groups of new antiulcer drugs discovered and patented in our lab in Boston and Long Beach/Irvine (Table 1). Actually, the first group, pyrazole and its derivatives can be used for prevention, i.e., long lasting protection of gastric mucosa against alcohol- or NSAID-induced erosions. Dopamine seems to be a new etiologic treatment for both upper and lower GI tract ulcers. Angiogenic growth factors like bFGF or PDGF (daily administration as peptides orally or by rectal enemas, or as single or double-dose of gene therapy) accelerated the healing of gastroduodenal ulcers and UC, while VEGF seems to be effective only for upper GI tract ulcers. Last but not least, a novel group of angiogenic steroids which not only stimulate new blood vessel formation and granulation tissue production (essential elements of healing of ulcer types) but may also exert mild or prominent antiinflammatory action and seem to be ideal drugs for the treatment of IBD.

Microbiological characteristics of sepsis in a University hospital.

BackgroundMicrobiological characteristics of sepsis and antimicrobial resistance are well studied, although in State University of Campinas, no data has been published yet.MethodsThe main agents related to sepsis and antimicrobial resistance were analyzed. The blood culture records requested from 4,793 hospitalized patients were analyzed. The samples were processed using the Bact/Alert® system for agent identification and antimicrobial susceptibility.ResultsA total of 1,017 patients met the inclusion criteria for a sepsis diagnosis, with 2,309 samples tested (2.27 samples/patient). There were 489 positive samples (21% positive) isolated from 337 patients (33.13%), but more rigorous criteria excluding potential contaminants resulted in analysis being restricted to 266 patients (315 agents). The prevalent microorganisms were coagulase negative Staphylococcus (CNS) (15.87%), Escherichia coli (13.0%), Staphylococcus aureus (11.7%), Klebsiella pneumoniae (9.8%), Enterobacter sp (9.5%), Acinetobacter baumannii (9.2%), Pseudomonas aeruginosa (5.7%) and Candida sp (5.1%). Examining antimicrobial resistance in the agents revealed that 51% of the S. aureus isolates were methicillin-resistant S. aureus (MRSA) and 80% of the CNS isolates were oxacillin-resistant. For A. baumannii, the ideal profile drugs were ampicillin sulbactam and piperacillin/tazobactam, and for P. aeruginosa, they were piperacillin/tazobactam and ceftazidime. Enterobacteria showed on average 32.5% and 35.7% resistance to beta-lactams and ciprofloxacin, respectively. When all Gram-negative bacteria were considered, the resistance to beta-lactams rose to 40.5%, and the resistance to ciprofloxacin rose to 42.3%.ConclusionsEighty percent of the agents identified in blood cultures from patients with sepsis belonged to a group of eight different agents. For empirical treatment, carbapenems and vancomycin unfortunately still remain the best therapeutic choice, except for A. baumannii and P. aeruginosa, for which piperacillin/tazobactan is the best option.

Orexin/hypocretin based pharmacotherapies for the treatment of addiction: DORA or SORA?

Addiction is a chronic relapsing disorder which presents a significant global health burden and unmet medical need. The orexin/hypocretin system is an attractive potential therapeutic target as demonstrated by the successful clinical trials of antagonist medications like Suvorexant for insomnia. It is composed of two neuropeptides, orexin-A and orexin-B and two excitatory and promiscuous G-protein coupled receptors, OX1 and OX2. Orexins are known to have a variety of functions, most notably in regulating arousal, appetite and reward. The orexins have been shown to have a role in mediating the effects of several drugs of abuse, such as cocaine, morphine and alcohol via projections to key brain regions such as the ventral tegmental area, nucleus accumbens and prefrontal cortex. However, it has not yet been demonstrated whether the dual orexin receptor antagonists (DORAs) under development for insomnia are ideal drugs for the treatment of addiction. The question of whether to use a DORA or single orexin receptor antagonist (SORA) for the treatment of addiction is a key question that will need to be answered in order to maximize the clinical utility of orexin receptor antagonists. This review will examine the role of the orexin/hypocretin system in addiction, orexin-based pharmacotherapies under development and factors affecting the selection of one or both orexin receptors as drug targets for the treatment of addiction.

Application of CADD on multi-target drug R&D in natural products

Multi-target drugs can simultaneously adjust multiple links of the disease network. Despite the higher efficacy and lower toxicity caused by single targets, multi-target drugs become ideal drugs for treating complicated diseases as well the main direction of drug R & D. By virtue of their structural diversity, higher multi-target activity and lower toxicity, natural products become an important source for developing multi-target drugs. Computer-aided drug design (CADD) is a commonly used multi-target drug R&D method, which mainly includes virtual screening and pharmacophore design. In this paper, the authors made a systematical analysis and discussed the prospects and advantages of various methods for multi-target drug R&D with natural products.

Depolarization Controls TRAIL-Sensitization and Tumor-Selective Killing of Cancer Cells: Crosstalk with ROS.

Conventional genotoxic anti-cancer drugs target the proliferative advantage of tumor cells over normal cells. This kind of approach lacks the selectivity of treatment to cancer cells, because most of the targeted pathways are essential for the survival of normal cells. As a result, traditional cancer treatments are often limited by undesirable damage to normal cells (side-effects). Ideal anti-cancer drugs are expected to be highly effective against malignant tumor cells with minimal cytotoxicity toward normal cells. Such selective killing can be achieved by targeting pathways essential for the survival of cancer cells, but not normal cells. As cancer cells are characterized by their resistance to apoptosis, selective apoptosis induction is a promising approach for selective killing of cancer cells. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising tumor-selective anti-cancer drug. However, the congenital and acquired resistance of some cancer cell types, including malignant melanoma cells, currently impedes effective TRAIL therapy, and an innovative approach that can override TRAIL resistance is urgently required. Apoptosis is characterized by cell shrinkage caused by disruption of the maintenance of the normal physiological concentrations of K+ and Na+ and intracellular ion homeostasis. The disrupted ion homeostasis leads to depolarization and apoptosis. Recent evidence suggests that depolarization is an early and prerequisite event during TRAIL-induced apoptosis. Moreover, diverse natural products and synthetic chemicals capable of depolarizing the cell membrane exhibit tumor-selective killing and TRAIL-sensitizing effects. Here, we discuss the role of depolarization in selective killing of cancer cells in connection with the emerging concept that oxidative stress is a critical mediator of mitochondrial and endoplasmic reticulum dysfunctions and serves as a tumor-selective target in cancer treatment.

Something old, something new and something very old: drugs for treating type 2 diabetes

Diabetes mellitus belongs to the most rapidly increasing diseases worldwide. Approximately 90-95% of these patients suffer from type 2 diabetes mellitus, which is characterized by peripheral insulin resistance and the progressive loss of beta-cell function and mass. Considering the complications of this chronic disease, a reliable anti-diabetic treatment is indispensable. An ideal oral anti-diabetic drug should not only correct glucose homeostasis but also preserve or even augment beta-cell function and mass, ameliorate the subclinical inflammation present under insulin-resistant conditions and prevent the macro- and microvascular consequences of diabetes in order to reduce the mortality. Despite the many anti-diabetic drugs already in use, there is an ongoing research for additional drugs, guided by different concepts of the pathogenesis of type 2 diabetes. This review will briefly summarize current oral anti-diabetic drugs. In addition, emerging strategies for the treatment of diabetes will be described, among them the inhibition of glucagon action and anti-inflammatory drugs. Their suitability as 'ideal anti-diabetic drugs' will be discussed.

Now is the Right Time to Establish a New Strategy for Managing Chronic Cough as a Neuropathic Disorder.

Now is the Right Time to Establish a New Strategy for Managing Chronic Cough as a Neuropathic Disorder.

Smooth muscle-specific drug targets for next-generation drug-eluting stent

The occurrence of stent thrombosis is one of the major obstacles limiting the long-term clinical efficacy of percutaneous coronary intervention. The anti-smooth muscle proliferation drugs coated on drug-eluting stents (DES) often indistinguishably block re-endothelialization, an essential step toward successful vascular repair, due to their nonspecific effect on endothelial cells (ECs). Therefore, identification of therapeutic targets that differentially regulate vascular smooth muscle cell (VSMC) and EC proliferation may lead to the development of ideal drugs for the next-generation DES. Our recent studies have shown that CTP synthase 1 (CTPS1) differentially regulates the proliferation of VSMC and EC after vascular injury. Therefore, CTPS1 inhibitors are promising agents for DES. In addition to CTPS1, other factors have also shown cell-specific effects on VSMC and/or EC proliferation and thus may become potential molecular targets for developing drugs to coat stents.

Specific inhibition of tumor cells by oncogenic EGFR specific silencing by RNA interference.

Anticancer agents that have minimal effects on normal cells and tissues are ideal cancer drugs. Here, we show specific inhibition of human cancer cells carrying oncogenic mutations in the epidermal growth factor receptor (EGFR) gene by means of oncogenic allele-specific RNA interference (RNAi), both in vivo and in vitro. The allele-specific RNAi (ASP-RNAi) treatment did not affect normal cells or tissues that had no target oncogenic allele, whereas the suppression of a normal EGFR allele by a conventional in vivo RNAi caused adverse effects, i.e., normal EGFR is vital. Taken together, our current findings suggest that specific inhibition of oncogenic EGFR alleles without affecting the normal EGFR allele may provide a safe treatment approach for cancer patients and that ASP-RNAi treatment may be capable of becoming a safe and effective, anticancer treatment method.

Do angiotensin receptor blockers prevent Alzheimer's disease?

The recent advances in our understanding of Alzheimer's disease pathophysiology and the renin angiotensin system pathways suggest that angiotensin receptor blockers (ARBs) are ideal drugs to explore for Alzheimer's disease therapy. New evidence suggests that the brain renin angiotensin system has two opposing pathways: a damaging pathway and a neuro-protective pathway. Both pathways are involved in the amyloid hypothesis (Aβ cascades) and vascular mechanisms of Alzheimer's disease. Studies in animal models suggest that ARBs have cognitive protective effects that are related to their ability to decrease production and oligomerization and increase degradation of Aβ and their vascular effects (improve blood-brain barrier, restore endothelial function, decrease inflammation, and increase cerebral blood flow). Human observational studies have further suggested that ARB use is associated with decreased risk of Alzheimer's disease and protection against future cognitive decline. Our work has suggested that ARB use is associated with decreased amyloid deposition in the brain in Alzheimer's disease and can provide cognitive protection in those with mild cognitive impairment, a prodromal state for Alzheimer's disease, and dementia. To date, no robust clinical trial of ARBs in Alzheimer's disease has been performed. All things being equal, it is reasonable to consider ARBs in those with cognitive risks.

Antibody Glycosylation and Inflammation

IgG antibodies are the basis of some of the most effective therapeutics developed over the last 20 years. These antibodies are highly specific, have long serum-half lives, and can be produced relatively routinely, making them ideal drugs for immunotherapy. The degree of regulation on IgG antibody effector functions by the composition of the single, N-linked glycan attached to the Fc is increasingly appreciated. IgG antibodies with identical protein sequences can gain a 50-fold potency, in terms of initiating antibody-dependent cellular cytotoxicity (ADCC) by removal of the single fucose residue from the Fc glycan. Conversely, the addition of sialic acid to the terminus of the Fc glycan converts IgG antibodies into anti-inflammatory mediators, capable of suppressing autoantibody driven inflammation. This review will discuss the contribution of the Fc glycan to IgG antibody effector functions, the regulation of the antibody glycosylation in vivo, implications for the rational design of IgG antibody-based therapeutics, and touch upon the contribution of glycosylation to other immunoglobulin isotypes.

QSAR Modeling for the Antimalarial Activity of 1,4-Naphthoquinonyl Derivatives as Potential Antimalarial Agents

Malaria has been known as one of the major causes of morbidity and mortality on a large scale in tropical countries until now. In the past decades, many scientific groups have focused their attention on looking for ideal drugs to this disease. So far, this research area is still a hot topic. In the present study, the antimalarial activity of 1, 4- naphthoquinonyl derivatives was modeled by linear and nonlinear statistical methods, that is to say, by forward stepwise multilinear regression (MLR) and radial basis function neural networks (RBFNN). The derived QSAR models have been statistically validated both internally - by means of the Leave One Out (LOO) and Leave Many Out (LMO) crossvalidation, and Y-scrambling techniques, as well as externally (by means of an external test set). The statistical parameters provided by the MLR model were R(2) =0.7876, LOOq(2) =0.7068, RMS =0.3377, R0 2 =0.7876, k =1.0000 for the training set,and R(2) =0.7648, q(2) ext =0.7597, RMS=0.2556, R0 2=0.7598, k=1.0417 for the external test set. The RBFNN model gave the following statistical results, namely: R(2)=0.8338, LOOq(2)=0.5869, RMS=0.2781, R0 2 = 0.8335, k=1.0000 for the training set, and R(2) =0.7586, q(2) ext =0.7189, RMS=0.2788, R0 2=0.7129, k=1.0284 for the external test set. Overall, these results suggest that the QSAR MLR-based model is a simple, reliable, credible and fast tool for the prediction and virtual screening of 1, 4-naphoquinone derivatives with high antimalarial activity. In addition, the energies of the highest occupied molecular orbital were found to have high correlation with the activity.

Strategies to Improve the Anti-Cancer Properties of Gold(III) Complexes

cis-Diamminedichloroplatinum(II) (cisplatin or cis-[PtII(NH3)2(Cl)2]) with biological properties discovered serendipitously by Rosenberg in 1965 and with approval given by the Food and Drug Administration in 1978 went on to become an important clinically-used agent for the treatment of cancers. This platinum drug together with its derivatives carboplatin and oxaliplatin are highly effective towards various kinds of cancers such as testicular cancer. Nevertheless, the toxic side effects of these platinum(II) complexes, including nephrotoxicity, emetogenesis and neurotoxicity, along with the wide range of cisplatin-resistant cancer cells, make them far from ideal drugs. The tandem success and limitations of these platinum(II)-based drugs opened up a wealth of research into other classes of metal-based chemotherapeutic agents.

Anesthetic considerations for orthognathic surgery: Clinical case report

ObjectiveSelection of ideal anesthetic drugs in maxillofacial surgery. Material and methodsA 22-year-old male patient weighing 75kg and 171cm in height, with no premedication. Pre-operative vital parameters were BP 120/70, HR 72×min, SpO2 96%, temperature 36.5°C, sinus rhythm on 5-lead EKG, capnograpy. Patient was subjected to 5min of pre-oxygenation through a facial mask. The sniff test was performed, good ventilation was confirmed and a Q-tip impregnated in 0.05% oxymetazoline was applied. An intravenous continuous infusion of dexmedetomidine (solution concentration of 0.8μcg/ml) was initiated at a rate of 0.05mcg/kg/h with a score of 2 on the Ramsay scale. Induction was initiated with fentanyl 3mcg/kg, propofol 2mg/kg, rocuronium 0.6mg/kg. A No. 7 Murphy endotracheal tube lubricated with a 10% lidocaine spray was introduced through the right nostril down to the nasopharynx. At the start of surgery, the dose of dexmedetomidine was increased to 0.1mcg/kg/h. Intra-operatively, BP was maintained between 84/55mmHg and 90/53mmHg, and HR between 58 and 76 per minute. ResultsThe selection of anesthetic drugs allowed for hemodynamic stability and comfort on awakening. ConclusionAnesthesia for orthognathic surgery, as it has evolved today, requires combining different anesthetic techniques in order to ensure that the patient remains calm, comfortable and reassured, with adequate post-operative analgesia.

Consideraciones anestésicas para cirugía ortognática: reporte de un caso clínico

ObjectiveSelection of ideal anesthetic drugs in maxillofacial surgery. Material and methodsA 22-year-old male patient weighing 75kg and 171cm in height, with no premedication. Pre-operative vital parameters were BP 120/70, HR 72× min, SpO2 96%, temperature 36.5°C, sinus rhythm on 5-lead EKG, capnograpy. The patient was subjected to 5min of pre-oxygenation through a facial mask. The sniff test was performed, good ventilation was confirmed and a Q-tip impregnated in 0.05% oxymetazoline was applied. An intravenous continuous infusion of dexmedetomidine (solution concentration of 0.8cg/ml) was initiated at a rate of 0.05mcg/kg/h with a score of 2 on the Ramsay scale. Induction was initiated with fentanyl 3mcg/kg, propofol 2mg/kg, rocuronium 0.6mg/kg. A No. 7 Murphy endotracheal tube lubricated with a 10% lidocaine spray was introduced through the right nostril down to the nasopharynx. At the start of surgery, the dose of dexmedetomidine was increased to 0.1mcg/kg/h. Intra-operatively, BP was maintained between 84/55mmHg and 90/53mmHg, and HR between 58 and 76 per minute. ResultsThe selection of anesthetic drugs allowed for hemodynamic stability and comfort on awakening. ConclusionAnesthesia for orthognathic surgery, as it has evolved today, requires combining different anesthetic techniques in order to ensure that the patient remains calm, comfortable and reassured, with adequate post-operative analgesia.

Optimal use of non-biologic therapy in the treatment of rheumatoid arthritis

With the evolution of therapies for RA, new treatment strategies and goals of therapy have evolved. Recent European League Against Rheumatism (EULAR) guidelines on the treatment of RA proposed three phases of therapy: phase I comprising first-line synthetic DMARD with or without glucocorticoid; phase II comprising second-line synthetic DMARD with or without glucocorticoid, or combination synthetic DMARD therapy, or (if prognostic factors are poor) first-line biologic DMARD; and phase III comprising alternative biologic DMARDs. In all phases, the key principle is tight control: striving to achieve a predefined goal of remission or low disease activity (treat to target) with frequent dose and medication adjustments tailored to the individual patient, preferably within the window of opportunity during early RA. In all phases, MTX is recognized as an anchor drug; it is characterized by proven efficacy in combination DMARD strategies, relatively low cost, relatively rapid onset of action, proven beneficial impact on radiological progression and mortality and a wide dose range that facilitates dose adjustments. Prednisone and its active metabolite, prednisolone, have similar characteristics, making them ideal anchor drugs too. The EULAR guidelines reserve a place for MTX and glucocorticoids in all phases of treatment. The second CAMERA (Computer Assisted Management in Early Rheumatoid Arthritis) study in early RA has demonstrated that including prednisone from the start in an MTX-based tight control strategy aimed at remission improves disease activity variables, time to remission, functional disability and radiological joint damage compared with the same strategy without prednisone. In conclusion, both MTX and prednisone play key roles in modern RA treatment strategies.

Current Issues on the Angiotensin II Receptor Blocker in Cardiovascular Disease

❙ABSTRACT❙ To reduce cardio-cerebro-vascular and renal morbidity and mortality, the current guidelines on the treatment of hypertension recommend evaluating and managing total cardiovascular risks of the patient with hypertension, not just focused on reducing blood pressure itself. In this point of view, the angiotensin converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) are considered to be ideal drugs in the treatment of hypertension, because the angiotensin II plays a pivotal role in every stage of cardiovascular disease continuum. Many studies have shown that the ARBs were not only effective in lowering blood pressure, but also had another role in reducing morbidity and mortality of heart failure, myocardial infarction, stroke, diabetic nephropathy, chronic kidney disease, and the recurrence of atrial fibrillation, so called beyond blood pressure lowering effects or pleiotropic effects. However, these favorable effects of ARBs are counter-balanced by some debating issues, myocardial infarction paradox or cancer risk. Furthermore, the issue whether ARBs could replace the role of ACEIs in the treatment of cardiovascular diseases is not resolved yet. Because there have been no randomized studies proving the ARBs are better than ACEIs in terms of cardiovascular morbidity or mortality, the current status of the role of ARBs are an reasonable alternative of ACEIs. In this review, the current issues and status of ARBs will be discussed. (J Korean Soc Hypertens 2012;18(1):17-23)

Photochemical internalization of tumor-targeted protein toxins

Photochemical internalization (PCI) is a method for intracellular delivery of hydrophilic macromolecular drugs with intracellular targets as well as other drugs with limited ability to penetrate cellular membranes. Such drugs enter cells by means of endocytosis and are to a large extent degraded by hydrolytic enzymes in the lysosomes unless they possess a mechanism for cytosolic translocation. PCI is based on photodynamic therapy (PDT) specifically targeting the endosomes and lysosomes of the cells, so that the drugs in these vesicles can escape into the cytosol from where they can reach their targets. The preferential retention of the photosensitizer (PS) in tumor tissue in combination with controlled light delivery makes PCI relatively selective for cancer tissue. The tumor specificity of PCI can be further increased by delivery of drugs that selectively target the tumors. Indeed, this has been shown by PCI delivery of several targeted protein toxins. Targeted protein toxins may be regarded as ideal drugs for PCI delivery, and may represent the clinical future for the PCI technology.

An experimental approach to studying the effectiveness and safety of meglumine antimoniate formulations

Among the problems associated to leishmaniasis, the two most outstanding ones are the lack of a vaccine and the adverse effects caused by drugs use for its control. Meglumine antimoniate compounds are the first-line drugs in the treatment for cutaneous leishmaniasis (the most prevalent form of the disease in Colombia); nevertheless, they are far from being ideal drugs due to their toxicity (not to mention the emergence of drug-resistant parasites), all of which has prompted current search for new strategies to improve their safety. This work assesses the effectiveness and safety (toxicity including new aspects related with immunotoxicity not reported previously) of two different meglumine antimoniate formulations using an in vitro and in vivo murine model. The results evidence that although both injectable formulations induce an equally efficient (clearance of intracellular parasites), both give rise to adverse effects, including a preferential immunomodulation on Balb/c mice and in a lesser proportion on ICR mice. These results are comparable to human trials reporting variable reactions when following the same treatment regimen. The model presented herein is proposed as a tool for evaluating the effectiveness and safety of meglumine antimoniate-based antileishmanial formulations.

Repositioning chloroquine and metformin to eliminate cancer stem cell traits in pre-malignant lesions

Ideal oncology drugs would be curative after a short treatment course if they could eliminate epithelium-originated carcinomas at their non-invasive, pre-malignant stages. Such ideal molecules, which are expected to molecularly abrogate all the instrumental mechanisms acquired by migrating cancer stem cells (CSCs) to by-pass tumour suppressor barriers, might already exist. We here illustrate how system biology strategies for repositioning existing FDA-approved drugs may accelerate our therapeutic capacity to eliminate CSC traits in pre-invasive intraepithelial neoplasias. First, we describe a signalling network signature that overrides bioenergetics stress- and oncogene-induced senescence (OIS) phenomena in CSCs residing at pre-invasive lesions. Second, we functionally map the anti-malarial chloroquine and the anti-diabetic metformin ("old drugs") to their recently recognized CSC targets ("new uses") within the network. By discussing the preclinical efficacy of chloroquine and metformin to inhibiting the genesis and self-renewal of CSCs we finally underscore the expected translational impact of the "old drugs-new uses" repurposing strategy to open a new CSC-targeted chemoprevention era.