Current Pharmaceutical Design - Volume 24, Issue 6, 2018

The plants of the Colchicum family were known during the archaic period in Greece for their deleterious properties. Later on, they were used for the treatment of podagra. The treatment was introduced by the ancient Greek physicians and passed on to the Byzantine and Arabian physicians to endure until nowadays. The first plant was most probably named "Medea" from the notorious Colchican witch. As the most common member of the family blossoms in autumn, the plant was named Colchicum autumnale. Various nominations were also used, such as Ephemeron, Hermodactyl, Anima articulorum and Surugen. Our article discusses them, while at the same time presents the most notable authorities who have used Colchicum plants in herbal medicine and toxicology.

Colchicine is a tricyclic alkaloid extracted from the herbaceous plant Colchicum autumnale. Known since antiquity for its therapeutic efficacy in the treatment of gout, colchicine was reintroduced in 19th century pharmacopeia, thanks to the work of the French chemists and pharmacists Pierre-Joseph Pelletier (1788-1842) and Joseph Bienaimé Caventou (1795-1877) who in 1819, isolated a peculiar substance in the roots of Colchicum autumnale. In 1833, the substance was further analyzed by the German pharmacist and chemist Philipp Lorenz Geiger (1785-1836), who coined the name colchicine. In 1884, the French pharmacist Alfred Houde (1854-1919) produced for the first time pure crystallized colchicine in granules of 1milligram which is still sold under this trade name in several countries. In the last two centuries, colchicine's indications were furthermore expanded. From anti-gout drug during antiquity and a diuretic in 19th century, colchicine is currently administered in several affections such as Adamantiades-Behcet's disease, familial Mediterranean fever, pericarditis and atrial fibrillation.

Colchicine is a tricyclic, lipid-soluble alkaloid derived from the plant of the Lily family Colchicum autumnale, sometimes called the “autumn crocus”. It is predominantly metabolized in the gastrointestinal tract. Two proteins, P-glycoprotein (P-gp) and CYP3A4 seem to play a pivotal role, governing its pharmacokinetic. The commonest side effects are gastrointestinal (nausea, vomiting and particularly dose-related-diarrhea) occurring in 5-10% of patients. Colchicine exerts its unique action mainly through inhibition of microtubule polymerization. Microtubule polymerization affects a variety of cellular processes including maintenance of shape, signaling, division, migration, and cellular transport. Colchicine interferes with several inflammatory pathways including adhesion and recruitment of neutrophils, superoxide production, inflammasome activation, the RhoA/Rho effector kinase (ROCK) pathway and the tumor necrosis factor alpha (TNF-α) -induced nuclear factor Κ (NF-Κ) pathway attenuating the inflammatory response. This concise paper attempts to give a brief review of its pharmacokinetic properties and its main mechanisms of action.

Background: Colchicine is an ancient drug. Many uses have been reported in medical books and reports through the centuries. Currently the understanding of its mechanism of action has opened new horizons to its use. Objective: This article aims to discuss the use of colchicine in various neurosurgical conditions. Methods: A pubmed database and clinical trials search was performed, using the key words “colchicine”, “Neurosurgery”, “low back pain”, “stroke” and “glioma”. Results: Various reports were found contemplating the use of colchicine in chronic low-back pain. The effect of the drug on neutrophil chemotaxis and its role as an anti-inflammatory agent has been the main argument upon which such use of colchicine has been structured. These characteristics have been the key to initiate colchicine as a preventive agent in vascular conditions. Furthermore, as colchicine is an antimitotic drug, it is currently being studied as a potential anti-glioma agent. However, the narrow therapeutic index of the drug is a discouraging factor in clinical application of colchicine in these entities. Therefore, colchicine derivatives that can exert the same effectiveness in lower doses are being studied, forming a new direction in colchicine use. Conclusion: Colchicine is a drug that over the years has shown promising results in certain neurosurgical entities. Its derivatives or potential colchicine-like agents might have a more significant place in neurosurgical practice.

Introduction: Despite the proven efficacy of anti-thrombotic, lipid-lowering, anti-hypertensive therapies and lifestyle modification changes for secondary ischemic stroke prevention, the risk of recurrent stroke, coronary events and vascular death remains substantial even for patients treated with high rates of established secondary preventive medications. Methods: In the present review, we summarize available literature data on the association between systemic inflammation and symptomatic atherosclerosis including recurrent cerebral ischemia. We also highlight the potential role of colchicine in the suppression of atherosclerosis-induced inflammation, plaque stabilization and thromboembolism prevention. Results: Accumulating evidence suggests that inflammation is of key importance in the pathophysiology of atherosclerotic plaque de-stabilization and thromboembolism, with inflammatory cells being involved in all stages of atherosclerosis development. Therefore, anti-inflammatory therapies targeting the atherosclerotic plaque inflammation may be important contributors in plaque stabilization and in the prevention of thromboembolic events. Colchicine is known to have multiple anti-inflammatory properties including inhibition of microtubule polymerization, leading to reduced secretion in monocyte-macrophages. Currently the randomized controlled CONVINCE trial is enrolling stroke patients to evaluate the effect of a daily low-dose of colchicine in reducing the rate of recurrent stroke and major vascular events. Conclusion: Inflammatory pathways seem to be key mediators in the development of atherosclerotic process, atheromatous plaque destabilization and thromboembolism. Colchicine as a novel therapeutic agent could be a safe and effective inhibitor of the inflammation cascade in patients with extra- or intracranial atherosclerosis or arteriolosclerosis, resulting in reduced vascular events.

Colchicine is a lipophilic alkaloid drug, which exhibits ant-inflammatory and anti-fibrotic properties. Cardinal mechanisms of action of colchicine are the disruption of the microtubule system and the inhibition of neutrophil adhesion and recruitment. Colchicine is indicated in the prevention and treatment of gouty arthritis and familial Mediterranean fever. In this review, we summarize current and potentially future pharmacologic activities of colchicine in various renal disease entities along with pharmacokinetic and pharmacodynamic properties. Additionally, we will refer to main interactions of colchicine with medications used in renal medicine, as well as dosing recommendations in patients with reduced glomerular filtration rate.

Despite the fact that colchicine is by far the most ancient treatment for gout, new data are still being gathered. In gout, colchicine's ability to block polymerization of tubulin prevents the activation of the inflammasome. Efficacy of colchicine for the treatment of gout flares has been demonstrated only recently by a randomized- controlled trial, but it still has not been compared to other drugs. Use of colchicine is impaired by the impact of underlying comorbid conditions and drug interactions that can considerably modify its pharmacokinetics and pharmacodynamics. This manuscript reviews the state-of-the-art of colchicine in gout, from its known mechanisms of action to its effects, wanted and unwanted, expected and unexpected.

Colchicine has been longstanding and widely used for the treatment of acute gout flares and prevention of gout relapses. Its use has been extended to a series of autoinflammatory diseases, such as familial Mediterranean fever and more recently to periodic fever with aphthous stomatitis, pharyngitis and adenitis, Behcet's disease and idiopathic recurrent acute pericarditis. In this review, we summarize current indications of colchicine use, discuss its pharmacokinetics and mechanism of action and examine its use in the treatment of autoinflammatory diseases. Further understanding of the underlying mechanisms of the latter conditions as well as identification of the therapeutic efficacy and treatment target of colchicine may lead to more effective management of these diseases.

Post-operative atrial fibrillation (POAF) is a frequent entity increasing hospitalization duration, stroke and mortality. In the recent years, a few studies have sought to investigate the potential effect of colchicine in POAF prevention after cardiac surgery or catheter pulmonary vein isolation for AF. In the present review article, we intend to provide a synopsis of clinical practice guidelines, summarize and critically approach current evidence for or against colchicine as a means of POAF prevention.

Background: Colchicine is an old drug originally employed for the treatment of inflammatory disorders such as acute gout and familiar Mediterranean fever. Methods: In the past few decades, colchicine has been at the forefront of the pharmacotherapy of several cardiac diseases, including acute and recurrent pericarditis, coronary artery disease, prevention of atrial fibrillation and heart failure. In this review, we have summarized the current evidence based medicine and guidelines recommendations in the specific context of pericardial syndromes. Results: Colchicine has been firstly engaged in the treatment of recurrent pericarditis of viral, idiopathic and autoimmune origin. Shortly thereafter colchicine use has been expanded to the primary prevention of recurrences in patients with a first episode of pericarditis depicting similarly good results. The acquisition of high quality scientific data in the course of time from prospective randomized placebo-controlled trials and metanalyses have established colchicine as first line treatment option in acute and recurrent pericarditis, on top of the conventional treatment. The only concerns related to the use of colchicine are the side effects (mainly gastrointestinal intolerance) which although generally not serious, may account for treatment withdrawal in some cases. Conclusion: Colchicine has been established as a first line medication in the treatment of acute (first episode) and recurrent pericarditis on top of the conventional treatment as well as for the prevention of postpericardiotomy syndrome. It depicts a good safety profile with gastrointestinal intolerance being the most common side effect.

Recently, the risk of viral infection has dramatically increased owing to changes in human ecology such as global warming and an increased geographical movement of people and goods. However, the efficacy of vaccines and remedies for infectious diseases is limited by the high mutation rates of viruses, especially, RNA viruses. Here, we comprehensively review the effectiveness of several probiotics and paraprobiotics (sterilized probiotics) for the prevention or treatment of virally-induced infectious diseases. We discuss the unique roles of these agents in modulating the cross-talk between commensal bacteria and the mucosal immune system. In addition, we provide an overview of the unique mechanism by which viruses are eliminated through the stimulation of type 1 interferon production by probiotics and paraprobiotics via the activation of dendritic cells. Although further detailed research is necessary in the future, probiotics and/or paraprobiotics are expected to be among the rational adjunctive options for the treatment of various viral diseases.

Background: Host, vector, and culture conditions (including cultivation media) are considered among the three main elements contributing to a successful production of recombinant proteins. Accordingly, one of the most common hosts to produce recombinant therapeutic proteins is Escherichia coli. Methodology: A comprehensive literature review was performed to identify important factors affecting production of recombinant proteins in Escherichia coli. Results: Escherichia coli is taken into account as the easiest, quickest, and cheapest host with a fully known genome. Thus, numerous modifications have been carried out on Escherichia coli to optimize it as a good candidate for protein expression and; as a result, several engineered strains of Escherichia coli have been designed. In general; host strain, vector, and cultivation parameters are recognized as crucial ones determining success of recombinant protein expression in Escherichia coli. In this review, the role of host, vector, and culture conditions along with current pros and cons of different types of these factors leading to success of recombinant protein expression in Escherichia coli were discussed. Conclusion: Successful protein expression in Escherichia coli necessitates a broad knowledge about physicochemical properties of recombinant proteins, selection among common strains of Escherichia coli and vectors, as well as factors related to media including time, temperature, and inducer.

Background: The concern about the frequent use of ciprofloxacin in veterinary medicine is linked to increased antimicrobial resistance. The corresponding fluoroquinolone for veterinary use is enrofloxacin. A new solvate form of enrofloxacin, as dihydrate-hydrochloride (enro-C) with higher water solubility than the parent compound, was formulated as an ophthalmic solution (pH 5). A multicentre, longitudinal, non-inferiority clinical study in a non-hospital environment was designed to treat 36 dogs affected by tobramycin-unresponsive conjunctivitis with either the experimental 0.5% enro-C ophthalmic preparation (enro-CG) or a commercial preparation of ciprofloxacin (cipro-G). Other causes of conjunctivitis were ruled out. Pathogens were isolated and minimum inhibitory concentration (MIC) studies of tobramycin were carried out. Three blocks of bacterial resistance were set up, beginning at the established breakpoint i.e., 4 μg/mL; 8 μg/mL and 16 μg/mL. Eighteen dogs were randomly assigned to each block. The enro-CG group was treated with two drops of the referred preparation (10 mg/eye) twice a day for 7 days, and the cipro-G group was treated with four drops of a 0.3% commercially available ciprofloxacin eye-drop preparation (9 mg/eye) twice a day, also for 7 days. Clinical and bacteriological cure rates were evaluated. Results: Enro-C-treated dogs achieved a clinical cure one day earlier than ciprofloxacin-treated dogs, and unlike this latter group, enro-CG achieved bacteriological cure in all cases. No side effects were observed in either group, but dogs treated with enro-C showed no discomfort, allowing easier treatment-compliance. Conclusion: This is the first study reported on the successful formulation of enrofloxacin as an ophthalmic solution. Clinical assessment reveals outstanding clinical efficacy. It is necessary to conduct further research on clinical efficacy and toxicity, with the chronic use of this preparation under different clinical challenges.

Backgound: Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a crucial role in the process of cancer angiogenesis. Type I inhibitors constitute the major ATP-competitive inhibitors and recognize mainly the active conformation of VEGFR-2. Meanwhile, type II inhibitors recognize the inactive DFG (Asp- Phe-Gly)-out conformation of VEGFR-2, which was a more promising approach for drug intervention. Methods: According to the lead compound of uracil skeleton, being screened out by structure-based virtual screening, a series of uracil derivatives were designed and synthesized. Results: The inhibitory activities were investigated against VEGFR-2 kinase in vitro. The results turned out that series A performed moderate inhibitory activities, especially compound A4 exhibited the most potent inhibitory activity (IC50=0.029 μM). Conclusion: The lead compound was screened out by structure-based pharmacophore models, then two series of uracil derivatives were synthesized according to it and evaluated for their inhibitory activities against VEGFR-2. In this study, not only a potential inhibitor has been discovered, it also demonstrates the feasibility of structure-based virtual screening method for drug discovery.