Pharmaceuticals, Volume 2, Issue 3 (December 2009) – 17 articles , Pages 66-298

Therapeutic strategies for Alzheimer disease (AD) have yet to offer a diseasemodifying effect to stop the debilitating progression of neurodegeneration and cognitive decline. Rather, treatments thus far are limited to agents that slow disease progression without halting it, and although much work towards a cure is underway, a greater understanding of disease etiology is certainly necessary for any such achievement. Mitochondria, as the centers of cellular metabolic activity and the primary generators of reactive oxidative species in the cell, received particular attention especially given that mitochondrial defects are known to contribute to cellular damage. Furthermore, as oxidative stress has come to the forefront of AD as a causal theory, and as mitochondrial damage is known to precede much of the hallmark pathologies of AD, it seems increasingly apparent that this metabolic organelle is ultimately responsible for much, if not all of disease pathogenesis. In this review, we review the role of neuronal mitochondria in the pathogenesis of AD and critically assess treatment strategies that utilize this upstream access point as a method for disease prevention. We suspect that, with a revived focus on mitochondrial repair and protection, an effective and realistic therapeutic agent can be successfully developed. Full article

Insulin, besides its glucose lowering effects, is involved in the modulation of lifespan, aging and memory and learning processes. As the population ages, neurodegenerative disorders become epidemic and a connection between insulin signaling dysregulation, cognitive decline and dementia has been established. Mitochondria are intracellular organelles that despite playing a critical role in cellular metabolism are also one of the major sources of reactive oxygen species. Mitochondrial dysfunction, oxidative stress and neuroinflammation, hallmarks of neurodegeneration, can result from impaired insulin signaling. Insulin-sensitizing drugs such as the thiazolidinediones are a new class of synthetic compounds that potentiate insulin action in the target tissues and act as specific agonists of the peroxisome proliferator-activated receptor gamma (PPAR-γ). Recently, several PPAR agonists have been proposed as novel and possible therapeutic agents for neurodegenerative disorders. Indeed, the literature shows that these agents are able to protect against mitochondrial dysfunction, oxidative damage, inflammation and apoptosis. This review discusses the role of mitochondria and insulin signaling in normal brain function and in neurodegeneration. Furthermore, the potential protective role of insulin and insulin sensitizers in Alzheimer´s, Parkinson´s and Huntington´s diseases and amyotrophic lateral sclerosis will be also discussed. Full article

We used Neuromolecular Imaging (NMI) and trademarked BRODERICK PROBE^® mini-implantable biosensors, to selectively and separately detect neurotransmitters in vivo, on line, within seconds in the dorsal striatal brain of the Parkinson’s Disease (PD) animal model. We directly compared our results derived from PD to the normal striatal brain of the non-Parkinson’s Disease (non-PD) animal. This advanced biotechnology enabled the imaging of dopamine (DA), serotonin (5-HT), homovanillic acid (HVA) a metabolite of DA, L-tryptophan (L-TP) a precursor to 5-HT and peptides, dynorphin A 1-17 (Dyn A) and somatostatin (somatostatin releasing inhibitory factor) (SRIF). Each neurotransmitter and neurochemical was imaged at a signature electroactive oxidation/half-wave potential in dorsal striatum of the PD as compared with the non-PD animal. Both endogenous and bromocriptine-treated neurochemical profiles in PD and non-PD were imaged using the same experimental paradigm and detection sensitivities. Results showed that we have found significant neurotransmitter peptide biomarkers in the dorsal striatal brain of endogenous and bromocriptine-treated PD animals. The peptide biomarkers were not imaged in dorsal striatal brain of non-PD animals, either endogenously or bromocriptine-treated. These findings provide new pharmacotherapeutic strategies for PD patients. Thus, our findings are highly applicable to the clinical treatment of PD. Full article

Three thermally and hydrolytically stable silylamide trioxanes have been prepared from the natural trioxane artemisinin in only five simple chemical steps and in at least 56% overall yield. Two of these new chemical entities completely cured malariainfected mice at a single oral dose of only 8 mg/kg combined with 24 mg/kg of mefloquine hydrochloride. The high efficacy of this ACT chemotherapy is considerably better than the efficacy using the popular trioxane drug artemether plus mefloquine hydrochloride. Full article

Soluble epoxide hydrolase inhibitors (sEHIs) are demonstrating promise as potential pharmaceutical agents for the treatment of cardiovascular disease, diabetes, inflammation, and kidney disease. The present study determined the ability of a first-inclass sEHI, AR9281, to decrease blood pressure, improve vascular function, and decrease renal inflammation and injury in angiotensin hypertension. Rats were infused with angiotensin and AR9281 was given orally during the 14-day infusion period. Systolic blood pressure averaged 180 ± 5 mmHg in vehicle treated and AR9281 treatment significantly lowered blood pressure to 142 ± 7 mmHg in angiotensin hypertension. Histological analysis demonstrated decreased injury to the juxtamedullary glomeruli. Renal expression of inflammatory genes was increased in angiotensin hypertension and two weeks of AR9281 treatment decreased this index of renal inflammation. Vascular function in angiotensin hypertension was also improved by AR9281 treatment. Decreased afferent arteriolar and mesenteric resistance endothelial dependent dilator responses were ameliorated by AR9281 treatment of angiotensin hypertensive rats. These data demonstrate that the first-in-class sEHI, AR9281, lowers blood pressure, improves vascular function and reduces renal damage in angiotensin hypertension. Full article

For more than 20 years after the excitement engendered by their discovery in 1957 as antiviral agents, there were no significant clinical uses of interferons; however, following their cloning they have been employed as effective treatment for several viral, autoimmune, and neoplastic diseases. Full article

The prevention of aging is one of the most fascinating areas in biomedicine. The first step in the development of effective drugs for aging prevention is a knowledge of the biochemical pathways responsible for the cellular aging process. In this context it seems clear that free radicals play a key role in the aging process. However, in recent years it has been demonstrated that the families of enzymes called sirtuins, specifically situin 1 (SIRT1), have an anti-aging action. Thus, the natural compound resveratrol is a natural compound that shows a very strong activation of SIRT1 and also shows antioxidant effects. By activating sirtuin 1, resveratrol modulates the activity of numerous proteins, including peroxisome proliferator-activated receptor coactivator-1α (PGC-1 alpha), the FOXO family, Akt (protein kinase B) and NFκβ. In the present review, we suggest that resveratrol may constitute a potential drug for prevention of ageing and for the treatment of several diseases due to its antioxidant properties and sirtuin activation. Full article

The effect of different metal ions on the intestinal transport and the antibacterial activity of cefadroxil [(6R,7R)-7-{[(2R)-2-amino-2-(4-hydroxyphenyl)acetyl]amino}-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid] was investigated. The [¹⁴C]Gly-Sar uptake via PEPT1 was inhibited by Zn²⁺ and Cu²⁺ treatment in a concentration-dependent manner (K_i values 107 ± 23 and 19 ± 5 μM, respectively). Kinetic analysis showed that the K_t of Gly-Sar uptake was increased 2-fold in the presence of zinc sulphate (150 μM) whereas the V_max value were not affected suggesting that zinc ions inhibited Gly-Sar uptake by PEPT1 in a competitively manner. Ni²⁺ exhibited moderate inhibitory effect, whereas Co²⁺, Mg²⁺, Al³⁺ ions showed no inhibitory effect on Gly-Sar uptake via PEPT1. Subsequently, we examined the effect of Zn²⁺ and Al³⁺ ions on the transepithelial transport of cefadroxil across Caco-2 cells cultured on permeable supports. The results showed that zinc ions inhibited the transepithelial flux of cefadroxil at Caco-2 cell monolayers while Al³⁺ ions had no effect. The interaction of cephalosporins with the metal ions could suggest negative effects of some metal ions on the clinical aspects of small intestinal peptide and drug transport. Finally, the effect of Zn²⁺, Cu²⁺ and Al³⁺ ions on the antibacterial activity of cefadroxil was tested. It was found that there is no significant difference between the activity of cefadroxil and the cefadroxil metal ion complexes studied against the investigated sensitive bacterial species. Full article

Oxytocin (OT), traditionally associated with reproductive functions, was revisited recently, and several new functions in cardiovascular regulation were discovered. These functions include stimulation of the cardioprotective mediators nitric oxide (NO) and atrial natriuretic peptide. OT’s cardiovascular outcomes comprise: (i) natriuresis, (ii) blood pressure reduction, (iii) negative inotropic and chronotropic effects, (iv) parasympathetic neuromodulation, (v) NO pathway involvement in vasodilatation and endothelial cell growth, (vi) anti-inflammatory and (vii) antioxidant activities as well as (viii) metabolic effects. In addition, we have reported abundant OT in the early developing heart with its capacity to generate cardiomyocytes (CMs) from mouse embryonic stem cells and stem cells residing in the heart. OT increases glucose uptake by cultured CMs, in normal, hypoxic and even in insulin resistance conditions. In experimentally-induced myocardial infarction in rats, continuous in vivo OT delivery improves the cardiac healing process and cardiac work, diminishes inflammation, and stimulates angiogenesis. Therefore, in pathological situations, OT plays an anti-inflammatory and cardioprotective role, enhancing vascular and metabolic functions, with potential therapeutic application(s). Full article

Neurodegenerative diseases are a common late-life scourge for which diseasemodifying treatments are sorely needed. Mitochondrial perturbation is commonly observed in these diseases, so pursuing treatment development strategies that target mitochondria or processes affected by mitochondria seems reasonable. This review discusses the rationale underlying past and current efforts to treat neurodegenerative diseases using mitochondrial medicine, and tries to predict how future efforts might proceed. Full article

Coenzyme Q10 (CoQ10, or ubiquinone) is a small electron carrier of the mitochondrial respiratory chain with antioxidant properties. CoQ10 supplementation has been widely used for mitochondrial disorders. The rationale for using CoQ10 is very powerful when this compound is primary decreased because of defective synthesis. Primary CoQ10 deficiency is a treatable condition, so heightened “clinical awareness” about this diagnosis is essential. CoQ10 and its analogue, idebenone, have also been widely used in the treatment of other neurodegenerative disorders. These compounds could potentially play a therapeutic role in Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, Friedreich’s ataxia, and other conditions which have been linked to mitochondrial dysfunction. This article reviews the physiological roles of CoQ10, as well as the rationale and the role in clinical practice of CoQ10 supplementation in different neurological diseases, from primary CoQ10 deficiency to neurodegenerative disorders. Full article

Background: Combination therapy with antihypertensive agents utilises different mechanisms of action and may be responsible for a more effective decrease in blood pressure. Objective: To review the recently published trials on efficacy and safety of the combination therapy with olmesartan and amlodipine. Results: The double-blind American COACH (Combination of Olmesartan Medoxomil and Amlopdine Besylate in Controlling High Blood Pressure) study (2008) showed in 1,940 patients that after eight weeks of treatment the BP goals were most frequently achieved in the ‘combination therapy group’, with 56.3% (54.1–58.5%) and 54.0% (51.8–56.2%) of patients reaching adequate blood pressure of <140/90 mmHg with olmesartan/amlodipine 20/10 and 40/10 respectively. Combination therapy was generally well tolerated. The most common side effect was oedema [olmesartan 20 mg 9.9% (8.6–11.3%), amlodipine 10 mg 36.8% (34.7–39.0%), placebo 12.3% (10.9–13.8%)]. The frequency of oedema was lower in the groups combining amlodipine 10 mg with olmesartan 10 mg (26.5%, 24.5–28.5%), 20 mg (25.6%, 23.7–27.6%) or 40 mg (23.5%, 21.6–25.4%). In 2009 three double-blind controlled European studies including 500–1,000 patients each and performed independently of one another have confirmed the above study, and have demonstrated similar efficacy-safety effects from the combination of olmesartan medoxomil with amlodipine, particularly for patients not achieving adequate blood pressure control with olmesartan monotherapy. Conclusions: Combinations of olmesartan and amlodipine were significantly more effective at reducing blood pressure and realising guideline blood pressure goals in patients with mild to severe hypertension than monotherapy (with a placebo component). Combination therapy is well tolerated and is associated with a lower incidence of side effects, such as oedema, compared to monotherapy with high amlodipine dosages (10 mg). Full article

The renin-angiotensin-aldosterone system (RAAS) plays a dominant role in the pathophysiology of hypertension, diabetes mellitus, chronic kidney disease and chronic heart failure. Therefore, drugs that block key components of the RAAS such as ACE inhibitors (ACEI) and angiotensin receptor blockers (ARBs) have gained wide clinical use for these indications. Despite progress, the morbidity and mortality of patients treated with ACEI or ARBs remain high. Aliskiren (Tekturna, Rasilez) is the first orally active inhibitor of renin approved for clinical use as an antihypertensive agent. The development program has established that at the licensed doses of 150 mg and 300 mg. Aliskiren is effective either as monotherapy or in combination with drugs from the other major classes. In this review we analyze and review the information already gained with Aliskiren, raises questions regarding the advantages of DRIs as monotherapy compared to marketed ACEIs and ARBs, their potential added value in combination with other RAAS modulators and other still unproven benefits in relation to prorenin and renin receptor biology. Full article

In the past several years a number of alterations in the PAFAH/PLA₂G7/LpPLA₂ gene have been described. These include inactivating mutations, polymorphisms in the coding region, and other genetic changes located in promoter and intronic regions of the gene. The consequences associated with these genetic variations have been evaluated from different perspectives, including in vitro biochemical and molecular studies and clinical analyses in human subjects. This review highlights the current state of the field and suggests new approaches that can be used to evaluate functional consequences associated with mutations and polymorphisms in the PAF-AH gene. Full article

Aim: To investigate the association of uncontrolled hypertension with psychological factors associated with high cardiovascular morbidity and mortality (type D personality, depression, posttraumatic stress-related symptoms). Methods: 205 consecutive outpatient hypertensives completed three questionnaires evaluating Type D personality (DS 16), post traumatic symptoms (revised Impact of Events Scale), symptoms of anxiety, hostility, depression and obsessive-compulsive traits (subscales of the Symptom Checklist). Uncontrolled hypertension was diagnosed when clinic sitting blood pressure was above 140/90 mmHg (130/80 in the presence of diabetes or nephropathy), despite reported adherence to treatment with at least three antihypertensive medications, including a diuretic. Results: Uncontrolled hypertension (39%), was predicted by lower scores at Symptom Checklist obsessive-compulsive subscale and higher number of post traumatic avoidance symptoms, older age, diabetes, higher systolic pressure at first visit and longstanding hypertension. Type D personality correlated with depression, hostility, anxiety, compulsiveness, history of malignancy, and older age, but not with uncontrolled hypertension. Conclusions: Uncontrolled hypertension is associated with low obsessionality and avoidance symptoms, which reduce compliance to treatment. On the contrary, type D personality is not correlated with uncontrolled hypertension, as it includes compulsiveness, which improves compliance. A multidisciplinary approach to the hypertensive patient is mandatory to establish if the psychological profile affects compliance. Full article

Many therapeutic agents are manufactured and administered in prodrug forms. In this paper, a new classification system for prodrugs is proposed to provide useful information about where in the body a prodrug is converted to the active drug. In this system, prodrugs are classified into Type I or Type II and the respective Subtypes IA, IB, IIA, IIB or IIC based on their sites of conversion into the final active drug form. For Type I prodrugs, conversion occurs intracellularly (e.g., antiviral nucleoside analogs, lipid-lowering statins), whereas conversion of Type II prodrugs occurs extracellularly, for examples in digestive fluids, systemic circulation or other extracellular body fluids (e.g., etoposide phosphate, valganciclovir, fosamprenavir). Type IA prodrugs refer to those that are converted at the cellular targets of therapeutic actions, whereas Type IB prodrugs’ conversion occurs in the primary metabolic tissues such as liver, gut, or lung. For Type II prodrugs, the conversion process could either take place extracellularly in the milieu of gastrointestinal fluids (Type IIA), in the systemic circulation and/or other systemic extracellular fluid compartments (Type IIB), or near therapeutical target cells (Type IIC). A prodrug may belong to multiple categories and be recognized as a Mixed-Type prodrug. For example a prodrug may be converted both in target cells and metabolic tissues such as liver (i.e., named as a Type IA/IB prodrug), or one converted in both GI fluids and systemic circulations (i.e., named as a Type IIA/IIB prodrug). The Mixed-Type compound can be further distinguished as a Parallel Mixed-Type or Sequential Mixed-Type prodrug depending on the conversion processes that proceed with, either in concurrent or in sequential steps. Because traditional analysis of drug actions has always been focused on the site of action and mode of action, the proposed classification of prodrugs based on cellular locations of conversion is in line with current thought processes of regulatory review and risk assessment of both prodrug and active drug. By gaining insights regarding the site of action through prodrug nomenclature, risk benefit evaluation can be made more efficiently because both information on kinetics and impact of tissues involved are adequately revealed through prodrug subtype designated. In conclusion, the new system of classification will add to existing knowledge of prodrug classifications, and will provide improved insight into the contributory roles of both prodrug and active drug in the product’s efficacy and safety, and their risk-benefit assessment. Full article

Over the last few decades, treatment for aortic dissection and thoracic aortic aneurysms has evolved significantly with improvement in outcomes. Treatment paradigms include medical, endovascular and surgical options. As aortic dissection presents as a hypertensive emergency, diligent control of BP is of utmost importance in order to reduce the progression of dissection with possible aortic branch malperfusion. Treatment should begin on arrival to the emergency department and continues in the intensive care unit, endovascular suite or the operating room. Novel antihypertensive medications with improved pharmacological profile and improved surgical techniques, have improved the prognosis of patients with aortic aneurysm and/or aortic dissection. Nevertheless, morbidity and mortality remain high and hypertensive emergency poses a significant challenge in aortic dissection and thoracic aortic aneurysms. Full article