A Review of the Development of Calcium Pterins and (250:1 Mol:Mol) Calcium Folate for the Immunotherapy of Certain Diseases

The development of a class of immunotherapeutics, the calcium pterins, beginning with Ca Pterin·2Cl (Ca-Pterin) and culminating with calcium pterin6-carboxylate chelate (CP6CC) for several immunologically-related preclinicaland clinical indications is reviewed here.

Immunotherapy

A preliminary analysis of their immuno-mechanisms of action is discussed. The preclinical murine models first tested with CaPterin and dipterinyl calcium pentahydrate (DCP), a dimerized version of CaPterin, were four murine breast tumor models. These four models included: C3H/HeN-MTV+ female mice with spontaneous mammary gland adenocarcinomas; Mammary EMT6 allografts implanted in nonimmune female Balb/c mice; MDA-MB-231 human breast tumor xenographs in SCID mice; and MDA-MB-231 human breast tumor xenographs in athymic nude mice. An analysis of the differing tumor responses in these breast tumor models led to the determination that B-cell antibody-based antitumor mechanisms were involved. A transgenic hepatitis B murine model and a diabetes-induced obese (DIO) type 2 diabetes murine model were also tested with DCP, giving positive results. Read more>>>>>>>

Acute and Sub-Chronic Oral Toxicity Study of Methanolic Extract of Caesalpinia volkensii (Harms)

The ability of plants to synthesize varieties of chemical compounds gives them both physiological and pharmacological effects hence their popular use as treatment agents and food. Moreover, medicinal plants use has been accompanied by greatresearch interests, which provides scientists and policy maker accurateinformation to regulate their use.There are several plants with diverse medicinal use in Kenya. However, their safety evaluation cannot match the rate at which they are used. Therefore, there is need to bridge this gap. Only a handful of medicinal plants have undergone safety profiling. In addition, there are no elaborate regulatory bodies in place. This predisposes most of herbal users to toxicity.

Easy availability of herbal medicine has led to their increased use. This has resulted to increased reports of their suspected toxicity and adverse events. Such unwanted reactions can be due to side effects; reactions occurring as a result of overdose, over duration, tolerance, dependence-addiction; hypersensitivity, allergic and idiosyncratic reactions; mid-term and long-term toxic effects. It is such reaction that necessitates toxicity evaluation.Mechanisms of toxicity can present in several ways. One of them is on target whereby the toxicant binds to a targeted receptor with unintended high affinity resulting to untoward reaction. Off target is another mechanism whereby the toxicant binds to unintended receptor resulting to unintended reaction.(Read More)

Therapeutic Potential of Resveratrol for Cardiovascular Protection

Cardiovascular Disease (CVD) including stroke is one of the leading causes of death and disability worldwide and an enormous economic burden to our societies. Based onthe latest statistics for heart and stroke disease released by the AmericanHeart Association in 2016, CVD is the leading global cause of death, accounting for more than 17.3 million deaths per year, a number that is expected to grow to more than 23.6 million by 2030. An estimated 83,600,000 adults in the United State (US) (>30%) have one or more types CVD of whom more than 90% have hypertension, 18% have Coronary Heart Disease (CHD), close to 10% have Myocardial Infarction (MI) and 8% have stroke. The total direct and indirect cost in the US alone for treatment of CVD (hospitalization, drugs, home healthcare, etc.) and loss of productivity and morbidity totalled more than $315 billion US per year. 

While there was a decline in cardiovascular mortality reported in the American Heart Association 2014 update, the disease burden to society remains high. Thus prevention by better diagnosis and treatment could provide a huge saving for the health care cost worldwide. Despite advancement in modern cardiovascular medicine, the prevalence of hypertension, Ischemic Heart Disease (IHD) and stroke is still on the rise, particularly in industrialized societies and in the elderly population, and finding an optimum drug therapy to slow disease progression remains a therapeutic challenge.(Read more)

Serotonin in the Frontal Cortex: A Potential Therapeutic Target for Neurological Disorders

Serotonin or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter which has broad distribution in the brain. It was discovered by Erspamer and Asero in the 1950s. 5-HT is synthesized in two steps, with Tryptophan Hydroxylase (TPH) as therate-limiting enzyme. First, tryptophan is converted to 5-hydroxytryptophan (5-HTP) by TPH. Second, the intermediate product, 5-HTP, is converted to 5-HT by aromatic acid decarboxylase (AADC). 5-HT is primarily degraded by the mitochondrial bound protein Monoamine Oxidase A (MAOA), leading to the generation of the metabolite, 5-hydroxyindoleacetic acid (5-HIAA). Importantly, serotonin is also a substrate for melatonin synthesis. 5-HT is released from the axonal terminals of serotoninergic neurons and acts on 14 distinct receptor subtypes that are classified into 7 different families: 5-HT1 (1A, 1B, 1D, 1E, 1F), 5-HT2 (2A, 2B, and 2C), 5-HT3, 5-HT4, 5- HT5 (5A, 5B), 5-HT6, and 5-HT7. Among all these receptors, only 5-HT3 receptor is a pentameric ligand-gated ion channel composed of several subunits of which 5 different types have been identified. All other 5-HT receptors are G-protein coupled receptors which regulate the activity of the neurons expressing them. Released serotonin is transported to the presynaptic neurons by serotonin transporter (SERT or 5-HTT), a type of monoamine transporter protein.

Serotonergic neurons are located in the raphe nuclei. While the more caudal raphe nuclei project to the Peripheral Nervous System (PNS), the neurons in the dorsal and median raphe nuclei (DRN and MRN) primarily send their projections to forebrain regions. 5-HT is critically involved in the development of many cortices, such as somatosensory cortex and barrel cortex. In adult brain, 5-HT neurons project to majority of cortical areas, including the entorhinal and cingulate cortices. However, of all cortical regions, the frontal lobe contains the highest density of serotonergic terminals and 5-HT receptors. These studies indicate that 5-HT regulates cognitive and emotional functions that rely on frontal cortical activity.(Read more)

Development and Validation of Liquid Chromatography (RP-HPLC) Methodology for Estimation of Efonidipine HCl Ethanolate (EFD)

Efonidipine hydrochloride ethanolate (NZ-105), (±)-2- [Benzyl(phenyl)amino]ethyl-1,4-dihydro-2,6-dimethyl-5-(5,5-dimethy -2-oxo-1,3,2-dioxaphosphorinan-2-yl)-4-(3-nitorophen-yl)-3- pyridine carboxylate hydrochloride ethanol, is a dihydropyridine calcium antagonist with aphosphonate backbone and that was discovered at Nissan Chemical Industries, Ltd. This active drug ingredient was initially studied for development as a hydrochloride salt without ethanol, obtained through the addition of hydrochloric acid to efonidipine acetone solution. It showed an excellent antihypertensive effect in patients with various kinds of hypertension (essential, severe, renal). Efonidipine has slow onset and long duration of action.

It is well known that many 1,4-dihydropyridine derivatives are subject to the first-pass effect, and that the primary metabolismstep of most derivatives involves oxidation of the dihydropyridine ring to the corresponding pyridine analogue. However, it has been suggested that efonidipine is less likely to be subject to the first-pass effect than other dihydropyridine derivatives and that its dihydropyridine ring is oxidized mainly after metabolism of the side chain. Additionally, efonidipine has distinct properties when compared with other calcium channel blockers. The studies indicated that efonidipine therapy simultaneously improves blood pressure, endothelial function, and metabolic parameters without substantially altering insulin sensitivity in non-diabetic patients with hypertension.(Read more)

The Expression of SIRT1 in Ocular Tissues.

Epigenetic alterations play important roles in a wide variety of physiological and pathological events. As one of the most important epigenetic regulators, Histone Deacetylases (HDACs) are able to deacetylate lysine residues on histone and non-histone proteins,regulating chromatin structure, gene expression and protein function. Eighteen human HDACs have been identified and grouped into 4 classes based on their homology to respective yeast orthologous. The human sirtuins family, homologs of the yeast silent information regulator 2(Sir2), belongs to class III HDACs. They are NAD+-dependent deacetylases and contain seven members (SIRT1-7) with varied functions, structures, and localizations. Among them, SIRT1 is the most extensively studied, primarily because of its regulation of diverse cellular targets and functions as well as its therapeutic potential.

Human SIRT1 comprises 747 amino acids divided into three main regions: the central core, possessing the deacetylase domain, which consists of a large NAD+-binding subdomain with a Rossmann fold and a smaller subdomain composed of a helical module and a Zn²⁺- binding module, and the N- and C-terminal domains, containing regulatory elements and binding domains for SIRT1 co-activators or repressors.(Read more) 

Magnetic Properties of Iron Oxides in the Human Globus pallidus

Iron, as the most abundant transition metal in the human brain, occurs with uneven distribution. Highest concentration of iron can be observed in areas associated with motor function (Globus pallidus, putamen, Substantia nigra) than in other areas of the human brain. Therefore, the actual role of iron accumulation in brain pathobiology isan active area of investigation nowadays.It is evident that amount of iron in brain gradually grows with age. Accumulation of iron in basal ganglia is probably associated with neuronal death leading to Alzheimer disease, Parkinson disease, epilepsy, Huntington disease, dementia with Lewy bodies, and multiple sclerosis. It was reported that iron participates in redox reactions, and catalyzes the formation of reactive oxygen species responsible for oxidative stress and damaging processes.

Iron in the human brain can be found mostly in the form of ferritin, hemosiderin (a product of ferritin breakdown) and other biomineralized oxidohydroxides and oxides such as hematite, magnetite, and maghemite. Ferritin, as an iron storage nonheme-protein with diameter up to 12 nm, consist of inorganic core (6 nm) formed of ferrihydrite and minor portion of magnetite and hematite that is enclosed by two types of polypeptides. The role of the heavy (Ft-H) form polypeptide coat of ferritin is to catalyze Fe(II) to Fe(III) ions whereas the light (Ft-L) polypeptide coat promotes the formation of ferritin iron core.The amount of Ft-H and Ft-L polypeptide coats changes during ageing and the magnetic properties of ferritin can also alter.(Read More)

Adjunctive Treatment Considerations for the Addressment of Inflammation in Neuromuscular Disorders.

At the root of many of society’s major health concerns plaguing millions of Americans each year is the concept of inflammation. Encompassing cardiovascular, oncologic, dermatologic, painmanagement, and neurologic diseases, the peripheral and systemic manifestations of inflammation has been increasingly shown to be a major culprit in disease spread. Broad examples of this can be seen in various neurologic disease states.

Demyelinating diseases such as Multiple Sclerosis and degenerative changes associated with dementia have many factors with inflammation being one of those. The inflammatory cascade with its incorporation of pro inflammatory cytokines and transcriptional factors has been shown to be suggestive in the pathophysiology of these diseases. Similarly, glial cells, acting as neural supports, have been shown to play a role in the production of these same pro inflammatory cells (IL-1B, IL-6, IL-8, TNF-alpha). The overproduction of these mediators is suggestive of neurodegenerative progression in both acute (ischemic injury) and chronic degenerative neural disorders. Acknowledgement and addressment of the inflammatory cascade has led to novel treatment strategies such as the use of sirtuins.(Read more)

Essential Oil Chemotypes of Three Ocimum Species Found in Sierra Leone and Nigeria.

The family Lamiaceae of which the genus Ocimum belongs is composed of diverse and rich source of essential oil containing plants. Ocimum contains between fifty to one hundredand fifty species of herbs and shrubs from the tropical regions of Asia, Africa, and Central and South America. O. gratissimum L. is referred to as holy basil. In Sierra Leone, it is known as “Tea bush” (Krio) and “orgbethor” (Themne) while it is known as “efirin nla” in the Yoruba speaking culture of Nigeria. O. basilicum L. is also referred to as sweet basil. It is known as “Patmenji” (Krio) and “Sorow” (Themne) of Sierra Leone and “efinrin wewe” by the Yorubas. O. americanum L. (synonym of O. canum Sims) is known as American basil or hoary basil. 

In Sierra Leone both the available varieties of O. americanum L and O. basilicum L. are used in culinary as “Patmengy” indiscriminately. The different varieties of O. gratissimum L. [implying different chemotypes] have been used extensively in the traditional system of medicine in many countries as had been reviewed. The main issues of concern with the use of herbal drugs remain safety, validation of claims and standardisation of product. There exist the problems of significant variation in the content of Ocimum plants across and within species, with implication of varied biological activities.(Read more)

Berberine Protects against Hydrogen Peroxide-Induced Oxidative Damage in PC12 Cells through Activation of ERK1/2 Pathway.

Neurodegenerative diseases (ND), such as Alzheimer's (AD) and Parkinson's disease (PD), are chronic degenerative pathologies of the Central Nervous System (CNS). NDs arecharacterized by progressive loss of specific neurons which further leads to adecline in brain functions. Despite the fact that pathologies have different clinical features, there are some common hallmarks, such as synaptic dysfunctioning, oxidative stress, and inflammation. The NDs are caused by an enhancement of ROS production via mitochondria and NADPH oxidase (NOX), which seems to account for tissue injury and neurodegeneration. 

Nowadays, NDs are chronic and incurable conditions, and the disabling effects may continue for years or even decades representing an enormous disease load, regarding human suffering and economic cost. In neuronal cells, the over production of ROS is considered as one of the risk factors for NDs. Disruption of redox homeostasis is a key phenotype of many pathological conditions. Hydrogen peroxide (H₂O₂), the main source of ROS, can cause cell membrane injury as well as lipid peroxidation and DNA damage in variety cells. However, antioxidants were able to protect cells against H₂O₂-induced cell death via reducing ROS production.(Read more)

The Hidden Ingredients Affecting Cancer Patients Outcome and the Mathematical Journey to Their Uncover.

Since the identification of Nitrogen mustard as a non-specific DNA alkylating agent and its clinical assessment by Gilman and Goodman at Yale University in 1942 for Lymphoma treatment, the field of medical oncology has rapidly expanded.It relies on understanding and exploring numerous factors affecting cancer patient’s outcome, 

including:1) Familiarity with the natural history of various malignancies and understanding the significant of patients' well-being as predictor to survive and tolerate therapy, scored as the "Performance Status";2) Basic biology events of normal cycling cells, and principals involved in cancer pathogenesis named "hallmarks of cancer," including sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, angiogenesis, activating invasion and metastasis, and recently expanded to include also reprogramming of energy metabolism and evading immune destruction .3) Identification of tumor features or biomarkers for tailored treatment approach including: "targeted" therapy (i.e., estrogen receptor expression for hormonal manipulations in breast cancer. (Read more)

Evaluation of Antioxidant, Antimicrobial and Cytotoxic Activity of the Bark of Alstonia scholaris

As a source of drugs the medicinal plants are used for the management and treatment of various human and livestock health disorders or diseases worldwide from ancient times to the present day. There are a total of 250,000 species of flowering plants referred to as medicinal plants. The World Health Organization (WHO) enlisted about 21,000 medicinal plant species . The global herbal market is about US$ 62 billion per annum. The annual growth of herbal market is about 15 percent and in 2050, it is expected to be about US$ 5 trillion. About 25% of prescribed drugs in the world are of plants source. 

In developing countries about 80% people believe on traditional plant based medicines for their primary health care purposes. Worldwide several thousands of plants had identified consisting medicinal values and it was used for the treatment of different diseases in various cultures. From the beginning to present majority of people are relying on the traditional medicine for the treatment of their primary health care. The high cost of imported conventional drugs and inaccessibility to western medical care facility, involve that traditional mode of health care is the only form of health care that is reasonably priced and accessible to the people of rural area.(Read more)

TITLE : A Review of the Development of Calcium Pterins and (250:1 Mol:Mol) Calcium Folate for the Immunotherapy of Certain Diseases.

Since the determination that oral calcium CaPterin is efficacious against tumor development in murine breast cancer models and a modulator of the immuno-regulatoryenzyme indoleamine 2,3-dioxygenase (IDO), further investigation into its mechanisms of action has been of crucial interest to investigators. 

Two of these studies also focused on the anti-tumor properties of oral dimeric DCP ,which forms CaPterin at pH<4 (gastric conditions). This chelation dissociates under gastric pH conditions and likely rechelates in the higher pH conditions of the duodenum. (Read more)

Time-Course of Buprenorphine Dose Increase in a Maintenance Program for Heroin Addicts: Retention in Treatment and Clinical Meaning

Buprenorphine is a major therapeutic option in the treatment of opiate addiction. Peculiarly, increasing dosages do not grant higher and higher levels of agonism, but a plateau is soon reached due to it’s the high affinity to the μ-receptor (ceiling effect). In terms of anticraving action, the ceiling level of agonism seemsto be equivalent to that provided by 80 mg of methadone. Differently from methadone, subjects with residual craving are challenged with strong opiate blockade, due to buprenorphine’s slow dissociation from receptors at high dosages, which may either cause treatment dropout or stabilisation, according to the strength of residual craving. 

In fact, early attrition in buprenorphine programs seems to be related to withdrawal buffering, and does not vary according to dosage, due to limited agonist potency. On the other hand, for those who stay in treatment at anti-withdrawal dosages, higher dosages grant with better outcomes in fixed dose comparison studies. However, it is notsharply clear whether the gap of effectiveness is mainly related to a higherlevel of agonism or the opioid blockade: In fact, some patients do respond to 2-4-6 mg regimens by a significant rate.

Phytotherapy of High Blood Pressure in Three Phytogeographic Regions of Cameroon

High blood pressure is a multifactor disease, provoked by the association of the genetic predisposition and certain phenotypes like the sensitivity of the arterial blood pressure with sodium concentration, hypocalcaemia and a stronginfluence of the environment, according to the W.H.O. High blood pressure is manifested when the blood pressure values, measured many times in the occasion of at least two different consultations in four months are superior or equal to 140 mmHg for systolic and superior or equal to 90 mmHg for diastolic. 

These parameters used to diagnose high blood pressure in occidental medicine are unknown in socio-cultural medicine. Traditional healers, mostly from the hinterland will indirectly control this disease by treating rather theirobserved and recognized symptoms and/or complications including nose bleeding, filling of the flies before the eyes, dizziness, insomnia, muscular and sexual weakness, edema, etc. The cost of the monthly treatment of non-complicated high blood pressure is 92.24€ per patient.

Fabrication of Surgical Sutures Coated with Curcumin Loaded Gold Nanoparticles

Sutures are biomaterials regarded as a major cause of Surgical Site Infections (SSIs). Present work aims at a novel strategy to reduce nosocomial infections by coating sutures with antimicrobial drugs. Gold Nanoparticles (GNPs) coated with antimicrobial drugs are well known for their antimicrobial activity. Hence, synthesis of gold nanoparticles by chemical reduction method followed by preparation of curcumin pegylated GNPs (CPGNPs) were carried out. 

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Why is Heart Rarely Affected by Cancer?

Cancer is a malignant neoplasm defined as an abnormal growth and division of cells. Molecular mechanisms of cancer predicted that there are two broad categories of genes such as proto-oncogenes and tumor suppressor genes control mitotic cell division. Tumor suppressor genes inhibit cell division, survival, or other properties of cancer cells. Oncogenes are the mutations of normal host genes which are proto-oncogene. Proto-oncogenes are good genes that normally control the essential cell functions such as cell proliferation and differentiation through signal transduction. 

Abnormal signal transduction can lead to cancer which engulfs the brain, blood, lymph nodes, lungs, bone, and every other bodily organ, part, or system. But why is heart rarely affected by the cancer? This answer is much more silent yet and literature on heart cancer is quite limited. So it is very crucial topic for the genomic scientist and pharmacologist to explore the reason behind this. Primary cardiac tumor was scarce whereas malignant heart tumors also known as angiosarcoma or cardiac sarcoma are extremely rare. A sarcoma is a type of tumor that originates in the soft tissues of the body. A type of rhabdomyosarcoma occurs in the cardiac muscle tissues

Adjunctive Treatment Considerations for the Addressment of Inflammation in Neuromuscular Disorders

At the root of many of society’s major health concerns plaguing millions of Americans each year is the concept of inflammation. Encompassingcardiovascular, oncologic, dermatologic, pain management, and neurologic diseases, the peripheral and systemic manifestations of inflammation has been increasingly shown to be a major culprit in disease spread.Broad examples of this can be seen in various neurologic disease states.

Demyelinating diseases such as Multiple Sclerosis and degenerative changes associated with dementia have many factors with inflammation being one of those. The inflammatory cascade with itsincorporation of pro inflammatory cytokines and transcriptional factors has been shown to be suggestive in the pathophysiology of these diseases . Similarly, glial cells, acting as neural supports, have been shown to play a role in the production of these same pro inflammatory cells (IL-1B, IL-6, IL-8, TNF-alpha). The overproduction of these mediators is suggestive of neurodegenerative progression in both acute (ischemic injury) and chronic degenerative neural disorders.

Perilla Derived Compounds Mediate Human TRPA1 Channel Activity

Transient Receptor Potential (TRP) channels are an evolutionarily ancient and diverse superfamily of cation channels. Many TRP channels are involved in the transduction of stimuli of different sensory modalities: photo-, thermoreception, chemosensory reception and perhaps, mechanoreception and the activity of several TRP channels appear to be directly mediated by osmolarity and/or humidity. Like many other species across different phyla, mammals use TRP channels to detect a variety of physical and chemical stimuli including compounds derived from food plants and spices. 

An interesting feature of some TRP channel family members is their ability to detect and integrate qualitatively different stimuli. For example, the temperature sensitive mammalian TRPV1 (sensitive to high temperature) and TRPM8 (sensitive to low temperature) channels were also demonstrated to interact with chemical compounds associated with high or low temperature perception, such as chili pepper derived capsaicinoids and menthol from peppermint respectively.

Co-administration of Medication with Albumin in Hypoalbuminemic patients

Among all one of the crucial factor that affects pharmacokinetic properties of drug distribution is protein binding. Of the total plasma protein by mass, protein albumin covers for approximately 60%.  Hypoalbuminemia is medical condition of abnormally low blood albumin levels resulting in changes of pharmacokinetic in aspects of dosing a patient’s medication. Author has reviewed the role of coadministration of albumin in patients suffering from Hypoalbuminemia in order to optimize pharmacotherapy. 

Protein binding is of great importance in pharmacokinetics and drug dosing due to the fact that protein bound drug is therapeutically unavailable for its intended action. It is only the unbound portion of the drug that is pharmacologically active. Thus, medications that are highly protein bound have a lower free fraction; the inverse relationship exists for minimally protein bound drugs.

Heme Activates Macrophage Hepcidin Expression via Toll like Receptor 4 and Extracellular Signal-Regulated Kinases Signaling Pathway

Hepcidin is a small peptide hormone produced by the liver, which ensures for a tight balance of systemic and cellular iron levels in the body. Although its function appeared to be related to drosophila’s antimicrobial peptides like defensins, hepcidin is nowadays established as the key systemic regulator of iron homeostasis. Hepcidin orchestrates systemic iron fluxes by blocking iron absorption form the duodenum and iron release from macrophages. It does so by binding to ferroportin, the sole iron-exporter predominantly expressed on macrophages and enterocytes, causing its internalization, degradation and subsequent iron retention within the macrophages . The principal function of hepcidin in the regulation of systemic iron levels has been revealed using genetically engineered mouse models with overexpression or loss-off hepcidin function. Lack of hepcidin expression or mutations affecting regulators of hepcidin expression (e.g. Hfe) cause hemochromatosis, a common genetic iron overload disorder.

Although hepcidin is produced mainly by the hepatocytes, many other cells/tissues are able to synthesize the hormone. However, the exact physiological role of the extra-hepatocytic hepcidin is still unknown. For example, it was shown that increased hepcidin expression by macrophages contributed to down regulation of ferroportin protein levels in an autocrine manner.

Examination of the Oxidative Stress-Related Parameters with Methotrexate-Induced Albino Wistar Rats

In 1940s a specific antagonist for folic acid is developed for first time known as Methotrexate which inhibits the proliferation of malignant cells basically byinhibiting the de novo synthesis of purines and pyrimidines. The presented study concludes that the acute exposure to Methotrexate produced no appreciable changes but in routine consultation of oxidative stress parameters including the glutathione metabolizing system in patients using long term MTX cure can be considered. 

Methotrexate is a folic acid antagonist, widely used as a chemotherapeutic agent in the treatment of various cancerous stages (leukaemia, lymphoma, osteosarcoma, head and neck tumours, lung cancer, breast cancer, etc.) and in the treatment of various inflammatory diseases. It is also used for the treatment of multiple sclerosis,dermatomyositis, sarcoidosis, psoriasis, and rheumatoid arthritis, disorders causing inflammation. Its side effects include hypersensitivity pneumonia, central and peripheral nervous system toxicity, liver and gastrointestinal system dysfunctions and hematologic failure.