The Interplay of Dysregulated pH and Electrolyte Imbalance in Cancer.

Cancer cells and tissues have an aberrant regulation of hydrogen ion dynamics driven by a combination of poor vascular perfusion, regional hypoxia, and increased the flux of carbons through fermentative glycolysis. This leads to extracellular acidosis and intracellular alkalinization. Dysregulated pH dynamics influence cancer cell biology, from cell transformation and tumorigenesis to proliferation, local growth, invasion, and metastasis. Moreover, this dysregulated intracellular pH (pHi) drives a metabolic shift to increased aerobic glycolysis and reduced mitochondrial oxidative phosphorylation, referred to as the Warburg effect, or Warburg metabolism, which is a selective feature of cancer. This metabolic reprogramming confers a thermodynamic advantage on cancer cells and tissues by protecting them against oxidative stress, enhancing their resistance to hypoxia, and allowing a rapid conversion of nutrients into biomass to enable cell proliferation. Indeed, most cancers have increased glucose uptake and lactic acid production. Furthermore, cancer cells have very dysregulated electrolyte balances, and in the interaction of the pH dynamics with electrolyte, dynamics is less well known. In this review, we highlight the interconnected roles of dysregulated pH dynamics and electrolytes imbalance in cancer initiation, progression, adaptation, and in determining the programming and reprogramming of tumor cell metabolism

The Pentose Phosphate Pathway Dynamics in Cancer and Its Dependency on Intracellular pH

The Pentose Phosphate Pathway (PPP) is one of the key metabolic pathways occurring in living cells to produce energy and maintain cellular homeostasis. Cancer cells have higher cytoplasmic utilization of glucose (glycolysis), even in the presence of oxygen; this is known as the “Warburg Effect”. However, cytoplasmic glucose utilization can also occur in cancer through the PPP. This pathway contributes to cancer cells by operating in many different ways: (i) as a defense mechanism via the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) to prevent apoptosis, (ii) as a provision for the maintenance of energy by intermediate glycolysis, (iii) by increasing genomic material to the cellular pool of nucleic acid bases, (iv) by promoting survival through increasing glycolysis, and so increasing acid production, and (v) by inducing cellular proliferation by the synthesis of nucleic acid, fatty acid, and amino acid. Each step of the PPP can be upregulated in some types of cancer but not in others. An interesting aspect of this metabolic pathway is the shared regulation of the glycolytic and PPP pathways by intracellular pH (pHi). Indeed, as with glycolysis, the optimum activity of the enzymes driving the PPP occurs at an alkaline pHi, which is compatible with the cytoplasmic pH of cancer cells. Here, we outline each step of the PPP and discuss its possible correlation with cancer

Linking Aromatic Hydroxy Metabolic Functionalization of Drug Molecules to Structure and Pharmacologic Activity

Drug functionalization through the formation of hydrophilic groups is the norm in the phase I metabolism of drugs for the modification of drug action. The reactions involved are mainly oxidative, catalyzed mostly by cytochrome P450 (CYP) isoenzymes. The benzene ring, whether phenyl or fused with other rings, is the most common hydrophobic pharmacophoric moiety in drug molecules. On the other hand, the alkoxy group (mainly methoxy) bonded to the benzene ring assumes an important and sometimes essential pharmacophoric status in some drug classes. Upon metabolic oxidation, both moieties, i.e., the benzene ring and the alkoxy group, produce hydroxy groups; the products are arenolic in nature. Through a pharmacokinetic effect, the hydroxy group enhances the water solubility and elimination of the metabolite with the consequent termination of drug action. However, through hydrogen bonding, the hydroxy group may modify the pharmacodynamics of the interaction of the metabolite with the site of parent drug action (i.e., the receptor). Accordingly, the expected pharmacologic outcome will be enhancement, retention, attenuation, or loss of activity of the metabolite relative to the parent drug. All the above issues are presented and discussed in this review using selected members of different classes of drugs with inferences regarding mechanisms, drug design, and drug development

Professional practices and perception towards rational use of medicines according to WHO methodology in United Arab Emirates

Inappropriate prescribing reduces the quality of medical care and leads to a waste of resources. No study has been reported concerning rational drug use in United Arab Emirates, UAE, recently. Objectives: 1. assessing patterns of use and defining problems regarding the rational drug use. 2. Setting baseline situational analysis study for practices in the health care system relevant to drug use. Method: A descriptive pilot study, consisting of pharmacists, physicians and patients (100 of each of category) from four private hospitals, (12) medical clinics, (80) community pharmacies in addition to 150 prescriptions. A questionnaire of three sections was designed to include WHO indicators regarding patients, facility and prescribing patterns that are relevant to rational drug use was carried out in four emirates of the UAE in the period December 2008- Febreuary 2009. Results: Consultation and dispensing times were 10 (SD=2.75) min and 68 (SD=9.7) seconds, respectively. Average no. of drugs per prescription was (2.9 + 0.97), % of prescriptions using generic name (7.35%), % of antibiotic containing prescriptions (31.1%), % of injection containing prescriptions (2.9%), adherence to Standard Treatment Protocols (46%), adherence to the essential drug list (64%), patient´s knowledge of correct dosage (55%), adequately labeled drugs (45%), patient´s information (65%). Conclusions: Several areas of deficiency in rational drug use had been defined in the private sector through UAE that can be remedied through adopting several strategies such as adherence to national standard treatment guidelines and essential drug list based on treatments of choice, interaction between health care system and providing drugs information to consumers.La prescripción inapropiada reduce la calidad de la atención médica y lleva a un desperdicio de recursos. No se ha escrito ningún estudio sobre el uso racional de medicamentos en los Emiratos Árabes Unidos (EAU) recientemente. Objetivos: 1, evaluar los patrones de uso y definir problemas en el uso racional de medicamentos. 2, establecer la situación de base para el estudio de prácticas en el sistema sanitario relevantes al uso de medicamentos. Métodos: Estudio piloto descriptivo, incluyendo farmacéuticos, médicos y pacientes (100 de cada categoría) de 4 hospitales privados, (12) consultas médicas, (80) farmacias comunitarias además de 150 prescriptores. Se diseñó un cuestionario de tres secciones incluyendo los indicadores de la OMS relativos a pacientes, local y patrones de prescripción relevantes al uso racional de medicamentos para los cuatro emiratos de EAU en el periodo de diciembre 2008 a febrero 2009. Resultados: los tiempos de consulta y dispensación fueron e 10 (SD=2,75) minutos y 68 (SD=9,7) segundos respectivamente. La media de medicamentos por receta fue de 2,9 (SD=0,97), el 7,35% de las recetas usaban nombres genéricos, el 31,1% contenía antibióticos, el 2,9% contenía inyectables, el 46% cumplía los protocolos estándar de tratamiento, el 64% contenía medicamentos de la lista de medicamentos esenciales, en el 55% había conocimiento de los pacientes de la dosis correcta, en el 45 hubo etiquetado adecuado de los medicamentos, y en el 65% hubo información a los pacientes. Conclusiones: Se identificaron varias deficiencias en cuento al uso racional de medicamentos en el sector privado en los EAU que pueden remediarse adoptando algunas estrategias como el cumplimiento de las guías de estándares nacionales tratamientos y la lista de medicamentos esenciales para la elección de tratamientos, la interacción entre el sistema sanitario y los proveedores de información sobre de medicamentos a los consumidores

Attitudes and practices of community pharmacists and barriers to their participation in public health activities in Yemen: mind the gap

Abstract Background Patients in Yemen commonly visit community pharmacies to obtain consultation or treatment for common ailments. Community pharmacists have an opportunity to optimize medication use and improve patient outcomes. This study aimed to evaluate the attitudes and practices of community pharmacists regarding their participation in public health activities and barriers to their participation in these activities. Methods This cross-sectional study was carried out among community pharmacists working in pharmacies located in urban areas of the Aden governorate of Yemen from March to June 2017 using a self-administered questionnaire. We selected pharmacies from a line list using proportional sampling according to the number of pharmacies in the urban areas of each district. The questionnaire contained four sections: demographic characteristics, attitudes, practices, and barriers encountered. Data were analyzed descriptively, and the Chi-square test was used for analyzing the association of variables (alpha = 0.05). Results The questionnaire was distributed to 200 community pharmacists working in community pharmacies. Of the 200 respondents, 62% (n = 124) were male. Overall, the mean age (sd) was 30.0 years (8.6) with the number of years of work experience between 2 and 9.9 years (n = 158, 79%). On average, 62.3% of the pharmacists had a positive attitude toward participation in public health activities. Providing education to stop tobacco chewing, smoking, alcohol drinking and improve oral hygiene was an important activity of the community pharmacists. Blood pressure measurements (86%, n = 172) and glucose tests (45%, n = 90) were commonly conducted for clients. Lack of time (71%, n = 142) and lack of teamwork (70%, n = 140) were mentioned as common barriers to participation in public health activities. Conclusions Community pharmacists had a positive attitude toward public health activities. Health education and routine health tests were important practices of the community pharmacists. Barriers need to be overcome to enable more active participation by community pharmacists in public health activities by consulting with all stakeholders, assessing the situation, considering alternatives and taking action

Of mitochondrion and COVID-19

COVID-19, a pandemic disease caused by a viral infection, is associated with a high mortality rate. Most of the signs and symptoms, e.g. cytokine storm, electrolytes imbalances, thromboembolism, etc., are related to mitochondrial dysfunction. Therefore, targeting mitochondrion will represent a more rational treatment of COVID-19. The current work outlines how COVID-19’s signs and symptoms are related to the mitochondrion. Proper understanding of the underlying causes might enhance the opportunity to treat COVID-19

The Interplay of Dysregulated pH and Electrolyte Imbalance in Cancer

Cancer cells and tissues have an aberrant regulation of hydrogen ion dynamics driven by a combination of poor vascular perfusion, regional hypoxia, and increased the flux of carbons through fermentative glycolysis. This leads to extracellular acidosis and intracellular alkalinization. Dysregulated pH dynamics influence cancer cell biology, from cell transformation and tumorigenesis to proliferation, local growth, invasion, and metastasis. Moreover, this dysregulated intracellular pH (pHi) drives a metabolic shift to increased aerobic glycolysis and reduced mitochondrial oxidative phosphorylation, referred to as the Warburg effect, or Warburg metabolism, which is a selective feature of cancer. This metabolic reprogramming confers a thermodynamic advantage on cancer cells and tissues by protecting them against oxidative stress, enhancing their resistance to hypoxia, and allowing a rapid conversion of nutrients into biomass to enable cell proliferation. Indeed, most cancers have increased glucose uptake and lactic acid production. Furthermore, cancer cells have very dysregulated electrolyte balances, and in the interaction of the pH dynamics with electrolyte, dynamics is less well known. In this review, we highlight the interconnected roles of dysregulated pH dynamics and electrolytes imbalance in cancer initiation, progression, adaptation, and in determining the programming and reprogramming of tumor cell metabolism

The Pentose Phosphate Pathway Dynamics in Cancer and Its Dependency on Intracellular pH

The Pentose Phosphate Pathway (PPP) is one of the key metabolic pathways occurring in living cells to produce energy and maintain cellular homeostasis. Cancer cells have higher cytoplasmic utilization of glucose (glycolysis), even in the presence of oxygen; this is known as the “Warburg Effect”. However, cytoplasmic glucose utilization can also occur in cancer through the PPP. This pathway contributes to cancer cells by operating in many different ways: (i) as a defense mechanism via the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) to prevent apoptosis, (ii) as a provision for the maintenance of energy by intermediate glycolysis, (iii) by increasing genomic material to the cellular pool of nucleic acid bases, (iv) by promoting survival through increasing glycolysis, and so increasing acid production, and (v) by inducing cellular proliferation by the synthesis of nucleic acid, fatty acid, and amino acid. Each step of the PPP can be upregulated in some types of cancer but not in others. An interesting aspect of this metabolic pathway is the shared regulation of the glycolytic and PPP pathways by intracellular pH (pHi). Indeed, as with glycolysis, the optimum activity of the enzymes driving the PPP occurs at an alkaline pHi, which is compatible with the cytoplasmic pH of cancer cells. Here, we outline each step of the PPP and discuss its possible correlation with cancer