stilbenes and Acidosis

The prevalence of cancer pain in patients with cancer is high. The majority of efforts are spent on research in cancer treatment, but only a small fraction focuses on cancer pain. Pain in cancer patients, viewed predominantly as a secondary issue, is considered to be due to the destruction of tissues, compression of the nerves, inflammation, and secretion of biological mediators from the necrotic tumor mass. As a result, opioid drugs have remained as the primary pharmacological therapy for cancer pain for the past hundred years. This report reviews evidence that cancer pain may be produced by the metabolic effects of two byproducts of cancer-high acidity in the cancer microenvironment and the secretion of formaldehyde and its metabolites. We propose the research and development of therapeutic approaches for preemptive, short- and long-term management of cancer pain using available drugs or nutraceutical agents that can suppress or neutralize lactic acid production in combination with formaldehyde scavengers. We believe this approach may not only improve cancer pain control but may also enhance the quality of life for patients.

Topics: Acidosis; Aldehyde Dehydrogenase; Dichloroacetic Acid; Formaldehyde; Glutathione; Humans; Hydrogen-Ion Concentration; Lactic Acid; Neoplasms; Pain; Pain Management; Quality of Life; Resveratrol; Sodium Bicarbonate; Stilbenes

Lung carbonic anhydrase (CA) permits rapid pH responses when changes in regional ventilation or perfusion alter airway and alveolar PCO2. These pH changes affect airway and vascular resistances and lung compliance to optimize the balance of regional ventilation (VA) and perfusion (Q) in the lung. To test the hypothesis that these or other CA-dependent mechanisms contribute to VA/Q matching, we administered acetazolamide (25 mg/kg intravenously) to six anesthetized and paralyzed dogs and measured VA/Q relationships before and after CA inhibition by the multiple inert gas elimination technique. Four other groups of dogs were studied to control for possible confounding effects of time under anesthesia and nonselective CA inhibition by acetazolamide: (a) saline placebo as a control for duration of anesthesia, (b) 4% CO2 inhalation to mimic systemic CO2 retention, (c) 1 mg/kg benzolamide (a selective renal CA inhibitor) or 0.5 meq/kg HCl to mimic systemic metabolic acidosis, and (d) 500 mg/kg 4,4'-dinitrostilbene-2,2'-disulfonate (an inhibitor of red cell band 3 protein) to mimic the respiratory acidosis arising from an intracapillary block to rapid mobilization of plasma HCO3- in CO2 exchange. Acetazolamide increased VA/Q mismatch and reduced arterial PO2 measured at equilibrium but these did not occur in the control group. There was no deterioration in VA/Q matching when systemic respiratory acidosis produced either by CO2 inhalation or 4,4'-dinitrostilbene-2,2'-disulfonate or metabolic acidosis (benzolamide or HCl) were imposed to mimic the effects of acetazolamide apart from its inhibition of lung CA. These results support the concept that lung CA subserves VA/Q matching in the normal lung.

Topics: Acetazolamide; Acidosis; Acidosis, Respiratory; Animals; Benzolamide; Blood Pressure; Carbon Dioxide; Carbonic Anhydrases; Cardiac Output; Dogs; Heart Rate; Hemodynamics; Lung; Oxygen; Partial Pressure; Pulmonary Circulation; Respiration; Stilbenes

Disulfonic stilbenes combine with the carrier protein involved in anion transport and inhibit the exchange of Cl- for HCO3- in a variety of biomembranes. Our aim was to determine whether such a mechanism is operative in the regulation of cerebrospinal fluid (CSF) [HCO3-] in metabolic alkalosis. In anesthetized, curarized, and artificially ventilated dogs either mock CSF (group I, 9 dogs) or mock CSF containing SITS, 4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonic acid (group II, 7 dogs) was periodically injected into both lateral cerebral ventricles. During 6 h of isocapnic metabolic alkalosis, produced by intravenous infusion of Na2CO3 solution, plasma [HCO3-] was increased by approximately 14 meq/l in both groups. In SITS-treated animals the mean cisternal CSF [HCO3-] increased by 7.7 meq/l after 6 h, and this was significantly higher than the respective increment, 3.5 meq/l, noted in the control group. Increments in CSF [HCO3-] in both groups were reciprocated by decrements in CSF [Cl-] with CSF [Na+] remaining unchanged. Cisternal CSF PCO2 and lactate concentrations showed similar increments in both groups. It is hypothesized that in metabolic alkalosis a carrier transports HCO3- out of cerebral fluid in exchange for Cl- and that SITS inhibits this mechanism. The efflux of HCO3- out of CSF in metabolic alkalosis would minimize the rise in CSF [HCO3-] brought about by HCO3-] influx from blood into CSF and therefore contributes to the CSF [H+] homeostasis.

Topics: 4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid; Acid-Base Equilibrium; Acidosis; Animals; Bicarbonates; Blood-Brain Barrier; Chlorides; Dogs; Osmolar Concentration; Phosphates; Sodium; Stilbenes