Vitamin E prevents deleterious effects of di (2-ethyl hexyl) phthalate, a plasticizer used in PVC blood storage bags.

Vitamin E administration prevented DEHP induced deleterious effects like (i) degenerative changes in the brain and thyroid, (ii) decrease in the activity of neuronal membrane Na+ - K+ ATPase, (iii) decrease in the concentration of insulin, cortisol and TSH, and (iv) the increase in T3 and T4 in female Albino rats. The results suggest use of vitamin E to prevent harmful effects of repeated transfusion of DEHP containing blood as in thalassemia patient. The possibility of using vitamin E to prevent the harmful effects of repeated transfusion of DEHP containing blood, as in thalassemia patients, is discussed.

Changes in some hormones by low doses of di (2-ethyl hexyl) phthalate (DEHP), a commonly used plasticizer in PVC blood storage bags & medical tubing.

BACKGROUND & OBJECTIVES: Di (2-ethyl hexyl) phthalate (DEHP), a plasticizer commonly used in PVC blood storage bags leaches out in significant amounts into blood during storage. In view of many reports on the toxicity of this compound, it was considered necessary to investigate the effect of DEHP at the low level solubilized in blood on some important hormones in rats and in human blood stored in DEHP plasticized blood bags. METHODS: Rats were administered DEHP at a low level of 750 microg/100 g body weight on alternate days for 14 days. Changes in the serum insulin, blood glucose, liver glycogen level and T3, T4 and thyroid stimulating hormone (TSH) as well as cortisol in the serum were studied. Changes in the hormones were also studied in blood stored in DEHP plasticized PVC bags. RESULTS: The results indicated decrease in serum insulin, cortisol and liver glycogen, and increase in blood glucose, serum T3 and T4 in rats receiving DEHP. These changes were reversed when administration of DEHP was stopped. Similar changes in hormones were also observed in the blood stored in DEHP plasticized blood bags. INTERPRETATION & CONCLUSION: The results indicated that administration of DEHP at low levels to rats caused symptoms of diabetes, thyroid and adrenocortical dysfunction. Though the results obtained in rats cannnot be extrapolated to human, the fact that similar hormonal changes seen in human blood stored in DEHP plasticized blood bags may suggest possibility of DEHP causing similar changes in human. The fact that these changes were reversed in rats when DEHP administration was stopped, indicates that transfusion of a few units of blood to a recipient may not be harmful, but it may pose a problem during repeated transfusions such as in thalassaemia patients.

Modified formulation of CPDA for storage of whole blood, and of SAGM for storage of red blood cells, to maintain the concentration of 2,3-diphosphoglycerate.

BACKGROUND AND OBJECTIVES: A dramatic decrease in the level of 2,3-diphosphoglycerate (2,3-DPG) takes place during the storage of whole blood (WB) in CPDA (citrate-phosphate-dextrose-adenine) and a similar decrease occurs during the storage of red blood cells (RBCs) in SAGM (saline-adenine-glucose-mannitol). The aim of the present study was to prevent this decrease by modifying CPDA and SAGM. MATERIALS AND METHODS: The pH of WB anticoagulant or RBC preservative solution was maintained at 7.6 by autoclaving the dextrose solution separately, by incorporating ascorbic acid and nicotinic acid into both CPDA and SAGM (to produce modified CPDA and SAGM solutions), and by reducing the concentration of adenine and adding citrate to the modified SAGM solution. The concentration of 2,3-DPG in WB after 28 days of storage in modified CPDA, and in RBCs stored in modified SAGM, was compared with that in WB or RBCs stored in unmodified solutions. RESULTS: The initial 2,3-DPG levels were maintained after 28 days in the modified formulations [10.63 +/- 2.58 microM/g of haemoglobin (Hb) in the case of modified CPDA and 12.07 +/- 1.47 microM/g of Hb in the case of modified SAGM], whereas in standard CPDA and SAGM solutions, the concentration of 2,3-DPG decreased to very low levels (0.86 +/- 0.97 microM/g Hb for CPDA and 0.12 +/- 0.008 for SAGM). CONCLUSIONS: Our modification in the formulation of CPDA or SAGM is effective in arresting the dramatic decrease in the level of 2,3-DPG that occurs during storage of WB and RBCs in unmodified solutions.

Changes in the isoprenoid pathway with transcendental meditation and Reiki healing practices in seizure disorder.

A quantal perceptive model of brain function has been postulated by several groups. Reiki-like healing practices in seizure disorder (ILAE classification-II E-generalized seizures-tonic clonic), involving transfer of life force or low level of electromagnetic force (EMF) from the healer to the recipient patient, may act via quantal perceptive mechanisms. Increased synthesis of an endogenous membrane Na+-K+ ATPase inhibitor digoxin and a related tyrosine / tryptophan transport defect has been demonstrated in refractory seizure disorder (ILAE classification-II E-generalized seizures-tonic clonic). Reiki-like healing practices in refractory epilepsy results in a reduction in seizure frequency. Reiki-like healing practices produce membrane stabilization and stimulation of membrane Na+-K+ ATPase activity by quantal perception of low levels of EMF. The consequent intracellular hypermagnesemia inhibits HMG CoA reductase activity and digoxin synthesis resulting in the alteration of the neutral amino acid transport (tryptophan / tyrosine) defect. A hypothalamic digoxin-mediated quantal perception model of brain function is proposed. The phenomena of biological transmutation and consequent hypermagnesemia occurring in the resultant neuronal quantal state is also discussed.

Hypothalamic digoxin, cerebral chemical dominance, and nitric oxide synthesis.

The biochemical differences between right hemispheric dominant and left hemispheric dominant individuals are assessed with regard to nitric oxide synthesis. Nitric oxide is an important neurotransmitter involved in erectile function. The following parameters were evaluated: the plasma HMG CoA reductase activity, isoprenoid metabolite-digoxin, plasma magnesium and RBC membrane Na(+)-K(+) ATPase activity, and NO levels. The results showed that right hemispheric dominant individuals had increased plasma HMG CoA reductase activity and elevated digoxin levels, decreased plasma magnesium and RBC membrane Na(+)-K(+) ATPase activity, and increased levels of NO. Left hemispheric dominant individuals had the opposite patterns with reduced nitric oxide synthesis. Cerebral chemical dominance can regulate nitric oxide synthesis.

Isoprenoid pathway dysfunction in human male infertility.

The isoprenoid pathway produces 3 key metabolites: digoxin (membrane sodium-potassium ATPase inhibitor and regulator of neurotransmitter transport), dolichol (regulates N-glycosylation of proteins), and ubiquinone (free radical scavenger). The pathway was assessed in patients with human male infertility (oligospermia and decreased motility). It was also studied for comparison in patients with right hemispheric, left hemispheric, and bihemispheric dominance. The results of the study showed that the isoprenoid pathway was upregulated with increased digoxin synthesis in all 3 groups of patients. There was also a reduction in membrane Na(+)-K(+) ATPase activity and serum magnesium levels. There was an increase in tryptophan catabolites and a reduction in tyrosine catabolites. The dolichol and glycoconjugate levels increased and lysosomal stability was reduced with increased serum lysosomal enzymes in all 3 groups. The ubiquinone levels were low and free radicals increased. The cholesterol:phospholipid ratio increased and glycoconjugate was reduced in the membrane of these patients. This pattern correlated with those in right hemispheric dominance. The significance of these factors in the pathogenesis of human male infertility is discussed.

Inhibition of membrane Na(+)-K+ Atpase of the brain, liver and RBC in rats administered di(2-ethyl hexyl) phthalate (DEHP) a plasticizer used in polyvinyl chloride (PVC) blood storage bags.

Significant amounts of di(2-ethylhexyl) phthalate (DEHP) leach out into blood stored in DEHP plasticized polyvinyl chloride (PVC) bags resulting in the exposure of recipients of blood transfusion to this compound. The aim of this study was to find out whether DEHP at these low levels has any effect on the activity of membrane Na(+)-K+ ATPase, since a decrease in this enzyme activity has been reported to take place in a number of disorders like neurodegenerative and psychiatric disorders, coronary artery disease and stroke, syndrome-X, tumours etc. DEHP was administered (ip) at a low dose of 750 microg/100 g body weight to rats and the activity of membrane Na(+)-K+ ATPase in liver, brain and RBC was estimated. Histopathology of brain, activity of HMG CoA reductase (a major rate limiting enzyme in the isoprenoid pathway of which digoxin, the physiological inhibitor of Na(+)-K+ ATPase is a product), intracellular concentration of Ca2+ and Mg2+ in RBC (which is altered as a result of inhibition of Na(+)-K+ ATPase) were also studied. (In the light of the observation of increase of intracellular Ca2+ load and intracellular depletion of Mg2+ when Na(+)-K+ ATPase is inhibited). Histopathology of brain revealed areas of degeneration in the rats administered DEHP. There was significant inhibition of membrane Na(+)-K+ ATPase in brain, liver and RBC. Intracellular Ca2+ increased in the RBC while intracellular Mg2+ decreased. However activity of hepatic HMG CoA reductase decreased. Activity of Na(+)-K+ ATPase and HMG CoA reductase, however returned to normal levels within 7 days of stopping administration of DEHP. The inhibition of membrane Na(+)-K+ ATPase activity by DEHP may indicate the possibility of predisposing recipients of transfusion of blood or hemodialysis to the various disorders mentioned above. However since this effect is reversed when DEHP administration is stopped, it may not be a serious problem in the case of a few transfusion; but in patients receiving repeated blood transfusion as in thalassemia patients or patients undergoing hemodialysis, possibility of this risk has to be considered. This inhibition is a direct effect of DEHP or its metabolites, since activity of HMG CoA reductase, (an enzyme which catalyses a major rate limiting step in the isoprenoid pathway by which digoxin, the physiological inhibitor of Na(+)-K+ ATPase is synthesized) showed a decrease.

Hypothalamic digoxin and brain function.

BACKGROUND AND OBJECTIVES: The study assessed the biochemical differences between right hemispheric-dominant and left hemispheric-dominant individuals. The chemical hemispheric-dominance in various systemic and neuropsychiatric diseases was also studied. METHODS: The isoprenoid metabolites, digoxin, dolichol and ubiquinone, glycoconjugate metabolism, free radical metabolism and the RBC membrane composition, were studied in individuals with differing hemispheric-dominance. The digoxin levels and RBC membrane Na+-K+ATPase activity were also studied in systemic and neuropsychiatric diseases. RESULTS: The results showed that right hemispheric-dominant individuals had elevated digoxin levels, increased free radical production and reduced scavenging, increased tryptophan catabolites and reduced tyrosine catabolites, increased glycoconjugate levels and increased cholesterol : phospholipid ratio of RBC membranes. Left hemispheric-dominant individuals had the opposite patterns. This patterns could be correlated with various systemic and neuropsychiatric diseases. CONCLUSION: Right hemispheric-dominance represents a hyperdigoxinaemic state with membrane sodium-potassium ATPase inhibition. Left hemispheric-dominance represents the reverse pattern with hypodigoxinaemia and membrane sodium-potassium ATPase stimulation. Hemispheric-dominance could predispose to various systemic and neuropsychiatric diseases.

Membrane Na(+)-K+ ATPase mediated cascade in bipolar mood disorder, major depressive disorder, and schizophrenia--relationship to hemispheric dominance.

The isoprenoid pathway produces digoxin, an endogenous membrane Na(+)-K+ ATPase inhibitor and regulator of neurotransmitter transport. The objective of the study was to relate digoxin status and hemispheric dominance to the pathogenesis of psychiatric disorders--bipolar mood disorder, major depressive disorder, and schizophrenia. The following parameters were assessed in bipolar mood disorder during the manic phase and depressive phase of the illness as well as in major depressive disorder, and schizophrenia: HMG CoA reductase activity, tryptophan and tyrosine catabolic patterns, red blood cell (RBC) Na(+)-K+ ATPase activity, and serum magnesium. These parameters were compared to individuals of differing hemispheric dominance. The levels of serum digoxin and HMG CoA reductase activity were found to be decreased in the depressive phase of bipolar mood disorder and major depressive disorder with a corresponding increase in RBC Na(+)-K+ ATPase activity and serum magnesium levels. There was increase in tyrosine and tyrosine catabolites, and a reduction in tryptophan and its catabolites, in the serum in the depressive phase of bipolar mood disorder and major depressive disorder. The neurotransmitter patterns and digoxin levels in the depressive phase of bipolar mood disorder/major depressive disorder correlated with those in right-handed/left hemisphere dominant individual. The neurotransmitter patterns and digoxin levels in the manic phase of bipolar mood disorder and schizophrenia correlated with those in left-handed/right hemisphere dominant individuals. Digoxin status and hemispheric dominance could correlate with the pathogenesis of psychiatric disorders--schizophrenia, major depressive disorder, and bipolar mood disorder.

Familial hypodigoxinemic membrane Na(+)-K(+) ATPase upregulatory syndrome - relation between digoxin status and cerebral dominance.

A family with coexistence of hypotension, recurrent respiratory infection, motor tics, obsessive compulsive disorder, major depressive disorder, early onset osteoporosis, low body mass index, bulimia nervosa and healthy aging with longevity is described. The family members had hyposexual behavior, less tendency for spirituality, had no insomnia but a tendency towards increased somnolence, no addictive behaviour, had more bonding and affectionate behavior and were less creative with an average IQ. There was no vascular thrombosis, systemic neoplasm and neuronal degeneration in the index family. All members of the family were left hemispheric dominant. The level of serum digoxin, HMG CoA reductase activity and dolichol was found to be decreased in all with a corresponding increase in RBC Na(+)-K(+) ATPase activity and serum ubiquinone magnesium level. There was increase in tyrosine catabolites and a reduction in tryptophan catabolites in serum. Total and individual glycosaminoglycan fractions, carbohydrate residues of glycoproteins, glycolipids, activity of GAG degrading enzymes and glycohydrolases were decreased in serum. The concentration of RBC membrane total GAG and carbohydrate residues of glycoproteins increased while cholesterol : phospholipid ratio of membrane decreased. The activity of free radical scavenging enzymes were increased while the concentration of free radicals decreased significantly. The same biochemical patterns were observed in left hemispheric dominance as opposed to right hemispheric dominance. The significance of these findings in the pathogenesis of these disorders is discussed.

Hypothalmic digoxin, cerebral dominance, and sexual orientation.

The human hypothalamus produces an endogenous membrane Na(+)-K(+) ATPase inhibitor, digoxin. Membrane Na(+)-K(+) ATPase inhibition leads to increase in intracellular calcium and upregulated nitric oxide synthesis. In homosexuals, promiscuous heterosexuals, and bisexuals there was increased digoxin synthesis, reduced membrane Na(+)-K(+) ATPase activity, increased nitric oxide levels, increased tryptophan catabolites, and reduced tyrosine catabolites. This pattern correlated with that obtained in right hemispheric chemical dominance. In nonpromiscuous heterosexuals and left hemispheric chemical dominance there was hypodigoxinemia and the reverse biochemical patterns. Hemispheric dominance and hypothalamic digoxin could regulate sexual orientation. This has to be viewed in the setting of hyperdigoxinemia reported in acquired immunodeficiency syndrome.

Endogenous sodium-potassium ATPase inhibition related biochemical cascade in trisomy 21 and Huntington's disease: neural regulation of genomic function.

The isoprenoid pathway related cascade was assessed in trisomy 21 and Huntington's disease. Membrane Na+-K+ ATPase activity, serum magnesium and ubiquinone were decreased while HMG CoA reductase activity, serum digoxin and dolichol levels were increased in both the disorders. There were increased levels of tryptophan catabolites (nicotine, strychnine, quinolinic acid and serotonin) and decreased levels of tyrosine catabolites (dopamine, noradrenaline and morphine) in both trisomy 21 and Huntington's disease. There was an increase in dolichol levels, carbohydrate residues of glycoproteins, glycolipids, total/individual GAG fractions and lysosomal enzymes in both disorders. Reduced levels of ubiquinone, reduced glutathione and free radical scavenging enzymes as well as increased lipid peroxidation products and nitric oxide were noticed in both the disorders. The role of hypothalamic digoxin and a disordered isoprenoid pathway in the pathogenesis of trisomy 21 and Huntington's disease is discussed.

Inhibition of membrane Na+-K+ ATPase activity: a common pathway in central nervous system disorders.

OBJECTIVES: The study was conducted to assess the role of hypothalamic digoxin in neuropsychiatric and systemic disorders. A hypothesis regarding the central role of hypothalamic digoxin in neuroimmunoendocrine integration is proposed. METHODOLOGY: Blood samples from patients of CNS glioma, multiple sclerosis, systemic lupus erythematosis, subacute sclerosing panencephalitis, primary generalized epilepsy, Parkinson's disease, Down syndrome, AIDS dementia with neuropsychiatric features, syndrome X with multiple lacunar state, senile dementia, familial group (a family with familial coexistence of schizophrenia, Parkinson's disease, primary generalized epilepsy, malignant neoplasia, rheumatoid arthritis and syndrome X over three generations), schizophrenia and manic depressive psychosis were analysed for RBC membrane Na+-K+ ATPase, levels of digoxin and Mg++. RESULTS: Inhibition of RBC membrane Na+-K+ ATPase activity was observed in most cases along with increase in the levels of serum digoxin and decrease in the level of serum Mg++. CONCLUSION: The decreased Na+-K+ ATPase activity can be due to increased digoxin, which is a potent inhibitor of this enzyme. The inhibition of Na+-K+ ATPase can contribute to increase in intracellular calcium and decrease in magnesium, which can result in 1) defective neurotransmitter transport mechanism, 2) neuronal degeneration and apoptosis, 3) mitochondrial dysfunction, 4) defective golgi body function and protein processing dysfunction, 5) immune dysfunction and oncogenesis. The mechanism of how increased intracellular calcium and decreased magnesium can contribute to the above effects is discussed.

Hypothalamic digoxin and regulation of body mass index.

The hypothalamus produces digoxin, an endogenous membrane Na+-K+ ATPase inhibitor and regulator of neurotransmission. Digoxin being a steroidal glycoside, is synthesised by the isoprenoid pathway. In view of the reports of elevated digoxin levels in metabolic syndrome X with high body mass index, the isoprenoid pathway mediated biochemical cascade was assessed in individuals with high and low body mass index. It was also assessed in individuals with differing hemispheric dominance to find out the relationship between digoxin status, body mass index and hemispheric dominance. The isoprenoid pathway metabolites, tryptophan / tyrosine catabolic patterns and membrane composition were assessed. In individuals with high body mass index an upregulated isoprenoid pathway with increased HMG CoA reductase activity, serum digoxin and dolichol levels and low ubiquinone levels were observed. The RBC membrane Na+-K+ ATPase activity and serum magnesium levels were decreased. The tyrosine catabolites (dopamine, morphine, epinephrine and norepinephrine) were reduced and the tryptophan catabolites (serotonin, quinolinic acid, strychnine and nicotine) were increased. There was an increase in membrane cholesterol : phospholipid ratio and a reduction in membrane glycoconjugates in individuals with high body mass index. The reverse patterns were seen in individuals with low body mass index. The patterns in individuals with high body mass index and low body mass index correlated with right hemispheric dominance and left hemispheric dominance respectively. Hemispheric dominance and digoxin status regulates the differential metabolic pattern observed in individuals with high and low body mass index.

Hypothalamic digoxin and irritable bowel syndrome.

BACKGROUND: The hypothalamus produces an endogenous membrane Na+-K+ ATPase inhibitor digoxin that can modulate neurotransmitter transport and may play a role in hemispheric dominance. It can also modulate glycoconjugate synthesis and thus affect synaptic connectivity in the bowel wall. Digoxin could play a role in the genesis of irritable bowel syndrome (IBS). AIM: To study digoxin status in IBS and to correlate it with hemispheric dominance. METHODS: The isoprenoid pathway, tryptophan/tyrosine catabolic patterns and glycoconjugate metabolism were assessed in patients with IBS and in right hemispheric dominant/left hemispheric dominant/bihemispheric dominant individuals. RESULTS: The isoprenoid pathway was upregulated in IBS, with increased HMG CoA reductase activity (0.8 [0.07] vs 0.4 [0.06] in controls; p<0.01), serum digoxin (14.8 [1.0] vs 29.0 [1.2] ng/dL; p<0.01) and dolichol levels (63.8 [3.0] vs 120.3 [3.6] mg/dL; p<0.01). RBC membrane Na+-K+ ATPase activity (3.0 [0.2] vs 1.0 [0.1] microg/p/mg protein; p<0.01), serum magnesium (1.7 [0.1] vs 1.0 [0.1] mg/dL; p<0.01) and ubiquinone (86.4 [5.9] vs 39.8 [1.2] microg/dL; p<0.01) were reduced. There was increase in tryptophan catabolites and reduction in tyrosine catabolites. Serum total glycosaminoglycan and carbohydrate component of glycoproteins were increased in IBS. The activity of glycosaminoglycan degrading enzymes and glycohydrolases were increased. This pattern correlated with those obtained in right hemispheric chemical dominance. CONCLUSION: Hypothalamic digoxin and right hemispheric dominance could play a role in the genesis of irritable bowel syndrome.

A hypothalamic digoxin mediated model for conscious and subliminal perception.

The isoprenoid pathway and its metabolites--digoxin, dolichol and ubiquinone were assessed in schizophrenia. There was an upregulation of the isoprenoid pathway as evidenced by elevated HMG CoA reductase activity. Digoxin, an endogenous Na+-K+ ATPase inhibitor secreted by the hypothalamus was found to be elevated and RBC membrane Na+-K+ ATPase activity was found to be reduced in schizophrenia. Membrane Na+-K+ ATPase inhibition can result in increased intracellular Ca2+ and reduced magnesium levels. Hypothalamic digoxin can modulate conscious and subliminal perception and its dysfunction may lead on to schizophrenia. Digoxin can also preferentially upregulate tryptophan transport over tyrosine resulting in increased levels of depolarising tryptophan catabolites--serotonin and quinolinic acid (NMDA agonist), and decreased levels of hyperpolarising tyrosine catabolites--dopamine and noradrenaline contributing to membrane Na+-K+ ATPase inhibition. NMDA excitotoxicity could result from hypomagnesemia induced by membrane Na+-K+ ATPase inhibition and quinolinic acid, an NMDA agonist acting on the NMDA receptor. Hypomagnesemia and increased dolichol level can affect glycoconjugate metabolism and membranogenesis leading on to disordered synaptic connectivity in the limbic allocortex and defective presentation of viral antigens and neuronal antigens contributing to autoimmunity and viral persistance important in the pathogenesis. Membrane Na+-K+ ATPase inhibition can produce immune activation, a component of autoimmunity. Mitochondrial dysfunction consequent to altered calcium/magnesium ratios and reduced ubiquinone levels can result in increased free radical generation and reduced free radical scavenging & defective apoptosis leading on to abnormal synaptogenesis. Schizophrenia can thus be considered as a syndrome of hypothalamic digoxin hypersecretion consequent to an upregulated isoprenoid pathway.

The isoprenoid pathway in lone atrial fibrillation with embolic stroke.

BACKGROUND: The isoprenoid pathway was assessed and compared in patients of lone atrial fibrillation with embolic stroke as well as in patients with right hemispheric, left hemispheric and bihemispheric dominance to determine the role of hemispheric dominance in its pathogenesis. METHODS AND RESULTS: The activities of hydroxyl methyl glutaryl-CoA reductase and RBC sodium-potasium ATPase as well as serum levels of plasma magnesium, digoxin, dolichol and ubiquinone were measured. The tyrosine/tryptophan catabolic patterns, glycoconjugate metabolism, free radical metabolism and RBC membrane composition were also assessed. In patients with lone atrial fibrillation with embolic stroke, there was elevated digoxin synthesis, increased dolichol and glycoconjugate levels, and low ubiquinone and elevated free radical levels. There was also an increase in tryptophan catabolites and a reduction in tyrosine catabolites: and an increase in the cholesterol: phospholipid ratio with a reduction in the glycoconjugate levels of the RBC membrane. The same biochemical patterns were obtained in individuals with right hemispheric dominance whereas the patterns were reversed in patients with left hemispheric dominance. CONCLUSIONS: Lone atrial fibrillation with embolic stroke is associated with an upregulated isoprenoid pathway and elevated digoxin secretion from the hypothalamus. This occurs in right hemisphere-dominant individuals.

Hypothalamic digoxin mediated model for oncogenesis.

This study assessed the changes in the isoprenoid pathway and its metabolites digoxin, dolichol and ubiquinone in neoplasms (CNS astrocytomas - glioblastoma multiforme and high grade non - Hodgkin's lymphoma). The following parameters were assessed-isoprenoid pathway metabolites, tyrosine and tryptophan catabolites, glycoconjugate metabolism, RBC membrane composition and free radical metabolism. There was an elevation in plasma HMG CoA reductase activity, serum digoxin and dolichol and a reduction in RBC membrane Na+-K+ ATPase activity, serum ubiquinone and magnesium levels. Serum tryptophan, serotonin, nicotine and quinolinic acid were elevated while tyrosine, dopamine, noradrenaline and morphine were decreased. The total serum glycosaminoglycans and glycosaminoglycan fractions (except dermatan sulphate in the case of CNS astrocytomas), the activity of GAG degrading enzymes and glycohydrolases, carbohydrate residues of glycoproteins and serum glycolipids were elevated. HDL cholesterol showed a significant decrease and free fatty acids & triglycerides were increased. The RBC membrane glycosaminoglycans, hexose and fucose residues of glycoproteins and phospholipids were reduced. The activity of all free radical scavenging enzymes, concentration of glutathione, iron binding capacity and ceruloplasmin decreased significantly while the concentration of malondialdehyde (MDA), hydroperoxides, conjugated dienes and NO increased. The concentration of alpha tocopherol was unaltered. Membrane Na+-K+ ATPase inhibition due to elevated digoxin, altered membrane structure and digoxin related tyrosine / tryptophan transport defect leading to increased levels of depolarising tryptophan catabolites and decreased levels of hyperpolarising tyrosine catabolites can lead to alteration in intracellular calcium/magnesium ratios and oncogene activation. Intracellular magnesium deficiency can produce defective microtubule related spindle fibre dysfunction and chromosomal non-dysjunction contributing to neoplastic cellular polyploidy and aneuploidy. Digoxin induced tryptophan/tyrosine transport defect can alter neurotransmitter patterns with increased serotonin, quinolinic acid, nicotine & glutamatergic transmission and reduced dopamine, morphine and noradrenaline levels leading to oncogenesis. Glycoconjugate metabolism is altered by elevated dolichol levels and magnesium depletion consequent to Na+-K+ ATPase inhibition. There is a qualitative alteration in proteoglycans and glycoproteins, defective membrane formation and structure and reduced lysosomal stability leading to disordered contact inhibition and tumour antigen presentation contributing to oncogenesis. Digoxin induced alteration in intracellular calcium/magnesium ratios and low ubiquinone levels can lead to a mitochondrial dysfunction resulting in increased free radical generation and reduced scavenging & caspase-3 activation producing a P21 defect contributing to oncogenesis.

Membrane Na+ K+ ATPase inhibition related dyslipidemia and insulin resistance in neuropsychiatric disorders.

There are several reports in literature implicating cholesterol metabolism in the pathogenesis of neuronal degenerations, oncogenesis, functional neuropsychiatric disorders and multiple sclerosis. Biosynthesis of cholesterol takes place by the isoprenoid pathway, which also produces digoxin, an inhibitor of membrane Na(+)-K+ ATPase. Inhibition of this enzyme results in intracellular Mg++ deficiency which can influence cholesterol metabolism. Digoxin also influences transport of tryptophan and tyrosine which are precursors of various neurotransmitters. Alterations in digoxin, membrane Na(+)-K+ ATPase and also in neurotransmitters have been reported in the disorders mentioned above. In view of this, serum lipid profile, activity of plasma HMG CoA reductase (the major rate limiting step in the isoprenoid pathway), RBC membrane Na(+)-K+ ATPase activity, serum Mg++ concentration, concentration of digoxin and concentration of serum neurotransmitters were studied in some neuropsychiatric disorders. The serum serotonin level was increased while that of serum dopamine and noradrenaline was reduced. Serum digoxin levels were high and RBC membrane sodium-potasium ATPase activity and serum magnesium were reduced. There was a reduction in HDL cholesterol and increase in plasma triglycerides (pattern similar to insulin resistance and syndrome X) in most of the disorders studied. The HMG CoA reductase activity was high, the serum total cholesterol was increased while RBC membrane cholesterol was reduced in most of the cases. The significance of increased digoxin with consequent inhibition of membrane Na(+)-K+ ATPase in relation to changes in cholesterol metabolism and insulin resistance type of dyslipidemia is discussed in this paper.

Serum and tissue glycoconjugates, digoxin and magnesium levels in chronic calcific pancreatitis.

BACKGROUND: Endogenous or exogenous digoxin can lead to membrane Na+,K+-ATPase inhibition and hypomagnesemia. Low magnesium levels can lead to increased glycosaminoglycans (GAG) concentration in many organs. AIM: To measure the serum levels of pancreatic GAG and glycoproteins, two major components of the extracellular matrix, in patients with chronic calcific pancreatitis (CCP). Serum levels of magnesium and digoxin were also assessed. METHODS: Patients with CCP and age- and sex-matched healthy control subjects (15 each) were studied. Serum GAG, Mg and digoxin levels were measured. RBC membrane Na+,K+-ATPase activity was also assessed. Pancreatic tissue obtained at autopsy from seven patients with CCP and sex- and age-matched healthy subjects who had died in accidents were also tested for GAG and glycoproteins. RESULTS: Total GAG levels were significantly increased in the serum and pancreas of patients with CCP. This was associated with lower serum Mg levels, increased serum digoxin levels and decreased RBC membrane Na+,K+-ATPase activity. CONCLUSION: Exogenous or endogenous digoxin-induced hypomagnesemia and the consequent altered glycoconjugate metabolism may be important in the pathogenesis of CCP.