Statin use in patients with non-HMGCR idiopathic inflammatory myopathies: A retrospective study.

BACKGROUND: Statins are the most widely used lipid lowering therapies which reduce cardiovascular risk, but are associated with muscular adverse events (AEs). Idiopathic inflammatory myopathies (IIM) are autoimmune diseases of the muscle with higher risk of cardiovascular disease. More data is needed regarding statin safety in patients with intrinsic muscle disease such as IIM. HYPOTHESIS: Statins are tolerated in patients with IIM without leading to significant increase in muscular AEs. METHODS: Statin use was retrospectively examined in a longitudinal IIM cohort. Safety analysis included assessment of muscular and nonmuscular AEs by chart review. IIM patients receiving a statin during the cohort follow-up period were matched to IIM patients not receiving a statin for comparative analysis of longitudinal outcomes. RESULTS: 33/214 patients had a history of statin use. 63% started for primary prevention, while others were started for clinical ASCVD events, vascular surgery, IIM related heart failure, and cardiac transplantation. A high intensity statin was used in nine patients with non-HMGCR myositis, and tolerated in 8/9 patients. Statin related muscular AE was noted in three patients. There were no cases of rhabdomyolysis, or statin related nonmuscular AEs in a median observation period of 5 years. In patients newly started on statins during cohort follow-up (n = 7) there was no change in disease activity after statin initiation. Long term outcomes were not different between statin and nonstatin IIM control groups. CONCLUSION: Statins were well tolerated in patients with non-HMGCR positive IIM. Given the accelerated atherosclerotic risk in IIM patients, further prospective studies of statin safety in IIM patients are warranted.

Semi-synthetic thymoquinone analogs: new prototypes as potential antihyperlipidemics in irradiated rats.

AIM: Thymoquinone (TQ), has been reported to possess strong antihyperlipidemic properties. However, a variety of serious side effects has been reported for TQ. The present study aimed to evaluate the potential antihyperlipidemic activity of newly synthesized TQ analogs. METHODS & RESULTS: first, novel TQ derivatives were studied against radiation-induced dyslipidemia in male rats. Second, the most promising sulfur derivatives (4-7), were further tested to elucidate their possible mechanism(s) of actions. Results showed that they possess Hydroxymethyl Glutaryl-Co A reductase inhibitory activity, as well as stimulatory effects on the activities of each of plasma Lecithin-Cholesterol Acyltransferase and lipoprotein lipase enzymes. CONCLUSION: TQ derivatives (4-7), could be considered as promising agents in pathologies implicating impaired lipid metabolism, preclinical evaluation is warranted. [Formula: see text].

Anti-3-hydroxy-3-methylglutaryl-coenzyme a reductase necrotizing myopathy masquerading as a muscular dystrophy in a child.

INTRODUCTION: Immune-mediated necrotizing myopathies (IMNMs) are characterized by progressive weakness, elevated serum creatine kinase levels, and necrotizing myopathic features on muscle biopsy. Presence of highly specific autoantibodies against signal recognition particle (SRP) or 3-hydroxy-3-methylglutaryl- coenzyme A reductase (HMGCR) can aid in recognition and confirmation of IMNMs. METHODS: In this study we describe a boy with HMGCR-positive necrotizing myopathy and highlight the clinical features of the patient. RESULTS: In contrast to most adults, the patient described had a more indolent disease course, reminiscent of a muscular dystrophy. Intravenous immunoglobulin monotherapy resulted in a dramatic clinical response with return to normal strength. CONCLUSIONS: Systematic consideration of IMNMs and testing for relevant autoantibodies in children with suspected but genetically unconfirmed muscular dystrophy may help improve diagnostic accuracy and allow timely treatment with potentially highly effective immunotherapies. Muscle Nerve 56: 175-179, 2017.

Clinical and genetic associations of autoantibodies to 3-hydroxy-3-methyl-glutaryl-coenzyme a reductase in patients with immune-mediated myositis and necrotizing myopathy.

INTRODUCTION: Inhibition of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) with statins may trigger idiopathic inflammatory myositis (IIM) or immune-mediated necrotizing myopathy (IMNM). Anti-HMGCR antibodies have been detected in patients with IIM/IMNM. We aimed to determine the associations of anti-HMGCR in IIM/IMNM. METHODS: Anti-HMGCR antibodies were detected by ELISA in sera from patients with IIM/IMNM. RESULTS: Anti-HMGCR antibodies were detected in 19 of 207 patients with IIM/IMNM, and there was a trend toward an association with male gender (P = 0.079). Anti-HMGCR antibodies were associated strongly with statin exposure (OR = 39, P = 0.0001) and HLA-DRB1*11 (OR = 50, P < 0.0001). The highest risk for development of anti-HMGCR antibodies was among HLA-DR11 carriers exposed to statins. Univariate analysis showed a strong association of anti-HMGCR antibodies with diabetes mellitus (P = 0.008), which was not confirmed by multiple regression. Among anti-HMGCR(+) patients there was a trend toward increased malignancy (P = 0.15). CONCLUSIONS: Anti-HMGCR antibodies are seen in all subtypes of IIM and IMNM and are associated strongly with statin use and HLA-DR11. Muscle Nerve 52: 196-203, 2015.

Hypocholesterolemic and antioxidant properties of 3-(4-hydroxyl)propanoic acid derivatives in high-cholesterol fed rats.

The purpose of the present study was to evaluate the in vivo efficacy of two cinnamic acid synthetic derivatives (allyl 3-[4-hydroxyphenyl]propanoate; HPP304, 1-naphthyl-methyl 3-[4-hydroxyphenyl]propanoate; HPP305) in high-cholesterol fed rats and compare their actions to that of cinnamic acid. Cinnamic acid and its synthetic derivatives were supplemented with a high-cholesterol diet for 42 days at a dose of 0.135 mmol/100g of diet. The supplementation of HPP304 and HPP305 significantly lowered cholesterol and triglyceride levels in the plasma and liver with a simultaneous increase in the HDL-cholesterol concentration, whereas cinnamic acid only lowered the plasma cholesterol concentration. Cinnamic acid lowered hepatic HMG-CoA reductase activity in high-cholesterol fed rats, however, its synthetic derivatives (HPP304 and HPP305) did not affect HMG-CoA reductase activity compared to the control group. Instead, the HPP304 and HPP305 supplements significantly lowered hepatic acyl coenzyme A:cholesterol acyltransferase activity and increased the fecal bile acid. The SOD activity of the erythrocytes and liver was not different between the groups, however, the activities of CAT and GSH-Px, and the level of GSH in the erythrocytes were significantly higher in the HPP304 and HPP305 groups than in the control group. On the other hand, the activities of CAT and GSH-Px, and the level of malondialdehyde in the liver were significantly lower in the HPP304 and HPP305 groups. The antioxidant activities of these cinnamic acid synthetic derivatives were similar to the cinnamic acid in the high-cholesterol fed rats. In addition, HPP304 and HPP305 lowered amniotransferase activity in the plasma. These results suggest that two cinnamic acid synthetic derivatives (HPP304 and HPP305) exert lipid-lowering action and antioxidant properties without hepatotoxicity in high-cholesterol fed rats.

Hypothalamic digoxin-mediated model for trisomy 21.

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

The isoprenoid pathway and the pathogenesis of Reye's syndrome.

UNLABELLED: The isoprenoid pathway produces three key metabolites: endogenous digoxin (regulator of neurotransmitter uptake), dolichol, and ubiquinone (free radical scavenger). Since a mitochondrial dysfunction has been described in Reye's syndrome, it was considered pertinent to assess the pathway in this disease. Since endogenous digoxin can regulate neurotransmitter transport, the pathway was also assessed in patients with right hemispheric, left hemispheric, and bihemispheric dominance to find out the role of hemispheric dominance in its pathogenesis. The plasma/serum activity of hydroxy methyl glutaryl (HMG) coenzyme A (CoA) reductase, magnesium, digoxin, dolichol, ubiquinone, tryptophan/tyrosine catabolic patterns, and free radical and lipid levels, as well as RBC Na+, K(+)-ATPase activity, were measured in the groups mentioned. RESULTS: In the patient group as well as in individuals with right hemispheric dominance similar patterns were obtained. There was elevated digoxin and dolichol levels with low levels of ubiquinone in patients with Reye's syndrome as well as in those with right hemispheric dominance. The serum magnesium and RBC Na+, K(+)-ATPase activity were reduced. There was also an increase in tryptophan catabolites and a reduction in tyrosine catabolites as well as increased free radical levels. Reye's syndrome is associated with an upregulated isoprenoid pathway, elevated hypothalamic digoxin secretion, and right hemispheric chemical dominance.

Schizoid neurochemical pathology-induced membrane Na(+)-K+ ATPase inhibition in relation to neurological disorders.

Psychiatric abnormalities have been described in primary neurological disorders like multiple sclerosis, primary generalized epilepsy, Parkinson's disease, subacute sclerosing panencephalitis (SSPE), central nervous system glioma, and syndrome X with vascular dementia. It was therefore considered pertinent to compare monoamine neurotransmitter pattern in schizophrenia with those in the disorders described above. The end result of neurotransmission is changes in membrane Na(+)-K+ ATPase activity. Membrane Na(+)-K+ ATPase inhibition can lead to magnesium depletion, which can lead to an upregulated isoprenoid pathway. The isoprenoid pathway produces three important metabolites--digoxin, an endogenous membrane Na(+) -K+ ATPase inhibitor; ubiquinone, a membrane antioxidant and component of mitochondrial electron transport chain; and dolichol, important in N-glycosylation of protein. The serum/plasma levels of digoxin, dolichol, ubiquinone, magnesium, HMG CoA reductase activity, and RBC Na(+)-K+ ATPase activity were estimated in all these disorders. The result showed that the concentration of serum tryptophan and serotonin was high and serum tyrosine, dopamine, adrenaline, and noradrenaline low in all the disorders studied. The plasma HMG CoA reductase activity, serum digoxin, and serum dolichol levels were high and serum ubiquinone levels, serum magnesium, and RBC Na(+)-K+ ATPase activity were low in all the disorders studied. The significance of these changes in the pathogenesis of syndrome X, multiple sclerosis, primary generalized epilepsy, schizophrenia, SSPE, and Parkinson's disease is discussed in the setting of the interrelationship between these disorders documented in literature.

Hypothalamic digoxin, hemispheric chemical dominance, and mesenteric artery occlusion.

The role of the isoprenoid pathway in vascular thrombosis, especially mesenteric artery occlusion and its relation to hemispheric dominance, was assessed in this study. The following parameters were measured in patients with mesenteric artery occlusion and individuals with right hemispheric, left hemispheric, and bihemispheric dominance: (1) plasma HMG CoA reductase, digoxin, dolichol, ubiquinone, and magnesium levels; (2) tryptophan/tyrosine catabolic patterns; (3) free radical metabolism; (4) glycoconjugate metabolism; and (5) membrane composition. In patients with mesenteric artery occlusion there was elevated digoxin synthesis, increased dolichol and glycoconjugate levels, low ubiquinone, and elevated free radical levels. The RBC membrane Na(+)-K+ ATPase activity and serum magnesium were decreased. There was also an increase in tryptophan catabolites and reduction in tyrosine catabolites in the serum. There was an increase in cholesterol:phospholipid ratio and a reduction in glycoconjugate level of RBC membrane in these patients. The biochemical patterns obtained in mesenteric artery occlusion is similar to those obtained in left-handed/right hemispheric dominant individuals by the dichotic listening test. But all the patients with mesenteric artery occlusion were right-handed/left hemispheric dominant by the dichotic listening test. Hemispheric chemical dominance has no correlation with handedness or the dichotic listening test. Mesenteric artery occlusion occurs in right hemispheric chemically dominant individuals and is a reflection of altered brain function. Hemispheric chemical dominance may thus control the risk for developing vascular thrombosis in individuals.

Hypothalamic-mediated model for systemic lupus erythematosis: relation to hemispheric chemical dominance.

The isoprenoid pathway including endogenous digoxin was assessed in systemic lupus erythematosis (SLE). All the patients with SLE were right-handed/left hemispheric dominant by the dichotic listening test. This was also studied for comparison in patients with right hemispheric and left hemispheric dominance. The isoprenoid pathway was upregulated with increased digoxin synthesis in patients with SLE and in those with right hemispheric dominance. In this group of patients (i) the tryptophan catabolites were increased and the tyrosine catabolites reduced, (ii) the dolichol and glycoconjugate levels were elevated, (iii) lysosomal stability was reduced, (iv) ubiquinone levels were low and free radical levels increased, and (v) the membrane cholesterol:phospholipid ratios were increased and membrane glycoconjugates reduced. On the other hand, in patients with left hemispheric dominance the reverse patterns were obtained. The biochemical patterns obtained in SLE is similar to those obtained in left-handed/right hemispheric chemically dominant individuals. But all the patients with SLE were right-handed/left hemispheric dominant by the dichotic listening test. Hemispheric chemical dominance has no correlation with handedness or the dichotic listening test. SLE occurs in right hemispheric chemically dominant individuals, and is a reflection of altered brain function. The role of the isoprenoid pathway in the pathogenesis of SLE and its relation to hemispheric dominance is discussed.

Isoprenoid pathway-related membrane dysfunction in neuropsychiatric disorders.

The membrane composition and the isoprenoid pathway metabolites important in maintaining cell membrane integrity was studied in neurological and psychiatric disorders. The results indicate alteration in cholesterol:phospholipid ratio of the RBC membrane which is increased in glioma, schizophrenia, and bipolar mood disorder (MDP); decreased in multiple sclerosis and Parkinson's disease; and not significantly altered in epilepsy. The concentration of total glycosaminoglycans (GAG), hexose, and fucose decreased in the RBC membrane and increased in the serum. The RBC membrane Na+-K+ ATPase activity was reduced and serum HMG CoA reductase activity was increased. There were increased serum levels of digoxin, cholesterol, and dolichol and decreased levels of ubiquinone. The serum magnesium and tyrosine levels were reduced and tryptophan increased. The results indicate a defect in membrane formation and a decreased membrane Na+-K+ ATPase activity in all the disorders studied. The results are discussed, and a hypothesis regarding the relationship between these disorders and defective membrane architecture and membrane Na+-K+ ATPase inhibition is presented.

Hypothalamic digoxin, hemispheric chemical dominance, and inflammatory bowel disease.

The isoprenoid pathway produces three key metabolites--endogenous digoxin, dolichol, and ubiquinone. It was considered pertinent to assess the pathway in inflammatory bowel disease (ulcerative colitis and regional ileitis). Since endogenous digoxin can regulate neurotransmitter transport, the pathway and the related cascade were also assessed in individuals with differing hemispheric dominance to find out the role of hemispheric dominance in its pathogenesis. All the patients with inflammatory bowel disease were right-handed/left hemispheric dominant by the dichotic listening test. The following parameters were measured in patients with inflammatory bowel disease and in individuals with differing hemispheric dominance: (1) plasma HMG CoA reductase, digoxin, dolichol, ubiquinone, and magnesium levels; (2) tryptophan/tyrosine catabolic patterns; (3) free-radical metabolism; (4) glycoconjugate metabolism; and (5) membrane composition and RBC membrane Na+-K+ ATPase activity. Statistical analysis was done by ANOVA. In patients with inflammatory bowel disease 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. There was an increase in cholesterol:phospholipid ratio and a reduction in glycoconjugate level of RBC membrane in these groups of patients. Inflammatory bowel disease is associated with an upregulated isoprenoid pathway and elevated digoxin secretion from the hypothalamus. This can contribute to immune activation, defective glycoprotein bowel antigen presentation, and autoimmunity and a schizophreniform psychosis important in its pathogenesis. The biochemical patterns obtained in inflammatory bowel disease is similar to those obtained in left-handed/right hemispheric dominant individuals by the dichotic listening test. But all the patients with peptic ulcer disease were right-handed/left hemispheric dominant by the dichotic listening test. Hemispheric chemical dominance has no correlation with handedness or the dichotic listening test. Inflammatory bowel disease occurs in right hemispheric chemically dominant individuals and is a reflection of altered brain function.

Hypothalamic digoxin, hemispheric chemical dominance, and chronic bronchitis emphysema.

The isoprenoid pathway produces three key metabolites--endogenous digoxin (membrane sodium-potassium ATPase inhibitor, immunomodulator, and regulator of neurotransmitter/amino acid transport), dolichol (regulates N-glycosylation of proteins), and ubiquinone (free radical scavenger). This was assessed in patients with chronic bronchitis emphysema. The pathway was also assessed in patients with right hemispheric, left hemispheric, and bihemispheric dominance to find the role of hemispheric dominance in the pathogenesis of chronic bronchitis emphysema. All the 15 patients with chronic bronchitis emphysema were right-handed/left hemispheric dominant by the dichotic listening test. In patients with chronic bronchitis emphysema 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. There was an increase in cholesterol:phospholipid ratio and a reduction in glycoconjugate levels of RBC membrane in patients with chronic bronchitis emphysema. The same biochemical patterns were obtained in individuals with right hemispheric dominance. Endogenous digoxin by activating the calcineurin signal transduction pathway of T-cell can contribute to immune activation in chronic bronchitis emphysema. Increased free radical generation can also lead to immune activation. Endogenous synthesis of nicotine can contribute to the pathogenesis of the disease. Altered glycoconjugate metabolism and membranogenesis can lead to defective lysosomal stability contributing to the disease process by increased release of lysosomal proteases. The role of an endogenous digoxin and hemispheric dominance in the pathogenesis of chronic bronchitis emphysema and in the regulation of lung structure/function is discussed. The biochemical patterns obtained in chronic bronchitis emphysema is similar to those obtained in left-handed/right hemispheric chemically dominant individuals by the dichotic listening test. But all the patients with chronic bronchitis emphysema were right-handed/left hemispheric dominant by the dichotic listening test. Hemispheric chemical dominance has no correlation with handedness or the dichotic listening test. Chronic bronchitis emphysema occurs in right hemispheric chemically dominant individuals and is a reflection of altered brain function. Hemispheric chemical dominance can play a role in the regulation of lung function and structure.

Endogenous hypodigoxinemia-related immune deficiency syndrome.

The isoprenoid pathway produces three key metabolites--digoxin (membrane Na+-K+ ATPase inhibitor, regulator of neurotransmitter transport, and an immunomodulatory agent), dolichol (a regulator of N-glycosylation of proteins), and ubiquinone (a free radical scavenger). The pathway was assessed in acute rheumatic fever patients with recurrent streptococcal infections, and who were also studied for differences in right and left hemispheric dominance. The isoprenoid pathway was downregulated with decreased digoxin synthesis in these patients and in those with left hemispheric chemical dominance. The tryptophan catabolites were decreased and the tyrosine catabolites increased. In these groups of patients the dolichol and glycoconjugate levels were reduced and lysosomal stability was increased. The ubiquinone levels were elevated and free radical levels decreased in these patients. The membrane cholesterol:phospholipid ratios were decreased and membrane glycoconjugates increased. On the other hand in right hemispheric chemical dominance the reverse patterns and hyperdigoxinemia with an upregulated isoprenoid pathway were noticed. The role of the isoprenoid pathway in the pathogenesis of acute rheumatic fever and recurrent streptococcal infections and its relation to hemispheric chemical dominance is discussed.

Hypothalamic digoxin-mediated model for Parkinson's disease.

The isoprenoid pathway produces four key metabolites important in cellular function--digoxin (endogenous membrane Na(+)-K+ ATPase inhibitor), dolichol (important in N-glycosylation of proteins), ubiquinone (free-radical scavenger), and cholesterol (component of cellular membranes). This study assessed the changes in the isoprenoid pathway and the consequences of its dysfunction in Parkinson's disease (PD). There was an elevation in plasma HMG CoA reductase activity, serum digoxin and dolichol levels, and a reduction in serum magnesium, RBC membrane Na(+)-K+ ATPase activity, and serum ubiquinone levels. Serum tryptophan, serotonin, strychnine, nicotine, and quinolinic acid were elevated, while tyrosine, morphine, dopamine, and noradrenaline were decreased. The total serum glycosaminoglycans (GAG) and glycosaminoglycan fractions (except chondroitin sulphates and hyaluronic acid), the activity of GAG degrading enzymes, carbohydrate residues of serum glycoproteins, the activity of glycohydrolase-beta galactosidase, and serum glycolipids were elevated. HDL cholesterol was reduced and free fatty acids increased. The RBC membrane glycosaminoglycans, hexose and fucose residues of glycoproteins and cholesterol were reduced, while phospholipid was increased. The activity of all serum free-radical scavenging enzymes, concentration of glutathione, alpha tocopherol, iron binding capacity, and ceruloplasmin decreased significantly in PD, while the concentration of serum lipid peroxidation products and nitric oxide increased. A dysfunctional isoprenoid pathway and related cascade are important in the pathogenesis of Parkinson's disease. A hypothalamic digoxin mediated model for Parkinson's disease is also postulated.

Hypothalamic digoxin, hemispheric chemical dominance, and sleep.

The isoprenoid path way produces endogenous digoxin, a substance that can regulate neurotransmitter and amino acid transport. Digoxin synthesis and neurotransmitter patterns were assessed in individuals with chronic insomnia. The patterns were compared in those with right hemispheric and left hemispheric dominance. The activity of HMG GoA reductase and serum levels of digoxin, magnesium, tryptophan catabolites, and tyrosine catabolites were measured in individuals with chronic insomnia and in individuals with differing hemispheric dominance. Digoxin synthesis was increased with upregulated tryptophan catabolism (increased levels of serotonin, strychnine, and nicotine), and downregulated tyrosine catabolism (decreased levels of dopamine, noradrenaline, and morphine) in those with chronic insomnia and right hemispheric chemical dominance. Digoxin synthesis was reduced with downregulated tryptophan catabolism (decreased levels of serotonin, strychnine, and nicotine) and upregulated tyrosine catabolism (increased levels of dopamine, noradrenaline, and morphine) in those with normal sleep patterns and left hemispheric chemical dominance. Hypothalamic digoxin plays a central role in the regulation of sleep behavior. Hemispheric chemical dominance in relation to digoxin status is also crucial.

Hypothalamic digoxin and isoprenoid pathway dysfunction relation to alcoholic addiction, alcoholic cirrhosis, and acquired hepatocerebral degeneration--relation to hemispheric chemical dominance.

The isoprenoid pathway produces three key metabolites--endogenous digoxin (modulate tryptophan/tyrosine transport), dolichol (important in N-glycosylation of proteins), and ubiquinone (free radical scavenger). It was considered pertinent to assess the pathway in alcoholic addiction, alcoholic cirrhosis, and acquired hepatocerebral degeneration. Since endogenous digoxin can regulate neurotransmitter transport, the pathway and the related cascade were also assessed in individuals with differing hemispheric dominance to find out the role of hemispheric dominance in its pathogenesis. In the patient group 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, as well as reduced endogenous morphine synthesis from tyrosine. There was an increase in cholesterol:phospholipid ratio and a reduction in glycoconjugate level of RBC membrane in these groups of patients. Alcoholic cirrhosis, alcoholic addiction, and acquired hepatocerebral degeneration are associated with an upregulated isoprenoid pathway and elevated digoxin secretion from the hypothalamus. This can contribute to NMDA excitotoxicity and altered connective tissue/lipid metabolism important in its pathogenesis. Endogenous morphine deficiency plays a role in alcoholic addiction. The same biochemical patterns were obtained in those with right hemispheric chemical dominance. Alcoholic addiction, alcoholic cirrhosis, and acquired hepatocerebral degeneration occur in right hemispheric, chemically dominant individuals.

Hypothalamic digoxin, hemispheric chemical dominance, and creativity.

The human hypothalamus produces an endogenous membrane Na(+)-K+ ATPase inhibitor, digoxin, which regulates neuronal transmission. The digoxin status and neurotransmitter patterns were studied in creative and non-creative individuals, as well as in individuals with differing hemispheric dominance, in order to find out the role of cerebral dominance in this respect. The activity of HMG CoA reductase and serum levels of digoxin, magnesium, tryptophan catabolites, and tyrosine catabolites were measured in creative/non-creative individuals, and in individuals with differing hemispheric dominance. In creative individuals there was increased digoxin synthesis, decreased membrane Na(+)-K+ ATPase activity, increased tryptophan catabolites (serotonin, quinolinic acid, and nicotine), and decreased tyrosine catabolites (dopamine, noradrenaline, and morphine). The pattern in creative individuals correlated with right hemispheric dominance. In non-creative individuals there was decreased digoxin synthesis, increased membrane Na(+)-K+ ATPase activity, decreased tryptophan catabolites (serotonin, quinolinic acid, and nicotine), and increased tyrosine catabolites (dopamine, noradrenaline, and morphine). This pattern in non-creative individuals correlated with that obtained in left hemispheric chemical dominance. Hemispheric chemical dominance and hypothalamic digoxin could regulate the predisposition to creative tendency.

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.