Recurrent headaches may be caused by cerebral toxoplasmosis.

AIM: To establish seroprevalence and provide characteristics of Toxoplasma gondii (TG) infection in children with recurrent headaches. METHODS: The study was performed in 178 children aged 7-17 years admitted consecutively to the Department of Pediatric Neurology from November 2009 to July 2011. The children were surveyed with a questionnaire with the help and assistance of their parents and blood samples taken on admission were studied for the presence of specific anti-TG IgM, IgG antibodies and IgG avidity using enzyme immunoassay Platelia Toxo IgM, IgG. RESULTS: The study showed that 19 children (8 boys, 11 girls; 8-17 years old, mean age 14.36 years) had high serum anti-TG IgG antibody levels (range: 32.2 > 240 UI/mL, mean 120.18 UI/mL; positive value for IgG was ≥ 9 UI/mL). The avidity index (AI) ranged from 0.202 to 0.925 (scale: ≥ 0.5 high AI). The results for IgM antibodies were all negative and the obtained results ranged from 0.113 to 0.25 U/mL (mean = 0.191 IU/mL) and all values below 0.8 IU/mL were considered negative. The most frequent complaints found in the seropositive patients were headaches that affected the frontal (13 children), occipital (4) and parietal areas (5). Headaches usually had a pulsating (in 7 patients) and squeezing (6) character and rarely were piercing, dull or expanding. Interestingly, 8 children did not feel discomfort during the headaches, probably because they did not have sufficiently increased intracranial pressure yet. The headaches usually appeared 1-2 times/mo, lasted for 2-6 h, and had a mean intensity of 5.5 points in a 10 point subjective scale. The comorbidities included epilepsy (5 patients), various infections in 3 children (chronic eustachitis, chronic rhinitis, chronic purulent tonsillitis, streptococcal pharyngitis, meningitis, allergic diseases), disturbances of behavior, deficits of attention, and ocular and motor concentration disorders in 1 child. The electroencephalographic and neuroimaging studies performed in our patients had a very limited value in establishing cerebral toxoplasmosis. CONCLUSION: Ten point six seven percent of the studied children had markedly increased serum anti-TG IgG antibodies and high AI indicated chronic infestation. It is suggested that tests for TG infection should be introduced to routine diagnostics in patients with recurrent headaches.

Toxoplasmosis--a global threat. Correlation of latent toxoplasmosis with specific disease burden in a set of 88 countries.

BACKGROUND: Toxoplasmosis is becoming a global health hazard as it infects 30-50% of the world human population. Clinically, the life-long presence of the parasite in tissues of a majority of infected individuals is usually considered asymptomatic. However, a number of studies show that this 'asymptomatic infection' may also lead to development of other human pathologies. AIMS OF THE STUDY: The purpose of the study was to collect available geoepidemiological data on seroprevalence of toxoplasmosis and search for its relationship with mortality and disability rates in different countries. METHODS AND FINDINGS: Prevalence data published between 1995-2008 for women in child-bearing age were collected for 88 countries (29 European). The association between prevalence of toxoplasmosis and specific disease burden estimated with age-standardized Disability Adjusted Life Year (DALY) or with mortality, was calculated using General Linear Method with Gross Domestic Product per capita (GDP), geolatitude and humidity as covariates, and also using nonparametric partial Kendall correlation test with GDP as a covariate. The prevalence of toxoplasmosis correlated with specific disease burden in particular countries explaining 23% of variability in disease burden in Europe. The analyses revealed that for example, DALY of 23 of 128 analyzed diseases and disease categories on the WHO list showed correlations (18 positive, 5 negative) with prevalence of toxoplasmosis and another 12 diseases showed positive trends (p<0.1). For several obtained significant correlations between the seroprevalence of toxoplasmosis and specific diseases/clinical entities, possible pathophysiological, biochemical and molecular explanations are presented. CONCLUSIONS: The seroprevalence of toxoplasmosis correlated with various disease burden. Statistical associations does not necessarily mean causality. The precautionary principle suggests however that possible role of toxoplasmosis as a triggering factor responsible for development of several clinical entities deserves much more attention and financial support both in everyday medical practice and future clinical research.

Possible link between Toxoplasma gondii and the anosmia associated with neurodegenerative diseases.

Toxoplasma gondii is an intracellular protozoan infecting 30% to 50% of global human population. Recently, it was suggested that chronic latent neuroinflammation caused by the parasite may be responsible for the development of several neurodegenerative diseases manifesting with the loss of smell. Studies in animals inoculated with the parasite revealed cysts in various regions of the brain, including olfactory bulb. Development of behavioral changes was paralleled by the preferential persistence of cysts in defined anatomic structures of the brain, depending on the host, strain of the parasite, its virulence, and route of inoculation. Olfactory dysfunction reported in Alzheimer's disease, multiple sclerosis, and schizophrenia was frequently associated with the significantly increased serum anti-T gondii immunoglobulin G antibody levels. Damage of the olfactory system may be also at least in part responsible for the development of depression because T gondii infection worsened mood in such patients, and the olfactory bulbectomized rat serves as a model of depression.

Migraine associated with patent foramen ovale may be caused by reactivation of cerebral toxoplasmosis triggered by arterial blood oxygen desaturation.

Approximately two billion people worldwide are chronically infected with T. gondii and yet with largely unknown consequences. On the other hand, several authors reported an association between migraine and patent foramen ovale (PFO), and different types of headaches, including migraine, may be precipitated by various diseased states or medications associated with marked immune irregularities, which sometimes cause reactivation of latent cerebral toxoplasmosis (CT). Recently, in a group of 104 subjects with migraine, 46 individuals (44.2%) were found to be seropositive for T. gondii. PFO, atrial septal defects, as well as pulmonary right-to-left shunts are usually associated with a various degree of arterial blood oxygen desaturation. Hypoxia is associated with an increase in the generation of several proinflammatory cytokines and other inflammation mediators, such as TNF-alpha, IL-1-beta, IL-6, IL-8, chemokines (monocyte chemoattractant protein-1, CC-chemokine receptor 2, macrophage inflammatory protein-1alpha, intercellular adhesion molecule-1), acute-phase protein gene expressions, COX-2 gene transcription, induction of iNOS, and reactive oxygen species. Moreover, hypoxia markedly decreased T-lymphocyte IL-2 mRNA, a key cytokine responsible for B-cell proliferation and immunoglobulin secretion, and ischemic tissues demonstrated intravascular neutrophil accumulation, vascular damage, and increased vascular wall permeability. Interestingly, T. gondii activates hypoxia-inducible factor 1 already at physiologically relevant oxygen levels and requires HIF1 for growth and survival. These abnormalities may cause imbalance in the host/T. gondii immune system, which finally results in the reactivation of CT. In addition, hypoxia may participate in paradoxical microembolism because arterial oxygen desaturation enhances expression of plasminogen activator inhibitor-1, an important factor which suppresses fibrinolysis, and this effect may be further amplified by a decreased expression of plasminogen activators, finally causing blood hypercoagulability and paradoxical microembolism. In summary, further studies are required to verify the above-presented pathomechanisms probably responsible for the association between PFO and the development of migraine. It is possible that some migraineurs with PFO may benefit from evaluation and treatment of toxoplasmosis in the future once more information is known.

Advances of molecular clinical pharmacology in gastroenterology and hepatology.

During developmental age, differences in pharmacodynamic reactions to several drugs may reflect polymorphisms of genes encoding drug-transporting proteins, receptors, drug targets, and gene products, whose disturbed activity sometimes plays an important role in certain diseases. Administration of drugs with a narrow therapeutic index may quite easily be associated with changes in pharmacokinetics and development of adverse drug reactions, which occasionally may cause fatalities. In such cases, polypragmasy and resulting drug interactions may enhance effects of changes in drug-metabolizing enzymes' activities. Phenotyping and genotyping of patients slowly are finding their place in some therapeutic regimens used in clinical gastroenterology and hepatology. At present, some assays to measure, for example, thiopurine S-methyltransferase activity are already commercially available. Polymorphisms of CYP450 enzymes, interleukins, and altered gene expression play an important role in some patients' various gastrointestinal tract and liver diseases. Herbal drugs also affect proinflammatory and antiinflammatory cytokine and nitric oxide balance in the body. Therapeutic use of recombined proteins, such as infliximab, natalizumab, onercept, humanized antibody to integrin α-4 ß-7, or IFN-ß in some large-bowel diseases increased therapeutic efficacy. IFN-α used in the patients with chronic hepatitis C improved cellular immunity in these subjects and exerted antiviral activity. Practical application of progress in pharmacogenetics, pharmacokinetics, pharmacodynamics, and use of bioproducts in novel therapeutic regimens has opened therapeutic frontiers and increased clinical safety.

Mollaret meningitis may be caused by reactivation of latent cerebral toxoplasmosis.

Mollaret meningitis (MM) occurs mainly in females and is characterized by recurrent episodes of headache, transient neurological abnormalities, and the cerebrospinal fluid containing mononuclear cells. HSV-2 was usually identified as the causative agent. Recently, we found that recurrent headaches in non-HIV-infected subjects were due to acquired cerebral toxoplasmosis (CT). The aim of the study was therefore to focus on molecular pathomechanisms that may lead to reactivation of latent CT and manifest as MM. Literature data cited in this work were selected to illustrate that various factors may affect latent CNS Toxoplasma gondii infection/inflammation intensity and/or host defense mechanisms, i.e., the production of NO, cytokines, tryptophan degradation by indoleamine 2,3-dioxygenase, mechanisms mediated by an IFN-gamma responsive gene family, limiting the availability of intracellular iron to T. gondii, and production of reactive oxygen/nitrogen species, finally inducing choroid plexitis and/or vasculitis. Examples of triggers revealing MM and accompanying disturbances of IFN-gamma-mediated immune responses that control HSV-2 and T. gondii include: female predominance (female mice are more susceptible to T. gondii infection than males); HSV-2 infection (increased IFN-gamma, IL-12); metaraminol (increased plasma catecholamine levels, changes in cytokine expression favoring T(H)2 cells responses); probably cholesterol contained in debris from ruptured epidermoid cysts (decreased NO; increased TNF-alpha, IL-6, IL-8). These irregularities induced by the triggers may be responsible for reactivation of latent CT and development of MM. Thus, subjects with MM should have test(s) for T. gondii infection performed obligatorily.

The importance of toxoplasma gondii infection in diseases presenting with headaches. Headaches and aseptic meningitis may be manifestations of the Jarisch-Herxheimer reaction.

Worldwide, approximately 2 billion people are chronically infected with T. gondii with largely unknown consequences. This review presents clinical symptoms, differential diagnosis, triggering factors, treatment, and pathomechanisms responsible for idiopathic intracranial hypertension, pseudotumor cerebri, and aseptic meningitis. Literature cited in this work illustrates that immune state and other biologic mediator imbalances due to various endogenous and exogenous triggering factors may markedly affect latent central nervous system T. gondii infection/inflammation intensity, and cause reactivation of cerebral toxoplasmosis (CT). Irregularities in pro- and anti-inflammatory processes may markedly disturb the host and/or T. gondii defense mechanisms important for immune control of the parasite thereby manifesting as a wide range of neurologic symptoms and signs observed in some patients with migraine, epilepsy, celiac disease, Henoch-Schönlein purpura, and other brain disorders. This is consistent with reactivation of CT in mice after treatment with dexamethasone associated with depression of type T(H)1 immune response, and development of CT after administration of etanercept or other bioproducts. It seems that various types of headaches, epilepsy, aseptic meningitis, systemic adverse reactions to drugs or other substances represent the Jarisch-Herxheimer reaction due to apoptosis of T. gondii tachyzoites. Also development of some brain tumors, such as ependymoma and glioma may be associated with a chronic course of CT. Thus, all these patients should be tested for T. gondii infection.

Recurrent headache as the main symptom of acquired cerebral toxoplasmosis in nonhuman immunodeficiency virus-infected subjects with no lymphadenopathy: the parasite may be responsible for the neurogenic inflammation postulated as a cause of different types of headaches.

Headache and/or migraine, a common problem in pediatrics and internal medicine, affect about 5% to 10% children and adolescents, and nearly 30% of middle-aged women. Headache is also one of the most common clinical manifestations of acquired Toxoplasma gondii infection of the central nervous system (CNS) in immunosuppressed subjects. We present 11 apparently nonhuman immunodeficiency virus-infected children aged 7 to 17 years (8 girls, 3 boys) and 1 adult woman with recurrent severe headaches in whom latent chronic CNS T. gondii infection not manifested by enlarged peripheral lymph nodes typical for toxoplasmosis, was found. In 7 patients, the mean serum IgG Toxoplasma antibodies concentration was 189 +/- 85 (SD) IU/mL (range 89 to 300 IU/mL), and in 5 other subjects, the indirect fluorescent antibody test titer ranged from 1:40 to 1:5120 IU/mL (n= <1:10 IU/mL). Some of the patients suffered also from atopic dermatitis (AD) and were exposed to cat and/or other pet allergens, associated with an increased IL-4 and decreased IFN-gamma production. These cytokine irregularities caused limited control of cerebral toxoplasmosis probably because IL-4 down-regulated both the production of IFN-gamma and its activity, and stimulated production of a low NO-producing population of monocytes, which allowed cysts rupture, increased parasite multiplication and finally reactivation of T. gondii infection. The immune studies performed in 4 subjects showed a decreased percentage of T lymphocytes, increased total number of lymphocytes B and serum IgM concentration, and impaired phagocytosis. In addition, few of them had also urinary tract diseases known to produce IL-6 that can mediate immunosuppressive functions, involving induction of the anti-inflammatory cytokine IL-10. These disturbances probably resulted from the host protective immune reactions associated with the chronic latent CNS T. gondii infection/inflammation. This is consistent with significantly lower enzyme indoleamine 2,3-dioxygenase (IDO) activity reported in atopic than in nonatopic individuals, and an important role that IDO and tryptophan degradation pathways plays in both, the host resistance to T. gondii infection and its reactivation. Analysis of literature information on the subjects with different types of headaches caused by foods, medications, and other substances, may suggest that their clinical symptoms and changes in laboratory data result at least in part from interference of these factors with dietary tryptophan biotransformation pathways. Several of these agents caused headache attacks through enhancing NO production via the conversion of arginine to citrulline and NO by the inducible nitric oxide synthase enzyme, which results in the high-output pathway of NO synthesis. This increased production of NO is, however, quickly down-regulated by NO itself because this biomolecule can directly inactivate NOS, may inhibit Ia expression on IFN-gamma-activated macrophages, which would limit antigen-presenting capability, and block T-cell proliferation, thus decreasing the antitoxoplasmatic activity. Moreover, NO inhibits IDO activity, thereby suppressing kynurenine formation, and at least one member of the kynurenine pathway, 3-hydroxyanthranilic acid, has been shown to inhibit NOS enzyme activity, the expression of NOS mRNA, and activation of the inflammatory transcription factor, nuclear factor-kB. In addition, the anti-inflammatory cytokines IL-4 and IL-10, TGF-beta, and a cytokine known as macrophage deactivating factor, have been shown to directly modulate NO production, sometimes expressing synergistic activity. On the other hand, IL-4 and TGF-beta can suppress IDO activity in some cells, for example human monocytes and fibroblasts, which is consistent with metabolic pathways controlled by IDO being a significant contributor to the proinflammatory system. Also, it seems that idiopathic intracranial hypertension, pseudotumor cerebri, and aseptic meningitis, induced by various factors, may result from their interference with IDO and inducible nitric oxide synthase activities, endogenous NO level, and cytokine irregularities which finally affect former T. gondii status 2mo in the brain. All these biochemical disturbances caused by the CNS T. gondii infection/inflammation may also be responsible for the relationship found between neurologic symptoms, such as headache, vertigo, and syncope observed in apparently immunocompetent children and adolescents, and physical and psychiatric symptoms in adulthood. We therefore believe that tests for T. gondii should be performed obligatorily in apparently immunocompetent patients with different types of headaches, even if they have no enlarged peripheral lymph nodes. This may help to avoid overlooking this treatable cause of the CNS disease, markedly reduce costs of hospitalization, diagnosis and treatment, and eventually prevent developing serious neurologic and psychiatric disorders.

Important role of proinflammatory cytokines/other endogenous substances in drug-induced hepatotoxicity: depression of drug metabolism during infections/inflammation states, and genetic polymorphisms of drug-metabolizing enzymes/cytokines may markedly contribute to this pathology.

Analysis of literature data on drug-induced hepatotoxicity reveals that often upper respiratory febrile illnesses and/or inflammation states precede liver injury/diseases related to administration of drugs or hepatotoxicity associated with administration of therapeutic doses of acetaminophen in some genetically predisposed subjects. The goals of this paper are to review the potential role of alterations in the balance between TH1 cells producing cytokines associated with a cell-mediated response and TH2 cells associated with an antibody response, as well as other endogenous substances, eg, growth factors, leading to a shift in immune response to one that may participate in the liver cells injury during administration of certain drugs, especially in subjects with genetic polymorphisms in drug-metabolizing enzymes. The papers cited in this review were selected to illustrate specific issue related to how profuse and dysregulated production of cytokines, growth factors, and/or other endogenous substances during viral/bacterial infections and inflammation states play a role in the development of drug-induced liver injury. Several cases of liver injury related to administration of drugs appear to be initiated or intensified by upper respiratory febrile illnesses and/or inflammation states, which stimulate sometimes dysregulated production of interferon gamma and/or other proinflammatory cytokines/growth factors. This, in turn, results in down-regulation of various induced and constitutive isoforms of cytochromes P-450, and other enzymes involved in the metabolism of several exogenous (eg, drugs) and endogenous lipophilic (eg, steroids) substances, thus having an important impact on the alterations in bioactivation and detoxication processes in the body and on the balance between production, utilization, and elimination of endogenous bioproducts of these reactions. Activation of systemic host defense mechanisms results in down-regulation of various enzymes involved in drug metabolism and elimination, as well as in production, utilization, and excretion of many endogenous substances that have beneficial effects on vital processes in the body. It seems that treatment of acute and chronic infections and/or inflammations with, for example, antibacterials not metabolized in the liver, and use of medications that decrease proinflammatory cytokine levels (eg, pentoxifylline, a TNF-alpha synthesis inhibitor, directed against TNF-alpha-induced priming of human neutrophils, immunotherapy with IL-4, IL-1 receptor antagonists or factors inducing IL-1ra, dietary supplementation with long-chain n-3 fatty acids, and other antioxidant agents) may perhaps, in some cases, be helpful in the prevention and management of drug-induced hepatotoxicity. Drug-mediated injuries may eventually be prevented by screening methods that can identify genetic polymorphism of drug-metabolizing enzymes and gene polymorphisms or RNA-expression profiles of some proinflammatory cytokines before a patient uses a drug.

Possible pathomechanisms of sudden infant death syndrome: key role of chronic hypoxia, infection/inflammation states, cytokine irregularities, and metabolic trauma in genetically predisposed infants.

Chronic hypoxia, viral infections/bacterial toxins, inflammation states, biochemical disorders, and genetic abnormalities are the most likely trigger of sudden infant death syndrome (SIDS). Autopsy studies have shown increased pulmonary density of macrophages and markedly more eosinophils in the lungs accompanied by increased T and B lymphocytes. The elevated levels of immunoglobulins, about 20% more muscle in the pulmonary arteries, increased airway smooth muscle cells, and increased fetal hemoglobin and erythropoietin are evidence of chronic hypoxia before death. Other abnormal findings included mucosal immune stimulation of the tracheal wall, duodenal mucosa, and palatine tonsils, and circulating interferon. Low normal or higher blood levels of cortisol often with petechiae on intrathoracic organs, depleted maternal IgG antibodies to endotoxin core (EndoCAb) and early IgM EndoCAb triggered, partial deletions of the C4 gene, and frequent IL-10-592*A polymorphism in SIDS victims as well as possible hypoxia-induced decreased production of antiinflammatory, antiimmune, and antifibrotic cytokine IL-10, may be responsible for the excessive reactions to otherwise harmless infections. In SIDS infants, during chronic hypoxia and times of infection/inflammation, several proinflammatory cytokines are released in large quantities, sometimes also representing a potential source of tissue damage if their production is not sufficiently well controlled, eg, by pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP). These proinflammatory cytokines down-regulate gene expression of major cytochrome P-450 and/or other enzymes with the specific effects on mRNA levels, protein expression, and enzyme activity, thus affecting metabolism of several endogenous lipophilic substances, such as steroids, lipid-soluble vitamins, prostaglandins, leukotrienes, thromboxanes, and exogenous substances. In SIDS victims, chronic hypoxia, TNF-alpha and other inflammatory cytokines, and arachidonic acid (AA) as well as n-3 polyunsaturated fatty acids (FA), stimulated and/or augmented superoxide generation by polymorphonuclear leukocytes, which contributed to tissue damage. Chronic hypoxia, increased amounts of nonheme iron in the liver and adrenals of these infants, enhanced activity of CYP2C9 regarded as the functional source of reactive oxygen species (ROS) in some endothelial cells, and nicotine accumulation in tissues also intensified production of ROS. These increased quantities of proinflammatory cytokines, ROS, AA, and nitric oxide (NO) also resulted in suppression of many CYP450 and other enzymes, eg, phosphoenolpyruvate carboxykinase (PEPCK), an enzyme important in the metabolism of FA during gluconeogenesis and glyceroneogenesis. PEPCK deficit found in SIDS infants (caused also by vitamin A deficiency) and eventually enhanced by PACAP lipolysis of adipocyte triglycerides resulted in an increased FA level in blood because of their impaired reesterification to triacylglycerol in adipocytes. In turn, the overproduction and release of FA into the blood of SIDS victims could lead to the metabolic syndrome and an early phase of type 2 diabetes. This is probably the reason for the secondary overexpression of the hepatic CYP2C8/9 content and activity reported in SIDS infants, which intensified AA metabolism. Pulmonary edema and petechial hemorrhages often present in SIDS victims may be the result of the vascular leak syndrome caused by IL-2 and IFN-alpha. Chronic hypoxia with the release of proinflammatory mediators IL-1alpha, IL-1beta and IL-6, and overloading of the cardiovascular and respiratory systems due to the narrowing airways and small pulmonary arteries of these children could also contribute to the development of these abnormalities. Moreover, chronic hypoxia of SIDS infants induced also production of hypoxia-inducible factor 1alpha (HIF-1alpha), which stimulated synthesis and release of different growth factors by vascular endothelial cells and intensified subclinical inflammatory reactions in the central nervous system, perhaps potentiated also by PACAP and VIP gene mutations. These processes could lead to the development of brainstem gliosis and disorders in the release of neuromediators important for physiologic sleep regulation. All these changes as well as eventual PACAP abnormalities could result in disturbed homeostatic control of the cardiovascular and respiratory responses of SIDS victims, which, combined with the nicotine effects and metabolic trauma, finally lead to death in these often genetically predisposed children.

Urinary tract diseases revealed after DTP vaccination in infants and young children: cytokine irregularities and down-regulation of cytochrome P-450 enzymes induced by the vaccine may uncover latent diseases in genetically predisposed subjects.

Prophylactic vaccinations may sometimes shorten the incubation period of some illnesses and/or convert a latent infection/inflammation into a clinically apparent disease. Cytokines play a major role in mediating the inflammatory process in various clinical entities and represent a potential source of tissue damage if their production is not sufficiently well controlled. It seems that irregularities in production of proinflammatory cytokines may be responsible for the abnormalities associated with full-blown clinical symptoms of various urinary tract diseases observed after DTP vaccination in 13 infants and young children hospitalized over the past 24 years. On admission, upper respiratory tract diseases, atopic dermatitis, and/or latent urinary tract infection/inflammation were found in these children. It is suggested that the whole-cell pertussis present in DTP vaccine, acting as an excessive stimulus in these patients, produced symptoms reminiscent of biologic responses to circulating proinflammatory monokines such as IL-1beta, TNF-alpha, and IL-6 because earlier it was reported that in vitro the whole-cell vaccine induced significantly more such cytokine production than did the acellular pertussis or diphtheria-tetanus-only vaccine. Analysis of the cellular immune disturbances previously reported in urinary tract infection/inflammation (increased serum and/or urinary IL-1alpha, IL-1 receptor antagonist, IL-6 and IL-8), steroid-sensitive nephrotic syndrome (increased IL-2, IFN-gamma, TNF-alpha, and decreased or increased IL-4, depending on the cells studied), and atopic dermatitis (decreased IFN-gamma and increased IL-4 production), may suggest that similar subclinical chronic cytokine-mediated abnormalities produced in the course of latent diseases revealed in our patients, combined with those caused by DTP vaccination stimulus, were responsible for the pathomechanism of these clinical entities. This speculation is in agreement with the reports on the long-lasting induction of cytokine release and down-regulation of hepatic cytochrome P-450 isoenzyme activities after administration of DTP vaccine to mice and may be supported by the fact that TH1 phenotype is associated with the up-regulation of intercellular adhesion molecule-1 and RANTES, whereas TH2 phenotype is associated with the up-regulation of the vascular cell adhesion molecule and P-selectin, which are key players in the migration into inflamed tissues and localization of lymphocytes and other allergic effector and inflammatory cells. Because several inflammatory cytokines down-regulate gene expression of major cytochrome P-450 and/or other enzymes with the specific effects on mRNA levels, protein expression, and enzyme activity, thus affecting the metabolism of several endogenous lipophilic substances such as steroids, lipid-soluble vitamins, prostaglandins, leukotrienes, thromboxanes, and exogenous substances, their irregularities in the body may eventually lead to the flare of latent diseases in some predisposed subjects. Also, interleukin genetic polymorphisms, especially the constellation of TNF-alpha and IL-6 genetic variants, might predispose some infants with infection to a more than usually intense inflammatory response in the kidneys after vaccination. It seems that the aforementioned pathomechanism may also be responsible for some cases of sudden infant death syndrome, which is often preceded by infection/inflammation.

Limitations in the clinical usefulness of single-dose pharmacokinetic studies of drugs and a bayesian approach for the estimation of kinetic parameters.

This review presents several clinical examples indicating that physiological changes in the body dependent and/or independent of developmental age, genetic polymorphisms, different disease states, acute and/or chronic inflammations, and physicochemical properties of drugs as well as some environmental factors, such as viral infections, may exert a significant effect on the first-time assessment of kinetic parameters of drug absorption, disposition, metabolism, and excretion after a single-dose administration in children and adults. The available pharmacokinetic data in the literature suggest that one must be cautious in interpretation and practical use of pharmacokinetic variables derived from either single-dose studies or bayesian methods, especially in a pediatric population.

Possible pathomechanism of autoimmune hepatitis.

The hepatotropic viruses, measles, and herpesviruses as well as different drugs were repeatedly shown to act presumably as a trigger in patients with autoimmune hepatitis (AI-H). On the other hand, it is known that viral infections stimulate interferon production, which inactivates the cytochrome P-450 enzymes involved in the metabolism of several endogenous substances and exogenous environmental agents. Moreover, it was reported that several cytokines, including interferons, as well as transforming growth factor beta1 and human hepatocyte growth factor, which are abundantly produced and released in the body during infections, also downregulated expression of major cytochrome P-450 and/or other biotransformation enzymes. It seems that all these factors, in addition to individual immune response and the nature and amount of the neoantigen(s) produced, impair the equilibrium of bioactivation and detoxication pathways, thus leading to the development of AI-H in a genetically predisposed person continually exposed to harmful environmental factor(s). Possible increased/decreased density of lysine residues at position D-related human leukocyte antigen locus (DR)beta71 of the antigen-binding groove may affect the eventual steroid-sparing effect of this critical amino acid at the cellular level. In addition, some food additives, such as monosodium glutamate (MSG) and/or aspartame regularly consumed in excessive amounts, may eventually disturb the delicate balance between a positively charged amino acid residue at position DRbeta71 (lysine or arginine) and a negatively charged amino acid residue at position P4 on the antigenic peptide (glutamic acid or aspartic acid). This may favor formation of a salt bridge between these amino acid residues within the hypervariable region 3 on the alpha-helix of the DRbeta polypeptide and facilitate autoantigen presentation and CD4 T-helper cell activation. MSG and aspartate may also depress serum concentrations of growth hormone, which downregulate the activity of several cytochrome P-450 hepatic and other drug-metabolizing enzymes, thus increasing sensitivity to some environmental agents and possibly influencing efficacy of treatment regimens and final outcome of patients with type 1 AI-H.

Autoinmune hepatitis and odour of a fish food proteins

No disponible

No disponible

Furosemide: progress in understanding its diuretic, anti-inflammatory, and bronchodilating mechanism of action, and use in the treatment of respiratory tract diseases.

Accumulated experimental and clinical data suggest that adrenocorticosteroids and/or endogenous ouabain-like substances may play an important role in the mechanism of furosemide diuretic action. It was reported that the drug is highly bound in the adrenals, lungs, kidney, spleen, and liver. In patients with liver cirrhosis, furosemide exerted a markedly decreased natriuretic effect compared with normal subjects, and the plasma levels of circulating endothelin and atrial natriuretic factor (ANF) were significantly elevated. In neonates, after administration of furosemide, the urinary excretion of endothelin-1 and aldosterone increased markedly, and it is known that endothelin may release ANF and aldosterone in a dose-dependent manner. Furosemide was used to stimulate zona glomerulosa, whereas ANF decreased the production of steroids in zona glomerulosa and fasciculata cell culture owing to stimulation by various factors. Because the concomitant use of ANF and furosemide appeared to be diuretically effective in newborns after cardiac surgery, one may suggest that furosemide competes with ANF for its effects on the adrenals. Furosemide administered by inhalation exerted a protective effect on allergic and perennial nonallergic rhinitis and was effective in preventing the postsurgical recurrence of nasal polyposis. The drug can also be used as an antiasthmatic agent. In preterm ventilator-dependent infants with chronic lung disease, aerosolized furosemide improved pulmonary function with no marked effect on diuresis. In adults and children with asthma, furosemide exerted a protective effect against bronchoconstriction induced by several indirect stimuli similar to that of disodium cromoglycate or nedocromil. Aerosolized furosemide had a preventive effect also on bronchoconstriction induced by inhaled lysine acetylsalicylate in patients with aspirin-sensitive asthma. In high-dose beclomethasone-dependent asthma, inhaled lysine acetylsalicylate and furosemide exerted a mutually potentiating antiasthmatic activity, allowing considerable sparing of the inhaled steroid. It is proposed that this effect may be explained by the corticosteroid-sparing action of lysine released from the lysine acetylsalicylate molecule because similar beneficial effects were also obtained after the concomitant use of epsilon-aminocaproic acid (whose chemical structure is almost the same as that of lysine) and prednisone. Furosemide exhibited an anti-inflammatory effect through inhibition of production and release of cytokines interleukin (IL)-6, IL-8, and tumor necrosis factor-alpha from peripheral mononuclear cells, which may have a beneficial effect on local inflamed tissue imbalance in the ratio of different cytokines, thus improving the sensitivity of target cells to endogenous glucocorticosteroids.

Important role of prodromal viral infections responsible for inhibition of xenobiotic metabolizing enzymes in the pathomechanism of idiopathic Reye's syndrome, Stevens-Johnson syndrome, autoimmune hepatitis, and hepatotoxicity of the therapeutic doses of acetaminophen used in genetically predisposed persons.

Upper respiratory tract febrile illnesses caused by various viruses, mycoplasma, chlamydia infections, and/or inflammatory diseases are usually observed a few days to a few (several) weeks before the onset of Reye's syndrome, Stevens-Johnson syndrome, autoimmune hepatitis (hepatotropic virus infections), or hepatotoxicity associated with therapeutic administration of acetaminophen in persons with varying degrees of deficits of important enzymatic activity. Activation of systemic host defense mechanisms by inflammatory component(s) results in depression of various induced and constitutive isoforms of cytochrome P-450 mixed-function oxidase system superfamily enzymes in the liver and most other tissues of the body. Because several cytochrome P-450 enzymes activities important for biotransformation of many endogenous and egzogenous substances show considerable variability between individuals, in some genetically predisposed persons, even the administration of therapeutic doses of a drug may result in serious clinical mishaps, if an important concomitant risk factor (eg, acute viral infection) is involved. Several inflammatory cytokines, such as interleukins, transforming growth factor beta1, human hepatocyte growth factor, and lymphotoxin, downregulate gene expression of major cytochrome P-450 enzymes with the specific effects on mRNA levels, protein expression, and enzyme activity observed with a given cytokine varying for each P-450 studied, thus eventually leading to metabolite-mediated adverse drug reactions and immunometallic diseases which sometimes result in tissue injury beyond the site(s) where metabolic bioactivation takes place. On the other hand, it must be emphasized that inhibition of metabolism of several drugs, as well as influence on the concentration and/or ratio of various cytokines in inflamed tissues, may exert beneficial effects in patients with different diseases, thus opening new therapeutic possibilities. Clinically relevant interactions may be exemplified by the effects of some fluoroquinolone antibiotics, such as pefloxacin and ciprofloxacin, which probably have a steroid-sparing effect in some patients with frequently relapsing nephrotic syndrome, and an increased bioavailability of several drugs following concomitant intake with freshly pressed grapefruit juice, eventually caused by inhibition of their metabolism, mediated mainly by CYP3A and specifically inhibited by naturally occurring flavonoids.