Blood tests and use of nutritional supplements in a cohort of Brazilian children with trisomy 21.

OBJECTIVE: To describe the use of nutritional supplements and blood status (hemogram, lipidogram, hepatic function, inflammatory markers, minerals, and homocysteine) in a sample of Brazilian T21 children with private health support before their first consultation with a T21 expert. METHOD: This descriptive cross-sectional study enrolled 102 participants. Brazilian families with a T21 member under 18 years old were contacted and those that consented answered a survey regarding socio-demographics and the use of nutritional supplements and shared the blood tests that their T21 members have collected for the first consultation with a T21 expert. RESULTS: Frequencies and percentages were used to describe the variables. The most used supplements included vitamins (A, C and D), minerals (zinc and iron), omega-3, and antioxidants (curcumin). Hypothyroidism was observed in 56.9% of the participants. Hemogram alterations (increased hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin and red cell distribution width, leukopenia, and lymphocytopenia), dyslipidemia, altered hepatic and inflammatory blood markers were frequently found. CONCLUSIONS: Nutritional supplements (mainly vitamins, minerals, omega-3 and antioxidants) are frequently used by Brazilian T21 children independently of professional counseling and/or supervision and should be a question to be raised during the clinical anamnesis since some of them may impact medical conduct. Moreover, many blood tests are altered in this population and clinicians should be aware of them in order to warrant an appropriate screening and the implementation of risk management measures as soon as possible and improve the general health of these persons.

Blood tests and use of nutritional supplements in a cohort of Brazilian children with trisomy 21

Abstract Objective: To describe the use of nutritional supplements and blood status (hemogram, lipidogram, hepatic function, inflammatory markers, minerals, and homocysteine) in a sample of Brazilian T21 children with private health support before their first consultation with a T21 expert. Method: This descriptive cross-sectional study enrolled 102 participants. Brazilian families with a T21 member under 18 years old were contacted and those that consented answered a survey regarding socio-demographics and the use of nutritional supplements and shared the blood tests that their T21 members have collected for the first consultation with a T21 expert. Results: Frequencies and percentages were used to describe the variables. The most used supplements included vitamins (A, C and D), minerals (zinc and iron), omega-3, and antioxidants (curcumin). Hypothyroidism was observed in 56.9% of the participants. Hemogram alterations (increased hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin and red cell distribution width, leukopenia, and lymphocytopenia), dyslipidemia, altered hepatic and inflammatory blood markers were frequently found. Conclusions: Nutritional supplements (mainly vitamins, minerals, omega-3 and antioxidants) are frequently used by Brazilian T21 children independently of professional counseling and/or supervision and should be a question to be raised during the clinical anamnesis since some of them may impact medical conduct. Moreover, many blood tests are altered in this population and clinicians should be aware of them in order to warrant an appropriate screening and the implementation of risk management measures as soon as possible and improve the general health of these persons.

Intrauterine and Lactational Exposure to Paracetamol: Cardiometabolic Evaluation in Adult Female and Male Offspring.

ABSTRACT: Paracetamol (PAR) is the most common over-the-counter drug recommended by physicians for treatment of pain and fever during gestation. This drug is not teratogenic, being considered safe for fetus; however, PAR crosses the blood-placental barrier. Considering that, the present study aimed to evaluate the vascular and metabolic safety of PAR exposure during intrauterine and neonatal development in adult male and female-exposed offspring. Wistar female rats were gavaged, with PAR (350 mg/kg/d), from gestational day 6-21 or from gestational day 6 until postnatal day 21. Control dams received water by gavage at the same periods. The male and female offspring were evaluated at adulthood (80 days of life). The thoracic aorta reactivity to acetylcholine, sodium nitroprusside, and phenylephrine was evaluated in male and female adult offspring. It was observed that aortic relaxation was similar between the PAR and control offspring. In addition, the contraction to phenylephrine was similar between the groups. Further, the insulin sensitivity, adipose tissue deposition and blood pressure were not different between PAR and control adult offspring. These results suggest that the protocol of PAR exposure used in the present study did not program vascular and metabolic alterations that would contribute to the development of cardiometabolic diseases in adult life, being safe for the exposed offspring.

The role of high-density lipoprotein cholesterol, apolipoprotein A and paraoxonase-1 in the pathophysiology of neuroprogressive disorders.

Lowered high-density lipoprotein (HDL) cholesterol has been reported in major depressive disorder, bipolar disorder, first episode of psychosis, and schizophrenia. HDL, its major apolipoprotein component, ApoA1, and the antioxidant enzyme paraoxonase (PON)1 (which is normally bound to ApoA1) all have anti-atherogenic, antioxidant, anti-inflammatory, and immunomodulatory roles, which are discussed in this paper. The paper details the pathways mediating the anti-inflammatory effects of HDL, ApoA1 and PON1 and describes the mechanisms leading to compromised HDL and PON1 levels and function in an environment of chronic inflammation. The molecular mechanisms by which changes in HDL, ApoA1 and PON1 might contribute to the pathophysiology of the neuroprogressive disorders are explained. Moreover, the anti-inflammatory actions of ApoM-mediated sphingosine 1-phosphate (S1P) signalling are reviewed as well as the deleterious effects of chronic inflammation and oxidative stress on ApoM/S1P signalling. Finally, therapeutic interventions specifically aimed at improving the levels and function of HDL and PON1 while reducing levels of inflammation and oxidative stress are considered. These include the so-called Mediterranean diet, extra virgin olive oil, polyphenols, flavonoids, isoflavones, pomegranate juice, melatonin and the Mediterranean diet combined with the ketogenic diet.

Menstruation distress is strongly associated with hormone-immune-metabolic biomarkers.

OBJECTIVE: To examine the associations between menstruation features and symptoms and hormone-immune-metabolic biomarkers. METHODS: Forty-one women completed questionnaires assessing characteristic menstruation symptoms, duration of menstrual cycle and number of pads used/day and completed the Daily Record of Severity of Problems (DRSP) during the consecutive days of their menstrual cycle. Menses-related symptoms (MsRS) were computed from the sum of 10 pre- and post-menses symptoms and the menstruation blood and duration index (MBDI) was computed based on the daily number of pads and duration of menses. We assayed serum levels of various biomarkers at days 7, 14, 21, and 28 of the subjects' menstrual cycle. RESULTS: MBDI was significantly associated with a) MsRS including low abdominal cramps, and gastro-intestinal (GI) and pain symptoms (positively); b) plasma levels of haptoglobin (Hp), CCL5, insulin growth factor (IGF)-1, and plasminogen activator inhibitor (PAI)1 (all positively); and c) estradiol and paraoxonase (PON)1 arylesterase activity (both inversely). MsRS were significantly predicted by CCL5 and IGF-1 (both positively) and progesterone (inversely). Low-abdominal cramps, and gastro-intestinal and pain symptoms were associated with lower progesterone levels. The MBDI+MsRS score was significantly predicted by the cumulative effects of (in descending order of importance): Hp, IGF-1, PON1 arylesterase, estradiol and PAI. CONCLUSION: Menstruation-related features including estimated blood loss, duration of menses, cramps, pain, and gastro-intestinal symptoms are associated with hormone-immune-metabolic biomarkers, which mechanistically may explain those features. Future research should construct a cross-validated algorithm using MBDI+MsRS features in a larger study group to delineate a useful case-definition of menstruation-related distress.

Deficit schizophrenia and its features are associated with PON1 Q192R genotypes and lowered paraoxonase 1 (PON1) enzymatic activity: effects on bacterial translocation.

BACKGROUND: Primary deficit schizophrenia (DS) is characterized by enduring negative symptoms and represents a qualitatively different disease entity with respect to non-deficit schizophrenia (NDS). No studies investigated the association between the enzyme paraoxonase 1 (PON1) and DS and its phenomenology. METHODS: In this case-control study, Thai women and men, aged 18 to 65 years, were divided in DS (n = 40) and NDS (n = 40) and were compared to controls (n = 40). PON1 activities against 4-(chloromethyl)phenyl acetate (CMPA) and phenylacetate were determined. Moreover, subjects were genotyped for their PON1 Q192R polymorphism and immunoglobulin A (IgA) levels responses directed to Gram-negative bacteria were measured. RESULTS: DS is significantly associated with the QQ genotype and the Q allele as compared with NDS and controls. PON1 activities are significantly and inversely associated with negative symptoms, formal thought disorders, psychomotor retardation, excitation and DS. The presence of the Q allele is associated with increased IgA responses to Pseudomonas aeruginosa, Morganella morganii, and Pseudomonas putida as compared with RR carriers. CONCLUSIONS: The PON1 Q allele and lower PON1 activities especially against CMPA are associated with DS, indicating lowered quorum quenching abilities as well as lowered defenses against lipoperoxidation and immune activation. It is suggested that lowered PON1 activity in DS constitutes an impairment in the innate immune system which together with lowered natural IgM may cause lower immune regulation thereby predisposing toward greater neurotoxic effects of immune-inflammatory, oxidative and nitrosative pathways and Gram-negative microbiota.

Effect of paracetamol treatment on maternal care and reproductive outcomes in female rat offspring.

Paracetamol (PAR) is one of the most commonly used drugs by pregnant women because it is considered safe for the mother and fetus. However, PAR is transferred into breast milk and crosses the blood-placental barrier, being present in the progeny during important stages of development. Intrauterine exposure to PAR may decrease the anogenital distance and follicle reserve in female rodent offspring. Therefore, the aim of the present study was to evaluate whether maternal PAR treatment altered the reproductive behaviour of dams and the sexual development of female rat offspring. Pregnant Wistar rats were gavaged daily with 350mg kg-1 day-1 PAR or water during gestation (from Gestation Day (GD) 6 until delivery) or during gestation and lactation (from GD6 until weaning). Maternal PAR treatment had maternal effects (increased grooming behaviour), and resulted in impaired sexual behaviour, decreased follicle reserve and increased plasma oestradiol concentrations in female offspring.

Lowered Antioxidant Defenses and Increased Oxidative Toxicity Are Hallmarks of Deficit Schizophrenia: a Nomothetic Network Psychiatry Approach.

There is now evidence that schizophrenia and deficit schizophrenia are neuro-immune conditions and that oxidative stress toxicity (OSTOX) may play a pathophysiological role. Aims of the study: to compare OSTOX biomarkers and antioxidant (ANTIOX) defenses in deficit versus non-deficit schizophrenia. We examined lipid hydroperoxides (LOOH), malondialdehyde (MDA), advanced oxidation protein products (AOPP), sulfhydryl (-SH) groups, paraoxonase 1 (PON1) activity and PON1 Q192R genotypes, and total radical-trapping antioxidant parameter (TRAP) as well as immune biomarkers in patients with deficit (n = 40) and non-deficit (n = 40) schizophrenia and healthy controls (n = 40). Deficit schizophrenia is characterized by significantly increased levels of AOPP and lowered -SH, and PON1 activity, while no changes in the OSTOX/ANTIOX biomarkers were found in non-deficit schizophrenia. An increased OSTOX/ANTIOX ratio was significantly associated with deficit versus non-deficit schizophrenia (odds ratio = 3.15, p < 0.001). Partial least squares analysis showed that 47.6% of the variance in a latent vector extracted from psychosis, excitation, hostility, mannerism, negative symptoms, psychomotor retardation, formal thought disorders, and neurocognitive test scores was explained by LOOH+AOPP, PON1 genotype + activity, CCL11, tumor necrosis factor (TNF)-α, and IgA responses to neurotoxic tryptophan catabolites (TRYCATs), whereas -SH groups and IgM responses to MDA showed indirect effects mediated by OSTOX and neuro-immune biomarkers. When overall severity of schizophrenia increases, multiple immune and oxidative (especially protein oxidation indicating chlorinative stress) neurotoxicities and impairments in immune-protective resilience become more prominent and shape a distinct nosological entity, namely deficit schizophrenia. The nomothetic network psychiatry approach allows building causal-pathway-phenotype models using machine learning techniques.

The role of immune and oxidative pathways in menstrual cycle associated depressive, physio-somatic, breast and anxiety symptoms: Modulation by sex hormones.

OBJECTIVE: To examine whether 1) immune and nitro-oxidative stress (IO&NS) biomarkers are associated with premenstrual syndrome (PMS); and 2) changes in IO&NS biomarkers during the menstrual cycle (MC) are associated with PMS symptoms and plasma estradiol and progesterone. METHODS: This longitudinal study examined 41 women who completed the Daily Record of Severity of Problems (DRSP) rating scale during 28 consecutive days and assayed plasma levels of complement C3 and C4, highly sensitive C-reactive protein (hsCRP), haptoglobin (Hp), advanced oxidation protein products (AOPP), lipid hydroperoxides (LOOH), nitric oxide metabolites (NOx), total radical-trapping antioxidant parameter (TRAP), sulfhydryl (-SH) groups and the activity of paraoxonase (PON)1 at days 7 (D7), 14 (D14), 21 (D21) and 28 (D28) of the MC. MC Associated Syndrome (MCAS) was diagnosed when the summed DRSP score during the MC is >0.666 percentile. RESULTS: All biomarkers, except hsCRP, showed significant alterations during the MC. Arylesterase (AREase) was lowered at D28, while LOOH increased at D14 and C4 at D21 in MCAS. Total DRSP scores were predicted by the combined effects of C4 (positively) and AREase and malondialdehyde (MDA) (both inversely associated). Progesterone lowered levels of LOOH, AOPP and C3 and estradiol lowered levels of Hp while both sex hormones increased 4-(chloromethyl)phenyl acetate (CMPA)ase and AREase activities and levels of -SH groups. CONCLUSION: PMS/MCAS is not accompanied by a peripheral inflammatory response. Lowered MDA and antioxidant defenses and increased C4 may play a role in MC symptoms while sex hormones may have a protective effect against oxidative stress toxicity.

Increased Levels of Plasma Tumor Necrosis Factor-α Mediate Schizophrenia Symptom Dimensions and Neurocognitive Impairments and Are Inversely Associated with Natural IgM Directed to Malondialdehyde and Paraoxonase 1 Activity.

Accumulating evidence suggests that TNF-α-mediated immune-neurotoxicity contributes to cognitive impairments and the overall severity of schizophrenia (OSOS). There are no data whether peripheral IL-6 and IL-4 may affect the phenome of schizophrenia above and beyond the effects of TNF-α and whether those cytokines are regulated by lowered natural IgM to malondialdehyde (MDA) and paraoxonase 1 enzyme activity. We assessed the aforementioned biomarkers in a cross-sectional study that enrolled schizophrenia patients with (n = 40) and without (n = 40) deficit schizophrenia and 40 healthy controls. Deficit schizophrenia was best predicted by a combination of increased IL-6 and PON1 status (QQ genotype and lowered CMPAase activity) and lowered IgM to MDA. Partial least squares bootstrapping shows that 41.0% of the variance in negative symptoms, psychosis, hostility, excitation, mannerism, psychomotor retardation, and formal thought disorders was explained by increased TNF-α and PON1 status (QQ genotype and lowered CMPAase activity), which lowered IL-4 and IgM to MDA as well as male sex and lowered education. We found that 47.9% of the variance in verbal fluency, word list memory, true recall, Mini-Mental State Examination, and executive functions was predicted by increased TNF-α and lowered IL-4, IgM to MDA, and education. In addition, both TNF-α and IL-4 levels were significantly associated with lowered IgM to MDA, while TNF-α was correlated with PON1 status. These data provide evidence that the symptomatic (both the deficit subtype and OSOS) and cognitive impairments in schizophrenia are to a large extent mediated by the effects of immune-mediated neurotoxicity as well as lowered regulation by the innate immune system.

Schizophrenia phenomenology comprises a bifactorial general severity and a single-group factor, which are differently associated with neurotoxic immune and immune-regulatory pathways.

In schizophrenia, a single latent trait underlies psychosis, hostility, excitation, mannerism, negative (PHEMN) symptoms, formal thought disorders (FTD) and psychomotor retardation (PMR). Schizophrenia is accompanied by a breakdown of gut and blood-brain-barrier (BBB) pathways, increased tryptophan catabolite (TRYCAT) levels, bacterial translocation, and lowered natural IgM and paraoxonase (PON)1 activity. The aim of this study was to examine the factor structure of schizophrenia symptom domains and the biomarker correlates of these factors. We recruited 80 patients with schizophrenia and 40 healthy subjects and assessed the IgA/IgM responses to paracellular/transcellular (PARA/TRANS) ratios, IgA responses to TRYCATs, natural IgM to malondialdehyde and Gram-negative bacteria, and PON1 enzymatic activity. Direct Hierarchical Exploratory Factor Analysis showed a bifactorial oblique model with a) a general factor which loaded highly on all symptom domains, named overall severity of schizophrenia ("OSOS"); and b) a single-group factor (SGF) loading on negative symptoms and PMR. We found that 40% of the variance in OSOS score was explained by IgA/IgM to PARA/TRANS ratio, male sex and education while 36.9% of the variance in SGF score was explained by IgA to PARA/TRANS, IgM to Gram-negative bacteria, female sex (positively associated) and IgM to MDA, and PON1 activity (negatively associated). Schizophrenia phenomenology comprises two biologically-validated dimensions, namely a general OSOS dimension and a single-group negative symptom dimension, which are associated with a breakdown of gut/BBB barriers, increased bacterial translocation and lowered protection against oxidation, inflammation and bacterial infections through lowered PON1 and natural IgM.

Maternal exposure to fluoxetine during gestation and lactation does not alter plasma concentrations of testosterone, oestrogen or corticosterone in peripubertal offspring.

Antidepressants are widely used around the world, primarily for the treatment of mood disorders, anxiety and pain syndromes. Women who use antidepressants often continue to use them during pregnancy. Selective serotonin reuptake inhibitors, including fluoxetine, are the main class of antidepressants prescribed to pregnant women. It is known that fluoxetine crosses the placental-blood barrier and is excreted in breast milk. Consequently, indirect exposure of the infant occurs. Knowing that fluoxetine alters the balance of neurotransmitters in the central nervous system, several studies have shown that maternal exposure to this drug leads to various adverse effects on the nervous, reproductive and cardiovascular systems of the offspring. The aim of the present study was to evaluate the effects of exposure to fluoxetine during gestation and lactation on parameters related to steroid hormones in prepubertal and pubertal male and female rats. The endpoints evaluated were date of puberty onset, plasma testosterone and oestrogen concentrations before and after puberty onset and corticosterone concentration before and after adrenocorticotrophin stimulus. None of the parameters was affected by fluoxetine exposure.

Intrauterine and lactational exposure to fluoxetine enhances endothelial modulation of aortic contractile response in adult female rats.

The study aimed to evaluate if maternal exposure to fluoxetine (FLX) during pregnancy and lactation would result in altered aortic reactivity in adult offspring. We also sought to understand the role of endothelium derived relaxing factors in aortic response. Wistar rats (75­80 days old), whose progenitors had received FLX (5 mg/kg, FLX offspring) or tap water (control offspring) during pregnancy and lactation were anesthetized, after which the aorta was removed and cut into two rings, one with (Endo+) and the other without (Endo-) endothelium. Concentration-effect curves for acetylcholine (ACh), sodium nitroprusside (SNP), and phenylephrine (Phe) were performed. The vasodilation to ACh and SNP was similar between control and FLX groups in both male and female offspring. In male rats, the response to Phe was similar between the FLX and control groups on Endo+ and Endo- rings. The response to Phe was reduced on Endo+ rings from female FLX when compared with the control group. The endothelium removal, as well as L-NAME, indomethacin, and tranylcypromine incubation corrected the reduced Phe-induced contraction in the aorta from the female FLX group. On the other hand, catalase, NS-398, and L-NIL did not interfere with the vasoconstriction. The aortic level of nitric oxide (NO) was higher in the female FLX than the control group. Although endothelial NO synthase isoform and cyclooxygenase (COX)-1 expressions were similar between the groups, there was a notable increment in neuronal NO synthase expression in the aorta of FLX-exposed female rats, suggesting an important role of this enzyme in the higher levels of NO. Our results show that developmental exposure to FLX causes sex-specific alteration in aortic function through a mechanism involving endothelial factors, probably NO and COX-1 products.

Intrauterine and lactation exposure to fluoxetine blunted in the offspring the aortic adaptive response induced by acute restraint stress.

Selective serotonin reuptake inhibitors are the most widely prescribed antidepressants to women during pregnancy. Maternal treatment with fluoxetine can expose fetuses and neonates to higher levels of serotonin that plays a role in stress response. Thus, the aim of the study was to evaluate whether maternal treatment with fluoxetine interferes with aorta reactivity of adult male offspring after acute restraint stress. Wistar rats were gavaged with fluoxetine (5mg/kg/day) or water (control) during pregnancy and lactation. The experiments were performed in adult male offspring, treated or not with reserpine (4mg/Kg, ip, 28h before the experimental protocol). Fluoxetine and control rats were submitted to a single restraint stress session (ST) for 1h. Curves to phenylephrine were performed in thoracic aorta with endothelium. Aortic nitric oxide (NOx) were evaluated by the Griess method. The aortic contraction induced by phenylephrine was similar between control and fluoxetine rats. The acute stress reduced contraction in aorta of control ST compared to control, and L-NAME equaled this response. In fluoxetine rats, ST did not change the aortic constriction. Reserpine treatment restored the vasoconstriction in control ST, but did not interfere with aortic contraction in control, fluoxetine or fluoxetine ST. The NOx concentration was higher in aortas from control ST than control rats, and reserpine reduced NOx levels of control ST. The NOx concentration was similar between fluoxetine and fluoxetine ST rats, treated or not with reserpine. In conclusion, maternal treatment with fluoxetine blunted acute restraint stress-induced NO system activation and aortic adaptation in adult offspring.

Does fish oil or folic acid prevent vascular changes in female progeny caused by maternal exposure to fluoxetine?

AIMS: Fluoxetine (FLX) is an antidepressant worldwide prescribed throughout life stages, including pregnancy and breastfeeding. Out of pregnancy, the combination of FLX with fish oil (FO) and folic acid (FA) is carried to enhance the therapeutic activity and reduce the side effects of the antidepressant. During pregnancy, FO and FA have been used to promote fetal development, and reduce, in mother, the risk of gestational and post-pregnancy depression. To evaluate if maternal exposure during pregnancy and lactation to FLX associated with FO or FA would prevent the antidepressant side effects in aorta reactivity and nitric oxide metabolites (NOx) plasmatic levels. We also sought to understand, in female offspring, the vascular effects of intrauterine and lactation exposure to FO and FA monotherapy. MAIN METHODS: Wistar rats were treated with water (control group), FLX (5mg/kg/day), FO (1.3g/kg/day), FA (3mg/kg/day), FLX+FO and FLX+FA, throughout pregnancy and lactation. On adulthood, in female offspring were evaluated the vascular reactivity to phenylephrine (Phe), the NOx and homocysteine (HCY) plasmatic levels. KEY FINDINGS: The developmental exposure to the associations of FO or FA with FLX did not correct the aortic hyporreactivity and increased NOx levels induced by intrauterine and lactation exposure to FLX. Also, isolated exposure to FO and FA did not interfere with Phe-induced aortic contraction and neither interferes with NOx and HCY plasmatic levels. SIGNIFICANCE: The developmental exposure to FO and FA was safe for vascular function of female offspring but did not prevent the vascular effects of FLX-exposure.

Acute stress affects the global DNA methylation profile in rat brain: modulation by physical exercise.

The vulnerability of epigenetic marks of brain cells to environmental stimuli and its implication for health have been recently debated. Thus, we used the rat model of acute restraint stress (ARS) to evaluate the impact of stress on the global DNA methylation and on the expression of the Dnmt1 and Bdnf genes of hippocampus, cortex, hypothalamus and periaqueductal gray (PAG). Furthermore, we verified the potential of physical exercise to modulate epigenetic responses evoked by ARS. Sedentary male Wistar rats were submitted to ARS at the 75th postnatal day (PND), whereas animals from a physically active group were previously submitted to swimming sessions (35-74th PND) and to ARS at the 75th PND. Global DNA methylation profile was quantified using an ELISA-based method and the quantitative expression of the Dnmt1 and Bdnf genes was evaluated by real-time PCR. ARS induced a decrease in global DNA methylation in hippocampus, cortex and PAG of sedentary animals and an increased expression of Bdnf in PAG. No change in DNA methylation was associated with ARS in the exercised animals, although it was associated with abnormal expression of Dnmt1 and Bdnf in cortex, hypothalamus and PAG. Our data reveal that ARS evokes adaptive changes in global DNA methylation of rat brain that are independent of the expression of the Dnmt1 gene but might be linked to abnormal expression of the Bdnf gene in the PAG. Furthermore, our evidence indicates that physical exercise has the potential to modulate changes in DNA methylation and gene expression consequent to ARS.

The Ehrlich tumor induces pain-like behavior in mice: a novel model of cancer pain for pathophysiological studies and pharmacological screening.

The Ehrlich tumor is a mammary adenocarcinoma of mice that can be developed in solid and ascitic forms depending on its administration in tissues or cavities, respectively. The present study investigates whether the subcutaneous plantar administration of the Ehrlich tumor cells induces pain-like behavior and initial pharmacological susceptibility characteristics. The Ehrlich tumor cells (1 × 10(4)-10(7) cells) induced dose-dependent mechanical hyperalgesia (electronic version of the von Frey filaments), paw edema/tumor growth (caliper), and flinches compared with the saline group between days 2 and 12. There was no difference between doses of cells regarding thermal hyperalgesia in the hot-plate test. Indomethacin (a cyclooxygenase inhibitor) and amitriptyline hydrochloride (a tricyclic antidepressant) treatments did not affect flinches or thermal and mechanical hyperalgesia. On the other hand, morphine (an opioid) inhibited the flinch behavior and the thermal and mechanical hyperalgesia. These effects of morphine on pain-like behavior were prevented by naloxone (an opioid receptor antagonist) treatment. None of the treatments affected paw edema/tumor growth. The results showed that, in addition to tumor growth, administration of the Ehrlich tumor cells may represent a novel model for the study of cancer pain, specially the pain that is susceptible to treatment with opioids, but not to cyclooxygenase inhibitor or to tricyclic antidepressant.

Developmental exposure to Passiflora incarnata induces behavioural alterations in the male progeny.

Passiflora incarnata is marketed in many countries as a phytomedicine and is prescribed mainly as a sedative and anxiolytic. Even though the directions of most marketed phytomedicines recommend them to be used under medical supervision, reproductive and developmental studies are sparse and not mandatory for regulatory purposes. To evaluate the reproductive and developmental toxicity of P. incarnata, Wistar female rats were gavaged with 30 or 300 mg kg(-1) of this herb from gestational Day (GD) 0 to postnatal Day (PND) 21. P. incarnata treatment did not influence dams' bodyweight or food intake or their reproductive performance (post-implantation loss, litter size, litter weight). There was also no influence on the physical development of pups (bodyweight gain, day of vaginal opening or preputial separation) or their behaviour in the open-field at PND 22, 35 and 75. Sexual behaviour was disrupted in adult male pups exposed to 300 mg kg(-1) of P. incarnata; in this group, only 3 out of 11 pups were sexually competent. This behavioural disruption was not accompanied by alterations in plasma testosterone levels, reproductive-related organs and glands weights or sperm count. It is hypothesised that aromatase inhibition may be involved in the observed effect.

Herbs of interest to the Brazilian Federal Government: female reproductive and developmental toxicity studies

In 2009 the Brazilian Ministry of Health published a document named RENISUS that lists 71 herbs traditionally used in Brazil that could result in phytomedicines to be dispensed by the governmental health care program. This manuscript reviews female reproductive and/or developmental toxicity information of these herbs. More than half (35) of the herbs lack information regarding female reproductive and/or developmental effects. From the fourteen herbs used traditionally to disturb female reproduction, five present experimental data corroborating their actions as abortifacients (Maytenus ilicifolia, Momordica charantia, Plectranthus barbatus, Ruta graveolens) or labour facilitator (Bidens pilosa). For 23 of the herbs evaluated experimentally for any type of female reproductive endpoint, only a single study was retrieved and at least twelve of these studies were conducted with a single dose. This scenario suggests that the scientific power of the published information is very low and that a scientifically-based risk/benefit analysis about the use of these herbs during pregnancy is not possible. Considering the appeal that phytomedicines have for pregnant women, usually aware and afraid of the risks that synthetic drugs may have in their pregnancy and progeny, well designed studies evaluating reproductive and/or developmental toxicity of these herbs urge.