N-Acetylcysteine Attenuates Cisplatin Toxicity in the Cerebrum and Lung of Young Rats with Artificially Induced Protein Deficiency.

Neurotoxicity is a major obstacle in the effectiveness of Cisplatin in cancer chemotherapy. In this process, oxidative stress and inflammation are considered to be the main mechanisms involved in brain and lung toxicity. The aim of the present work was to study the influence of the amount of protein on some oxidative parameters in the brain and lungs of rats treated with Cisplatin (CP) and N-Acetylcysteine (NAC) as neuroprotectors. Four groups of Wistar rats, each containing six animals, were fed with a protein diet at 7% for 15 days. Thereafter, the groups were given either a unique dose of CP® 5 mg/kg or NAC® 5 mg/kg as follows: group 1 (control), NaCl 0.9% vehicle; group 2, CP; group 3, NAC; and group 4, NAC + CP. The animals were sacrificed immediately after the treatments. Blood samples were collected upon sacrifice and used to measure blood triglycerides and glucose. The brain and lungs of each animal were obtained and used to assay lipid peroxidation (TBARS), glutathione (GSH), serotonin metabolite (5-HIAA), catalase, and the activity of Ca+2, and Mg+2 ATPase using validated methods. TBARS, H2O2, and GSH were found to be significantly decreased in the cortex and cerebellum/medulla oblongata of the groups treated with CP and NAC. The total ATPase showed a significant increase in the lung and cerebellum/medulla oblongata, while 5-HIAA showed the same tendency in the cortex of the same group of animals. The increase in 5-HIAA and ATPase during NAC and CP administration resulted in brain protection. This effect could be even more powerful when membrane fluidity is increased, thus proving the efficacy of combined NAC and CP drug therapy, which appears to be a promising strategy for future chemotherapy in malnourished patients.

NEDD4-1 deficiency impairs satellite cell function during skeletal muscle regeneration.

BACKGROUND: Satellite cells are tissue-specific stem cells primarily responsible for the regenerative capacity of skeletal muscle. Satellite cell function and maintenance are regulated by extrinsic and intrinsic mechanisms, including the ubiquitin-proteasome system, which is key for maintaining protein homeostasis. In this context, it has been shown that ubiquitin-ligase NEDD4-1 targets the transcription factor PAX7 for proteasome-dependent degradation, promoting muscle differentiation in vitro. Nonetheless, whether NEDD4-1 is required for satellite cell function in regenerating muscle remains to be determined. RESULTS: Using conditional gene ablation, we show that NEDD4-1 loss, specifically in the satellite cell population, impairs muscle regeneration resulting in a significant reduction of whole-muscle size. At the cellular level, NEDD4-1-null muscle progenitors exhibit a significant decrease in the ability to proliferate and differentiate, contributing to the formation of myofibers with reduced diameter. CONCLUSIONS: These results indicate that NEDD4-1 expression is critical for proper muscle regeneration in vivo and suggest that it may control satellite cell function at multiple levels.

Cholic and deoxycholic acids induce mitochondrial dysfunction, impaired biogenesis and autophagic flux in skeletal muscle cells.

BACKGROUND: Skeletal muscle is sensitive to bile acids (BA) because it expresses the TGR5 receptor for BA. Cholic (CA) and deoxycholic (DCA) acids induce a sarcopenia-like phenotype through TGR5-dependent mechanisms. Besides, a mouse model of cholestasis-induced sarcopenia was characterised by increased levels of serum BA and muscle weakness, alterations that are dependent on TGR5 expression. Mitochondrial alterations, such as decreased mitochondrial potential and oxygen consumption rate (OCR), increased mitochondrial reactive oxygen species (mtROS) and unbalanced biogenesis and mitophagy, have not been studied in BA-induced sarcopenia. METHODS: We evaluated the effects of DCA and CA on mitochondrial alterations in C2C12 myotubes and a mouse model of cholestasis-induced sarcopenia. We measured mitochondrial mass by TOM20 levels and mitochondrial DNA; ultrastructural alterations by transmission electronic microscopy; mitochondrial biogenesis by PGC-1α plasmid reporter activity and protein levels by western blot analysis; mitophagy by the co-localisation of the MitoTracker and LysoTracker fluorescent probes; mitochondrial potential by detecting the TMRE probe signal; protein levels of OXPHOS complexes and LC3B by western blot analysis; OCR by Seahorse measures; and mtROS by MitoSOX probe signals. RESULTS: DCA and CA caused a reduction in mitochondrial mass and decreased mitochondrial biogenesis. Interestingly, DCA and CA increased LC3II/LC3I ratio and decreased autophagic flux concordant with raised mitophagosome-like structures. In addition, DCA and CA decreased mitochondrial potential and reduced protein levels in OXPHOS complexes I and II. The results also demonstrated that DCA and CA decreased basal, ATP-linked, FCCP-induced maximal respiration and spare OCR. DCA and CA also reduced the number of cristae. In addition, DCA and CA increased the mtROS. In mice with cholestasis-induced sarcopenia, TOM20, OXPHOS complexes I, II and III, and OCR were diminished. Interestingly, the OCR and OXPHOS complexes were correlated with muscle strength and bile acid levels. CONCLUSION: Our results showed that DCA and CA decreased mitochondrial mass, possibly by reducing mitochondrial biogenesis, which affects mitochondrial function, thereby altering potential OCR and mtROS generation. Some mitochondrial alterations were also observed in a mouse model of cholestasis-induced sarcopenia characterised by increased levels of BA, such as DCA and CA.

Inflammatory Process and Immune System in Major Depressive Disorder.

Major depressive disorder (MDD) is one of the most common psychiatric illnesses in the general population. In mental disorders, the activation of inflammatory pathways in the brain is a major producer of excitotoxicity and an inducer of oxidative stress. The occurrence of these 2 events is partly responsible for the neuronal damage inherent in patients with mental disorders. In the case of MDD, the release of hormone and increase in pro-inflammatory cytokines in plasma and indicators of oxidative stress have been identified as consequences of this event. The most important affectations in patients with MDD are changes in their cognitive and executive functions due to brain inflammation. Hence, these biomarkers can serve as diagnostic and severity classification tools and treatment. In this work, we described the communication pathway between the immune and neuroendocrine systems in MDD and suggested possible therapeutic options for the disease.

Oseltamivir induces favorable response on oxidative damage in the brain of rats treated with Bezafibrate.

AIM: The purpose was to measure the effect of Oseltamivir on oxidative biomarkers and dopaminergic and serotonergic systems in brain of rats with induced hypotriglyceridemia by Bezafibrate.Male young Wistar rats were treated as follows: group 1, NaCl 0.9%, (Controls); group 2, Oseltamivir (100 mg/kg); group 3, single dose of Bezafibrate (150 mg/kg); group 4, four dose of Bezafibrate; group 5, single dose of Bezafibrate + Oseltamivir and group 6, four doses of Bezafibrate + Oseltamivir. Drugs were given orally. Triglycerides, Dopamine, 5-hydroxyindoleacetic acid (5-HIAA), Glutathione (GSH), Hydrogen peroxide (H2O2), lipid peroxidation, as well as total ATPase activity were measured using validated methods. RESULTS: Oseltamivir treated animals showed lower GSH and lipid peroxidation levels and an increment in 5-HIAA in the three evaluated brain regions. Treatment with Oseltamivir also reduces H2O2 in the cortex and cerebellum/medulla oblongata. ATPase enzyme increased in these regions in the groups that were administered with Bezafibrate in repeated doses and in combination with Oseltamivir in single dose. Dopamine concentrations decreased in groups treated with Oseltamivir in the three evaluated regions. Also, there was a decrease in dopamine concentrations in the cerebellum/medulla oblongata of the animals treated with the combination of Oseltamivir and Bezafibrate.Innovation and conclusion: Animals with bezafibrate induced hypo-triglyceridemia that received Oseltamivir, either in single or repeated doses, have a higher improvement of their antioxidant activity and also experienced changes in the dopaminergic and serotonergic system in their brain, intending establish the beneficial of joint administration of both drugs in obese patients.

A 20-year retrospective study of osteoarticular tuberculosis in a pediatric third level referral center.

PURPOSE: The objective of the present study is to describe the clinical, diagnostic, radiological and therapeutic aspects of osteoarticular tuberculosis (OATB) in patients in a tertiary pediatric hospital, to know if the diagnosis of OATB in pediatrics is a challenge due to its insidious clinical presentation. METHODS: A retrospective, descriptive study of the cases of Tuberculosis (TB) in children was carried out. A total of 159 cases met the condition for the analysis. RESULTS: The most frequent TB modality was extrapulmonary in 85%. Out of this, only 29% was OATB. The mean age was 4.9 years (range 8 months-16 years). Eighty-six per cent of cases received Bacille Calmette-Guérin (BCG) vaccination at birth. Median time of symptoms prior to diagnosis was 8 months. Microbiological confirmation was achieved only in five cases, with a high sensitivity to the antimicrobial treatment. Mycobacterium bovis BCG strain Tokio 172 was confirmed in three cases. Mortality rate was 0% during the time of study CONCLUSION: Our study describes the epidemiological characteristics of OATB cases in Mexican children. This data revealed a high prevalence of bone and joint TB infection. Pediatric OATB should be considered in cases with lytic bone lesions, fever and local pain. In countries with BCG immunization program, M. bovis should not be forgotten as an etiological agent. The low detection rate with one technique approach highlights the urgent need for more sensitive test to diagnose OATB in children.

Co-infection with Streptococcus anginosus and Mycobacterium tuberculosis in an immunocompetent pediatric patient. A case report.

BACKGROUND: Simultaneous infection in tuberculosis (TB) is rare. The mixed infection between Streptococcus anginosus group (SAG) and M. tuberculosis (MTB) has not been reported in children. The aim of this report was to describe a pediatric case with a pulmonary abscess caused by the duality SAG-MTB co-infection. CASE PRESENTATION: An 11-year-old boy with an acute onset of throbbing pain of two-day evolution located in the anterior chest wall. The patient reported a history of fever, cough and rhinorrhea during the last seven days. An anterior chest radiography revealed a heterogenic opacity at the lower right lobe while the lateral projection showed an obliteration at the anterior diaphragmatic insertion. Parenteral Ceftriaxone (100 mg/kg/day) and Dicloxacillin (200 mg/kg/day) was started. The abscess was subsequently drained and analyzed. After a year of follow-up, the patient remained asymptomatic. CONCLUSION: This case represents the first reported case of pulmonary co-infection involving MTB and SAG in an immunocompetent pediatric patient.

The Use of Trace and Essential Elements in Common Clinical Disorders: Roles in Assessment of Health and Oxidative Stress Status.

During the early life, the diet of infants is mainly dominated by milk. Milk is a natural food rich in trace elements focus on essential elements. These elements are very necessary for human metabolism and since they cannot be synthesized by the body, the only source available for the humans to obtain them is by ingestion of natural food. This mini-review aims at updating the knowledge on trace elements, outlining their natural food sources, and their possible implications in common clinical disorders in early and adult life. However, it was found that consumption of food with micronutrients and trace elements may release intracellular compounds and offer oxidative protection or exacerbate oxidative damage to metabolically compromised cells.

Riboflavin and pyridoxine restore dopamine levels and reduce oxidative stress in brain of rats.

BACKGROUND: Neurological disorders suggest that the excitotoxicity involves a drastic increase in intracellular Ca2+ concentrations and the formation of reactive oxygen species. The presence of these free radicals may also affect the dopaminergic system. The aim of this work was to determine if riboflavin (B2) and pyridoxine (B6) provide protection to the brain against free radicals generated by 3-nitropropionic acid (3-NPA) by measuring the levels of dopamine (DA) and selected oxidative stress markers. METHODS: Male Fisher rats were grouped (n = 6) and treated as follows: group 1, control (NaCl 0.9%); group 2, 3-NPA (20 mg/kg); group 3, B2 (10 mg/kg); group 4, B2 (10 mg/kg) + 3-NPA (20 mg/kg); group 5, B6 (10 mg/kg) and group 6, B6 + 3-NPA. All treatments were administered every 24 h for 5 days by intraperitoneal route. After sacrifice, the brain was obtained to measure DA, GSH, and lipid peroxidation, Ca2+, Mg2+, ATPase and H2O2. MAIN FINDINGS: Levels of dopamine increased in cortex, striatum and cerebellum/medulla oblongata of animals that received 3-NPA alone. The lipid peroxidation increased in cortex, striatum, and cerebellum/medulla oblongata, of animals treated with B2 vitamin alone. ATPase dependent on Ca+2, Mg+2 and H2O2 increased in all regions of animals that received 3-NPA alone. CONCLUSION: The results confirm the capacity of 3-NPA to generate oxidative stress. Besides, the study suggests that B2 or B6 vitamins restored the levels of DA and reduced oxidative stress in brain of rats. We believe that these results would help in the study of neurodegenerative diseases.

ß-Cyclodextrin and oleic acid increase levels of dopamine and potentiates oxidative damage in young and adult rat brain.

BACKGROUND: Cyclodextrins are active pharmaceutical ingredients to treat neurological diseases by reducing neurotoxicity. The aim of this study was to test if combined consumption of ß-cyclodextrin (BCD) and Oleic acid (OA) potentiates brain antioxidant protection. METHODS: Four groups of young Wistar rats, grouped in 6 animals each, were treated as follows: Group (G) 1, saline solution 0.9% (control); G2, BCD (0.7 g/kg); G3, OA (15 ml/kg); G4, BCD + OA. The same design was assayed for groups of adult rats. Treatments were daily administered by oral means for five consecutive days. On the last day of administration, brains of the animals were extracted to measure dopamine, 5-HIAA, glutathione (GSH), ATPase, Lipoperoxidation and H2O2. RESULTS: Oleic acid and ß-cyclodextrin upgraded the levels of dopamine, 5-HIAA and lipid peroxidation and downgraded the concentrations of GSH and H2O2 in cortex, hemispheres (striatum) and cerebellum/medulla oblongata regions. CONCLUSIONS: The results of the present study suggest that combined use of oleic acid and ß-cyclodextrin may increase oxidative damage in brain regions and promote alteration in dopamine and 5-HIAA amines and hence, constitutes health risks among age of subjects.

Restoration of muscle strength in dystrophic muscle by angiotensin-1-7 through inhibition of TGF-ß signalling.

Duchenne muscular dystrophy (DMD) is the most common inherited neuromuscular disease, and is characterized by the lack of dystrophin, muscle wasting, increased transforming growth factor (TGF)-ß Smad-dependent signalling and fibrosis. Acting via the Mas receptor, angiotensin-1-7 [Ang-(1-7)], is part of the renin-angiotensin system, with the opposite effect to that of angiotensin II. We hypothesized that the Ang-(1-7)/Mas receptor axis might protect chronically damaged tissues as in skeletal muscle of the DMD mouse model mdx. Infusion or oral administration of Ang-(1-7) in mdx mice normalized skeletal muscle architecture, decreased local fibrosis and improved muscle function in vitro and in vivo. These positive effects were mediated by the inhibition of TGF-ß Smad signalling, which in turn led to reduction of the pro-fibrotic microRNA miR-21 concomitant with a reduction in the number of TCF4 expressing fibroblasts. Mdx mice infused with Mas antagonist (A-779) and mdx deficient for the Mas receptor showed highly deteriorated muscular architecture, increased fibrosis and TGF-ß signalling with diminished muscle strength. These results suggest that this novel compound Ang-(1-7) might be used to improve quality of life and delay death in individuals with DMD and this drug should be investigated in further pre-clinical trials.

Connective tissue cells expressing fibro/adipogenic progenitor markers increase under chronic damage: relevance in fibroblast-myofibroblast differentiation and skeletal muscle fibrosis.

Fibrosis occurs in skeletal muscle under various pathophysiological conditions such as Duchenne muscular dystrophy (DMD), a devastating disease characterized by fiber degeneration that results in progressive loss of muscle mass, weakness and increased extracellular matrix (ECM) accumulation. Fibrosis is also observed after skeletal muscle denervation and repeated cycles of damage followed by regeneration. The ECM is synthesized largely by fibroblasts in the muscle connective tissue under normal conditions. Myofibroblasts, cells that express α-smooth muscle actin (α-SMA), play a role in many tissues affected by fibrosis. In skeletal muscle, fibro/adipogenic progenitors (FAPs) that express cell-surface platelet-derived growth factor receptor-α (PDGFR-α) and the transcription factor Tcf4 seem to be responsible for connective tissue synthesis and are good candidates for the origin of myofibroblasts. We show that cells positive for Tcf4 and PDGFR-α are expressed in skeletal muscle under normal conditions and are increased in various skeletal muscles of mdx mice, a murine model for DMD, wild type muscle after sciatic denervation and muscle subjected to chronic damage. These cells co-label with the myofibroblast marker α-SMA in dystrophic muscle but not in normal tissue. The Tcf4-positive cells lie near macrophages mainly concentrated in dystrophic necrotic-regenerating foci. The close proximity of Tcf4-positive cells to inflammatory cells and their previously described role in muscle regeneration might reflect an active interaction between these cell types and growth factors, possibly resulting in a muscular regenerative or fibrotic condition.

NEDD4 Regulates PAX7 Levels Promoting Activation of the Differentiation Program in Skeletal Muscle Precursors.

The transcription factor Pax7 regulates skeletal muscle stem cell (satellite cells) specification and maintenance through various mechanisms, including repressing the activity of the muscle regulatory factor MyoD. Hence, Pax7-to-MyoD protein ratios can determine maintenance of the committed-undifferentiated state or activation of the differentiation program. Pax7 expression decreases sharply in differentiating myoblasts but is maintained in cells (re)acquiring quiescence, yet the mechanisms regulating Pax7 levels based on differentiation status are not well understood. Here we show that Pax7 levels are directly regulated by the ubiquitin-ligase Nedd4. Our results indicate that Nedd4 is expressed in quiescent and activated satellite cells, that Nedd4 and Pax7 physically interact during early muscle differentiation-correlating with Pax7 ubiquitination and decline-and that Nedd4 loss of function prevented this effect. Furthermore, even transient nuclear accumulation of Nedd4 induced a drop in Pax7 levels and precocious muscle differentiation. Consequently, we propose that Nedd4 functions as a novel Pax7 regulator, which activity is temporally and spatially controlled to modulate the Pax7 protein levels and therefore satellite cell fate.

Pharmacokinetics of ranitidine in preterm and term neonates with gastroesophageal reflux.

BACKGROUND: The aim of this study was to determine the effect of gestational age on pharmacokinetics of ranitidine in newborns with gastroesophageal reflux. METHODS: A prospective, descriptive and pharmacokinetic study was carried out in 30 pre-term and 20 full-term babies. 3 mg/kg of ranitidine was administered intravenously to all the babies and at 0.25, 0.5, 1, 2, 4, and 8 h following the administration, samples of blood were drawn to assess ranitidine levels using high performance liquid chromatographic technique. RESULTS: Pharmacokinetics of ranitidine had a bi-exponential behavior with a half-life elimination of (t1/2el) 2.79 h, area under curve (AUC) of 1688 ng/mL, volume of distribution (Vd) of 1.44 L/kg, and clearance (Cl) of 5.9 L/kg/h. The median plasmatic concentration in pre-terms was 1113 ng/mL and 280 ng/mL in full-terms. Vd, t1/2 and Cl presented high values in preterm although the correlation of Cl with glomerular filtration in term newborns was better. CONCLUSIONS: Plasma levels of ranitidine depend on the gestational age of the newborns. However, the possible relationship between after-birth age and pharmacokinetics of the neonates as their internal organs get matured without minding their gestational background.

Assessment of the effects of oseltamivir and indomethacin on dopamine, 5-HIAA, and some oxidative stress markers in stomach and brain of Salmonella typhimurium-infected rats.

OBJECTIVES: The purpose of this study was to measure the effect of oseltamivir and indomethacin on dopamine and 5-HIAA levels and some oxidative biomarkers in brain and stomach of young rats in conditions of infection. METHODS: Female Sprague Dawley rats in absence or presence of a live culture of Salmonella typhimurium (S.Typh), were treated as follows: PBS, group 1 (control); oseltamivir (100 mg/kg), group 2; indomethacin (67 µg/kg) group 3; oseltamivir (100 mg/kg) + indomethacin (67 µg/kg), group 4. The drugs were administered intraperitoneally every 24 hr for 5 days while S. Typh was give orally in the first and third day. C-reactive proteins was measured in blood on sacrifice, and from brain extract, dopamine and 5-HIAA levels as well as GSH, calcium, and H2O2 and total ATPase activity were measured by validated methods. RESULTS: Dopamine increased significantly in cortex and cerebellum/medulla oblongata of groups that received indomethacin and oseltamivir. 5-HIAA increased significantly in all groups that received S.Typh. H2O2 decreased significantly in cortex regions of animals that received oseltamivir and indomethacin in presence of S.Typh. Total ATPase increased significantly in cortex and hemispheres of groups that received oseltamivir as well as in cerebellum/medulla oblongata and stomach of animals that received oseltamivir and indomethacin combined with S.Typh. GSH increased and calcium decreased significantly in stomach of animals that received oseltamivir or indomethacin alone or combined with S.Typh. CONCLUSION: These results demonstrate the association between inflammatory response, oxidative stress, dopaminergic, and serotonergic metabolism in an experimental inflammatory animal model.

Prescription and consumption of solid oral drugs dispensed as unitary doses in a third level hospital.

BACKGROUND: The knowledge about the pattern of prescription and consumption of solid oral drugs dispensed as unitary doses (UD) in Mexico is sparing. PURPOSE: The aim of this study was to describe the pattern of prescription and consumption of solid oral drugs dispensed as unitary doses (UD) in a third level private hospital of Mexico. A retrospective study of a 60-month period (from 2007 to 2011) was carried out to know the pattern of drugs dispensed as UD in a third level hospital. RESULTS: Among the principal drugs consumed were analgesic, antihypertensive, antibiotic, anti-inflammatory, antiepileptic, and diuretics. The dispensation of drugs per year was as follows: 181 drugs with 85,167 UD in 2007; 199 with 90,519 UD in 2008; 193 with 101,479 UD in 2009; 195 with 100,798 UD in 2010; and 198 with 103,913 UD in 2011. CONCLUSION: The findings confirmed that prescription and consumption of unitary doses in the hospitalization service increased, and revealed the extensive use of analgesics as the principal prescribed drug in this kind of hospital.

Endotoxin-induced skeletal muscle wasting is prevented by angiotensin-(1-7) through a p38 MAPK-dependent mechanism.

Skeletal muscle atrophy induced during sepsis syndrome produced by endotoxin in the form of LPS (lipopolysaccharide), is a pathological condition characterized by the loss of strength and muscle mass, an increase in MHC (myosin heavy chain) degradation, and an increase in the expression of atrogin-1 and MuRF-1 (muscle-specific RING-finger protein 1), two ubiquitin E3 ligases belonging to the ubiquitin-proteasome system. Ang-(1-7) [Angiotensin-(1-7)], through its Mas receptor, has beneficial effects in skeletal muscle. We evaluated in vivo the role of Ang-(1-7) and Mas receptor on the muscle wasting induced by LPS injection into C57BL/10J mice. In vitro studies were performed in murine C2C12 myotubes and isolated myofibres from EDL (extensor digitorum longus) muscle. In addition, the participation of p38 MAPK (mitogen-activated protein kinase) in the Ang-(1-7) effect on the LPS-induced muscle atrophy was evaluated. Our results show that Ang-(1-7) prevents the decrease in the diameter of myofibres and myotubes, the decrease in muscle strength, the diminution in MHC levels and the induction of atrogin-1 and MuRF-1 expression, all of which are induced by LPS. These effects were reversed by using A779, a Mas antagonist. Ang-(1-7) exerts these anti-atrophic effects at least in part by inhibiting the LPS-dependent activation of p38 MAPK both in vitro and in vivo. We have demonstrated for the first time that Ang-(1-7) counteracts the skeletal muscle atrophy induced by endotoxin through a mechanism dependent on the Mas receptor that involves a decrease in p38 MAPK phosphorylation. The present study indicates that Ang-(1-7) is a novel molecule with a potential therapeutic use to improve muscle wasting during endotoxin-induced sepsis syndrome.

Treatment of pulmonary arterial hypertension using extemporaneous formulation of sildenafil in Mexican children.

Pulmonary arterial hypertension (PAH) is a sickness with high rate of mortality that consists of elevation in pressure of the vessels through which blood flows to the lung. Sildenafil is a therapeutic option for the treatment of PAH in children for the fact that it relaxes the blood vessels and thereby improves pulmonary blood flow. The aim was to analyze the clinical behavior of an extemporaneous formulation of sildenafil as a therapeutic option in children with PAH, twelve children with PAH were studied. The ages and weights of the children ranged from 5 to 15 years and from 13 to 27 kg. All patients received a capsule of 1 mg/kg of sildenafil prepared as extemporaneous formulation in the pharmacology laboratory. Blood levels of sildenafil were analyzed in order to evaluate its availability of developed formulation. Management has derived from physiopathological knowledge and clinical presentations of patients. The mean maximum concentration was 550 ng/ml which is greater than levels reported in adults. Moreover, a therapeutic monitoring of sildenafil was carried out in order to establish an adequate therapeutic range for children and to show that dosages prepared extemporaneously meet the therapeutic needs for the management of PAH. With an average follow-up of once every 2 months, it was found that the evolution of the patients was favorable and without adverse effects that could put their life at risk. The management of PAH with sildenafil prepared as extemporaneous formulation might be considered as a good therapeutic option.

[Pharmacology for the fetus and the newborn]. / Farmacología del feto y el recién nacido.

During intrauterine life, the fetus can be exposed to a series of substances ingested by the mother, some of which are necessary for her health but detrimental to fetus. The noxious effects of such exposure could present immediately after exposure in the fetus or be manifested at the time of delivery and sometimes weeks after birth. The passage of drugs or nutrients across the placenta depends on some physicochemicals that have the ability to cross the placenta barrier, and thus get in contact with the fetus and produce harmful effects. Considering the physicochemical properties of the substances, the possibility of such compounds to cross the placenta barrier and thence to the fetus can be predicted. Equally, it is important to consider the characteristics of the newborn as an immature being, different from adults, when carrying out pharmacokinetic and pharmacodynamic processes. Based on the latter, it is important to know the behavior or characteristics of the fetus and the newborn in the face of drug management and above all consider the advantages and disadvantages of the use of such drugs for the care of a being yet in development, as is described in this work.

Pulmonary tuberculous: Symptoms, diagnosis and treatment. 19-year experience in a third level pediatric hospital.

BACKGROUND: Pulmonary tuberculosis (PTB) is an infectious disease that involves the lungs and can be lethal in many cases. Tuberculosis (TB) in children represents 5 to 20% of the total TB cases. However, there are few updated information on pediatric TB, reason why the objective of the present study is to know the real situation of PTB in the population of children in terms of its diagnosis and treatment in a third level pediatric hospital. METHODS: A retrospective study based on a revision of clinical files of patients less than 18 years old diagnosed with PTB from January 1994 to January 2013 at Instituto Nacional de Pediatria, Mexico City was carried out. A probable diagnosis was based on 3 or more of the following: two or more weeks of cough, fever, tuberculin purified protein derivative (PPD) +, previous TB exposure, suggestive chest X-ray, and favorable response to treatment. Definitive diagnosis was based on positive acid-fast bacilli (AFB) or culture. RESULTS: In the 19-year period of revision, 87 children were diagnosed with PTB; 57 (65.5%) had bacteriologic confirmation with ZN staining or culture positive (in fact, 22 were ZN and culture positive), and 30 (34.5%) had a probable diagnosis; 14(16.1%) were diagnosed with concomitant disease, while 69/81 were immunized. Median evolution time was 21 days (5-150). Fever was found in 94.3%, cough in 77%, and weight loss in 55.2%. History of contact with TB was established in 41.9%. Chest X-ray showed consolidation in 48.3% and mediastinal lymph node in 47.1%. PPD was positive in 59.2%, while positive AFB was found in 51.7% cases. Culture was positive in 24/79 patients (30.4%), PCR in 20/27 (74.1%). 39 (44.8%) patients were treated with rifampin, isoniazid, and pyrazinamide while 6 (6.9%) received the former drugs plus streptomycin and 42 (48.3%) the former plus ethambutol. There were three deaths. CONCLUSIONS: PTB in pediatric population represents a diagnostic challenge for the fact that clinical manifestations are unspecific and the diagnosis is not confirmed in all cases; that is why clinical suspicion, X-ray findings and PPD are indispensable for opportune start of treatment.