Rabdomiolisis secundaria a simvastatina y fenofibrato / Rhabdomyolysis secondary to simvastatin and phenofibrate

Las estatinas utilizadas como fármacos de primera línea en la prevención de enfermedad cardiovascular, son habitualmente seguras, aunque en algunos casos pueden desarrollar toxicidad muscular. La miopatía asociada a estatinas puede manifestarse como mialgias, miositis o rabdomiolisis. Solo un 0,44 por cada 10.000 tratados y a˜no, desarrollan rabdomiolisis. Existen numerosos factores de riesgo relacionados con el paciente y el tratamiento farmacológico. Un riesgo de toxicidad muscular del 1-5% ha sido descrito con la combinación de algunas estatinas con fibratos. El fibrato que presenta más riesgo de miopatía en asociación con las estatinas es gemfibrozilo, mientras fenofibrato parece ser el más seguro. Presentamos el caso de una mujer de 60 a˜nos de edad con sintomatología clínica y hallazgos analíticos sugestivos de rabdomiolisis secundaria a la combinación de simvastatina y fenofibrato. Así, este caso recuerda la necesidad de estrecha vigilancia de dichos pacientes, además de alertarlos sobre la aparición de dolor o debilidad muscular (AU)

Statins, which are used as first-line drugs in the prevention of cardiovascular disease, are usually safe, but in some cases there may be muscular toxicity. Statin-associated myopathy, can present as myalgia, myositis or rhabdomyolysis. Only 0.44 per 10,000 treated and per year, develop rhabdomyolysis. There are many risk factors associated with the patient and with the pharmacological treatment. A risk of muscle injury of 1-5% has been reported with some statins combined with fibrates. The fibrate with the highest risk of myopathy in combination with statins is gemfibrozil, while phenofibrate seems to be the safest.The case is presented of a 60 year-old woman with clinical symptoms and laboratory findings that suggested rhabdomyolysis secondary to a combination of simvastatin and phenofibrate. This case reminds physicians of the need to closely monitor these patients, in addition to alert them to the onset of muscle pain or weakness (AU)

[Rhabdomyolysis secondary to simvastatin and phenofibrate]. / Rabdomiolisis secundaria a simvastatina y fenofibrato.

Statins, which are used as first-line drugs in the prevention of cardiovascular disease, are usually safe, but in some cases there may be muscular toxicity. Statin-associated myopathy, can present as myalgia, myositis or rhabdomyolysis. Only 0.44 per 10,000 treated and per year, develop rhabdomyolysis. There are many risk factors associated with the patient and with the pharmacological treatment. A risk of muscle injury of 1-5% has been reported with some statins combined with fibrates. The fibrate with the highest risk of myopathy in combination with statins is gemfibrozil, while phenofibrate seems to be the safest. The case is presented of a 60 year-old woman with clinical symptoms and laboratory findings that suggested rhabdomyolysis secondary to a combination of simvastatin and phenofibrate. This case reminds physicians of the need to closely monitor these patients, in addition to alert them to the onset of muscle pain or weakness.

Evaluating the clinical effectiveness of pneumococcal vaccination in preventing myocardial infarction: The CAPAMIS study, three-year follow-up.

BACKGROUND: Cardiovascular benefits using the 23-valent pneumococcal polysaccharide vaccine (PPV23) are controversial. This study assessed clinical effectiveness of PPV23 in preventing acute myocardial infarction in people over 60-years. METHODOLOGY: We conducted a population-based cohort study involving 27,204 individuals ≥60 years-old in Tarragona, Spain, who were prospectively followed from 01/12/2008 until 30/11/2011. Outcomes were hospitalization for AMI, 30-day mortality from AMI and all-cause death. Cox regression was used to evaluate the association between pneumococcal vaccination and the risk of each outcome. RESULTS: Cohort members were followed for a total of 76,033 person-years, of which 29,065 were for vaccinated subjects. Overall, 359 cases of AMI, 55 deaths from AMI and 2465 all-cause deaths were observed. Pneumococcal vaccination did not alter the risk of AMI (multivariable hazard ratio [HR]: 0.95; 95% confidence interval [CI]: 0.76-1.18; p=0.630), death from AMI (HR: 1.32; 95% CI: 0.76-2.28; p=0.321) and all-cause death (HR: 0.97; 95% CI: 0.89-1.05; p=0.448). In analyses focused on people with and without history of prior coronary artery disease, pneumococcal vaccination did not emerge effective in preventing any analyzed event. CONCLUSIONS: This study supports that PPV23 does not provide any relevant benefit against AMI in the general population over 60 years, as in primary as well as in secondary prevention, although it is underpowered to exclude a small benefit of vaccination against rare outcomes.

Incidence of pneumococcal infections among children under 15 years in southern Catalonia throughout the heptavalent conjugate vaccine era, 2002-2009.

PURPOSE: Updating epidemiological studies to document current incidences of pneumococcal diseases are greatly needed in the current era of new pneumococcal conjugate vaccines (PCVs). The aim of this study is to analyze the incidence and distribution of different serotypes causing pneumococcal infections among the pediatric population in southern Catalonia, Spain, throughout the 2002-2009 PCV7 eras. METHODS: A population-based surveillance study was conducted among children aged ≤ 14 years in the region of Tarragona (Catalonia, Spain) during the period 2002-2009. All cases of pneumococcal infections (invasive and non-invasive cases) were included in the study. Incidence rates (per 100,000 population-year) and prevalence of infections caused by serotypes included in different PCV formulations were calculated for the 2002-2005 and 2006-2009 periods. RESULTS: Globally, across the total 2002-2009 period, the incidence of pneumococcal infections was 48.2 per 100,000 children-year (22.4 and 25.8 for invasive and non-invasive infections, respectively). Between 2002-2005 and 2006-2009, the incidence rates largely decreased among children aged <2 years (from 171 to 111 per 100,000 children-year; p = 0.059), but they did not substantially vary among children aged 2-14 years. The percentages of cases caused by serotypes included in PCV7 (60.0 vs. 16.7 %; p < 0.001), PCV10 (75.0 vs. 47.4 %; p = 0.028), and PCV13 (85.0 vs. 70.5 %; p = 0.190) decreased in both periods. CONCLUSION: In this study, which was conducted in a setting with intermediate PCV7 uptakes, a considerable protective direct effect of vaccination occurred among young infants, but an indirect protective effect did not emerge in the rest of the pediatric population. Despite new PCVs with higher serotype coverage, an important proportion of pneumococcal infections is still not covered by these vaccines.

Differential thermosensitivity of sensory neurons in the guinea pig trigeminal ganglion.

Intracellular recordings were employed to study the effects of temperature on membrane properties and excitability in sensory neurons of the intact guinea pig trigeminal ganglion (TG) maintained in vitro. Neurons were classified according to the shape and duration of the action potential into F (short-duration, fast spike) and S (long duration, slow spike with a "hump") types. Most type F (33/34) neurons had axons with conduction velocities >1.5 m/s, while only 30% (6/23) of type S neurons reached these conduction speeds suggesting differences in myelination. Cooling reduced axonal conduction velocity and prolonged spike duration in both neuronal types. In F-type neurons with strong inward rectification. cooling also increased the excitability, augmenting the input resistance and reducing the current firing threshold. These effects were not observed in S-type neurons lacking inward rectification. In striking contrast to results obtained in cultured TG neurons, cooling or menthol did not induce firing in recordings from the acutely isolated ganglion. However, after application of submillimolar concentrations (100 microM) of the potassium channel blocker 4-aminopyridine (4-AP), 29% previously unresponsive neurons developed cold sensitivity. An additional 31% developed ongoing activity that was sensitive to temperature. Only neurons with strong inward rectification (mostly F-type) became thermosensitive. Cooling- and 4-AP-evoked firing were insensitive to intracellular application of 4-AP or somatic membrane hyperpolarization, suggesting that their action was most prominent at the level of the axon. The lack of excitatory actions of low temperature in the excised intact ganglion contrasts with the impulse discharges induced by cooling in trigeminal nerve terminals of the same species, suggesting a critical difference between cold-transduction mechanisms at the level of the nerve terminals and the soma.

Effects of hypoxia on retinal pigmented epithelium cells: protection by antioxidants.

Age-related macular degeneration and other eye diseases, such as diabetic retinopathy, are probably linked to the effects of oxygen radicals derived from light or metabolic reactions. We have investigated the effects of hypoxia on bovine retinal pigmented epithelial cells (RPE) and the response of these cells to two antioxidants that have previously shown a beneficial action against free radical-linked senescent involution. The main results of the study were as follows: (i) Hypoxia induced apoptotic damage on RPE cells, with LDH leakage and ATP reduction; (ii) both vitamin C (VC) and N-acetyl-cysteine (NAC) treatment protected against hypoxia-induced apoptosis, with less DNA fragmentation. In our opinion, these findings justify further experimental and clinical work to investigate the role of hypoxia in the mechanisms of age-related RPE injury and death as well as the potential of antioxidant administration to prevent or delay retinal degenerative processes caused by oxygen-dependent pathophysiological conditions.

Sea level rise during past 40 years determined from satellite and in situ observations.

The 3.2 +/- 0.2 millimeter per year global mean sea level rise observed by the Topex/Poseidon satellite over 1993-98 is fully explained by thermal expansion of the oceans. For the period 1955-96, sea level rise derived from tide gauge data agrees well with thermal expansion computed at the same locations. However, we find that subsampling the thermosteric sea level at usual tide gauge positions leads to a thermosteric sea level rise twice as large as the "true" global mean. As a possible consequence, the 20th century sea level rise estimated from tide gauge records may have been overestimated.

Inhibition of COX in ocular tissues: an in vitro model to identify selective COX-2 inhibitors.

The aim of this work was to study the regulation of LPS-stimulated PGE 2 synthesis by traditional NSAIDs (piroxicam and diclofenac) and a selective COX-2 inhibitor (NS-398), in cultured bovine corneal endothelial cells and retinal pigmentary epithelial cells. The IC50 values of piroxicam and diclofenac were compared with IC50 values of NS-398, diclofenac, in both types of cells, showed higher potency than piroxicam. Diclofenac seemed to be a COX-2 inhibitor because its IC50 values were similar to the IC50 values of NS-398. We suggest that this in vitro cell assay system could be useful for identifying compounds that selectively inhibit COX-2 in ocular tissues.

Electrophysiological properties of identified trigeminal ganglion neurons innervating the cornea of the mouse.

The cornea is innervated by three functional types of neurons: mechanosensory, polymodal and cold-sensitive neurons, all of which are presumed to be nociceptive. To explore if corneal neurons constitute a heterogeneous population according to their electrophysiological properties, intracellular recordings were made in vitro from trigeminal ganglion neurons innervating the cornea of the mouse. Corneal neurons were labelled with FluoroGold applied after a corneal epithelial wound. Five days later, the trigeminal ganglion attached to the eye by its nerves was removed and placed in a superfusion chamber. FluoroGold-positive cells that also responded to electrical stimulation of the cornea were considered corneal neurons. Non-corneal neurons were also studied. Based on their conduction velocity at room temperature, corneal neurons were classified as myelinated A (>1.5m/s) or non-myelinated C (< or =1.5m/s) neurons. A and C neurons differed significantly in their passive and active electrical properties. Virtually all corneal C neurons and about two-thirds of A neurons exhibited a hump in the falling phase of the action potential (S neurons), while the remaining A neurons (F neurons) showed faster and narrower action potentials without a hump. Among non-corneal neurons, A neurons of the F type were found in a proportion of about 50%. Based on their ability to produce somatic action potentials in tetrodotoxin (0.1 microM), non-corneal neurons were classified as fully or partially tetrodotoxin sensitive, which were mainly of the Adelta type, and tetrodotoxin resistant, which were C neurons. Among the corneal neurons, those with a faster action potential, possibly associated to the expression of tetrodotoxin-sensitive Na(+) channels, may be pure corneal mechanosensory neurons, all of which are known to belong to the Adelta type. Neurons with a slower action potential showing a hump in the repolarization phase are both corneal Adelta and C polymodal nociceptive neurons, a type of cell in which tetrodotoxin-resistant Na(+) channels have been identified. The possibility is raised that the small population of neurons with a very high input resistance are cold-sensitive neurons. From the present results, we suggest that the electrophysiological properties of primary sensory neurons innervating the cornea are attributable not only to their conduction velocities, but also to the functional characteristics of their peripheral nerve terminals.

An in vitro model of ischemic-like stress in retinal pigmented epithelium cells: protective effects of antioxidants.

We have developed a model of in vitro cell oxidative stress in bovine retinal pigment epithelium cells exposed to a ischemia-like condition obtained by interference with glucose utilization through both oxidative phosphorylation and glycolysis. This resulted in a statistically significant decrease of the intracellular ATP levels, which reflects a bioenergetic decline similar to that associated with mitochondrial damage or loss in normal post-mitotic cells aging in vivo. This new model of cellular oxygen stress seems adequate for investigation of the protective action of antioxidants, in agreement with our finding of a statistically significant increase in the ATP levels over the values of the non-treated samples in retinal pigment epithelium cells exposed to the above oxygen stress in medium supplemented with 300 microM vitamin C or 10 mM N-acetylcysteine.

The ocular pharmacokinetics of topical diclofenac is affected by ocular inflammation.

The ocular pharmacokinetics of topical diclofenac sodium was studied in two experimental models of ocular inflammation and compared to physiological conditions. Keratitis or uveitis were induced by intrastromal injection of clove oil or by intravitreal lipopolysaccharide in rabbits. The control eyes were not inflamed. Simultaneously to the induction of inflammation, 30 microl of 0.1% diclofenac were applied topically in the right eye. Diclofenac levels were measured by HPLC in the cornea, aqueous humor (AH), iris/ciliary body (ICB) and plasma 30 min, 1, 3, 6 and 12 h after application. In physiological conditions, diclofenac reached a peak level in the cornea and ICB at 30 min slowly decreasing afterwards. Low levels of diclofenac were found in AH. In keratitic eyes, two peak levels which were significantly higher than in the controls were found in the cornea 30 min and 3 h after application. Diclofenac concentrations in keratitic AH and ICB were lower than in controls. In uveitic eyes, corneal and ICB levels peaked at 30 min, being significantly higher than in controls, and decreased quickly to very low levels at 1 h after application. In uveitic AH, diclofenac levels were lower than in controls. Plasma levels were very low (less than 0.1 microg/ml) in all experimental groups. It is concluded that the ocular pharmacokinetics of topical diclofenac is affected by inflammatory processes in the eye, reaching higher levels in the target tissues.

PGE2 synthesis by corneal endothelial cells: effect of glucocorticoids and NSAIDs.

The aim of this work was to study the effect of various anti-inflammatory drugs on PGE2 synthesis in cultured bovine corneal endothelial cells (BCECs) stimulated with calcium ionophore A23187 or lipopolysaccharide (LPS) of Salmonella typhimurium. NSAIDs were more potent in inhibiting LPS-stimulated PGE2 synthesis. Diclofenac was more potent than indomethacin, although both drugs showed a 98% maximal inhibitory effect. Dexamethasone inhibited 80% of the A23187-stimulated PGE2 synthesis and only 53% of the LPS-stimulated PGE2 synthesis. Prednisolone did not show an inhibitory effect. The results demonstrate the inhibitory effect of NSAIDs and show differences between the activity of glucocorticoids on PGE2 synthesis in BCECs. Prednisolone could not inhibit PGE2 synthesis in these cells in our experimental conditions.

Concomitant treatment with a 5-lipoxygenase inhibitor improves the anti-inflammatory effect of the inhibition of nitric oxide synthase during the early phase of endotoxin-induced uveitis in the rabbit.

Nitric oxide (NO) synthase inhibitors, such as NG-nitro-L-arginine methyl ester (L-NAME), have been shown to attenuate endotoxin-induced uveitis (EIU) but they could increase leukocyte adhesion to the vascular endothelium. We hypothesize that a concomitant treatment with the 5-lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA) in 50% dimethylsulfoxide (DMSO, a hydroxyl radical scavenger) could improve the anti-inflammatory activity of L-NAME. EIU was induced in albino rabbits by intravitreal injection of 100 ng lipopolysaccharide. Animals were treated with multiple intraperitoneal injections of 50% DMSO in phosphate-buffered saline (PBS), NDGA (10 mg/kg) in 50% DMSO, L-NAME (50 mg/ kg) in PBS, or the combination NDGA+L-NAME. Uveitis was assessed by slit lamp examination, protein levels in aqueous humor, and myeloperoxidase (MPO) activity in the iris/ciliary body 6 h after induction. Nitrite, leukotriene B4 (LTB4), prostaglandin E2 (PGE2), platelet-activating factor (PAF) and interleukin-1 beta (IL-1 beta) levels in aqueous humor were also determined. NDGA or L-NAME alone did not show a significant reduction of uveitis intensity, although a significant decrease in MPO or in proteins was found, respectively. The combination NDGA+L-NAME significantly reduced the uveitis intensity, MPO in the iris/ciliary body, and the levels of nitrites, LTB4, PGE2, and PAF in aqueous humor. IL-1 beta levels were lower than the detection limit of the radioimmunoassay in all treatment groups. We conclude that concomitant treatment with NDGA in DMSO improves the anti-inflammatory activity of L-NAME during the early phase of EIU, suggesting that the inhibition of NO synthesis could enhance leukocyte infiltration and the release of oxygen free radicals.

Additive effect of nitric oxide and prostaglandin-E2 synthesis inhibitors in endotoxin-induced uveitis in the rabbit.

The involvement of nitric oxide (NO) and prostaglandin E2 (PGE2) was investigated in a model of intraocular inflammation induced by intravitreal injection of endotoxin (lipopolysaccharide, LPS, 10 ng) in rabbits. The severity of uveitis, the myeloperoxidase (MPO) activity in iris-ciliary body, and the protein concentration in aqueous humor were determined. Nitric oxide synthase (NOS) and cyclooxygenase (COX) activities were assessed respectively by nitrite and PGE2 levels in aqueous humor. Treatment with inhibitors of NOS (NG-nitro-L-arginine methyl ester, L-NAME, 50 mg/kp i.p.) or COX (diclofenac, 30 micrograms, topically), alone or in combination, were compared to a saline-treated group. Diclofenac or L-NAME alone reduced or delayed the intensity of uveitis, and partially decreased the protein concentration in aqueous humor; diclofenac, but not L-NAME, partially reduced the polymorphonuclear leukocyte infiltration in the iris ciliary body as indicated by the MPO activity. Treatment with both inhibitors in combination diminished the clinical uveitis, the disruption of the blood-aqueous barrier and the MPO activity in the iris-ciliary body. We conclude that NO and PGE2 have additive effects in endotoxin-induced uveitis in rabbits, and that the inhibition of both pathways would improve the therapeutical management of uveitis.