Increased incidence of necrotizing enterocolitis associated with routine administration of Infloran™ in extremely preterm infants.

We aimed to evaluate the isolation of strains contained in the Infloran™ probiotic preparation in blood cultures and its efficacy in reducing necrotizing enterocolitis (NEC) and late-onset sepsis (LOS) in extremely preterm infants. Routine use of probiotics was implemented in 2008. Infants born at <28 weeks gestational age were prospectively followed and compared with historical controls (HC) born between 2005 and 2008. Data on sepsis due to any of the two probiotic strains contained in Infloran and rates of LOS and NEC were analysed. A total of 516 infants were included. During the probiotic period (PC), none of the strains included in the administered probiotic product were isolated from blood cultures. Probiotic administration was associated with an increase in NEC stage II or higher (HC 10/170 [5.9%]; PC 46/346 [13.3%]; P=0.010). Surgical NEC was 12.1% in PC (42/346) versus 5.9% (10/170) in HC (P=0.029). Adjusting for confounders (sex, gestational age, antenatal steroids and human milk) did not change those trends (P=0.019). Overall, clinical LOS and the incidence of staphylococcal sepsis were lower in PC (172/342, 50.3, and 37%, respectively) compared with HC (102/169, 60.3 and 50.9%, respectively) (P=0.038 and P=0.003, respectively). No episodes of sepsis attributable to the probiotic product were recorded. The period of probiotic administration was associated with an increased incidence of NEC after adjusting for neonatal factors, but also with a reduction in the LOS rate.

Sinovitis vellonodular pigmentada en rodilla y asociación a material extraño / Pigmented villonodular synovitis of the knee related to foreing material

Objetivos: Se pretende ver la asociación entre SVNP y la exposición a material extraño. Material y método: Analizamos retrospectivamente 201 pacientes sometidos a cirugía abierta durante 2016, dividiendo dicha muestra en 2 grupos, los pacientes con algún implante previo (PTR u osteosíntesis), y los que no habían tenido ningún material, las muestras de tejido sospechoso de proliferación fueron enviadas al anatomopatólogo, analizando los resultados con test Chi². Resultados: Se obtienen 7 casos de SVNP, de los cuales 6 de ellos habían estado en contacto con material extraño, tras analizar la asociación estadística, se obtiene una significación suficiente para aceptar que pueda haber relación entre la exposición a material y SVNP. Conclusión: La SVNP es una enfermedad rara, de etiología incierta, varías hipótesis intenta explicar el origen: alteraciones citogenéticas o cromosómicas, enfermedades que cursen con hemorragias articulares, traumatismos de repetición hiperplasia inflamatoria del tejido sinovial. Comunicaciones recientes han relacionado la etiología de la SVNP con una reacción del tejido sinovial a cuerpo extraño en cadera y rodilla, y con el presente trabajo se recalca la asociación entre material extraño y la aparición de esta rara entidad

Objectives: It is intended to approach the association between PVNS and exposure to foreign material. Material and method: We retrospectively analyzed 201 patients undergoing open surgery during 2016, dividing the sample into 2 groups, those with a previous implant (TKA or osteosynesis), and those who had not had any material, samples of tissue suspected of proliferation were sent to the anatomopathologist, analyzing the results using Chi² test Results: 7 cases of PVNS were obtained, of which 6 had been in contact with foreign material, after analyzing the statistical association, a sufficient significance was obtained to accept that there may be a relationship between the exposure to material and PVNS. Conclusion: PVNS is a rare disease of uncertain etiology, several hypotheses try to explain the origin: cytogenetic or chromosomal alterations, diseases that occur with joint hemorrhages, recurrent trauma, inflammatory hyperplasia of synovial tissue. Recent reports have linked the etiology of PVNS with a reaction of foreign body synovial tissue in the hip and knee, and the present work emphasizes the association between foreign material and the appearance of this rare entity

Congenital aneurysm of the left atrial appendage.

Congenital aneurysm of the left atrial appendage is quite infrequent. Most instances are asymptomatic. Patients can report a variety of symptoms, one of the most frequent being onset of auricular tachyarrhythmia. Various imaging techniques are useful in diagnosis and allow the differential diagnosis with other pathologies. We describe the case of a 24-year-old male with congenital aneurysm of the left atrial appendage. The patient presented with auricular fibrillation. Diagnosis was based on transthoracic and trans-esophageal echocardiography, and the patient was treated by surgical resection of the aneurysm under extracorporeal circulation.

A study on the influence of emulsion droplet size on the skin penetration of tetracaine.

OBJECTIVES/AIMS: The influence of emulsion droplet size on the skin penetration of a model drug, tetracaine, was studied. For this purpose, in vitro dermal and transdermal delivery of tetracaine from 6 emulsions (3 macro-emulsions with droplet sizes >1 microm and 3 nano-emulsions with droplet sizes <100 nm) were tested. METHODS: Two approaches were used: in the first one, the composition of the emulsions was kept constant, while in the second one, the surfactant concentration in the aqueous phase was kept constant by varying the overall surfactant concentration. RESULTS: The results from emulsions differing only in droplet size did not provide statistically significant evidence for the anticipated increase in transdermal or dermal delivery (after 24 h) when reducing emulsion droplet size. The same results were obtained when the surfactant concentration in the aqueous phase was kept constant, indicating that there is no influence of emulsion droplet size on the skin penetration of tetracaine within the droplet size range studied. CONCLUSION: This is in contrast to what has been reported in various publications that claim penetration to increase with reducing droplet size. It should be noted that the results reported so far are based on emulsions that apart from droplet size also differed in composition and/or system components.

Rapid human skin permeation and topical anaesthetic activity of a new amethocaine microemulsion.

We developed a fast-acting, topical, 4% (w/w) amethocaine microemulsion and tested its in vitro permeation in isolated human skin. Comparison with a commercial amethocaine gel (Ametop((R)) ) was performed using Franz diffusion cells. Permeability coefficient (k(p)), flux (J) and percentage permeation after 10 h of microemulsion application were, in all cases, 1.5 times higher than those of the gel. The values obtained for the P(1) parameter [1], 1.06.10(-2) cm (microemulsion) and 0.724.10(-2) cm (gel) indicate that the microemulsion excipients favour amethocaine deposition in the skin, increasing the permeability coefficient, amount of drug retained in the skin, and the flux achieved. Analgesic activity was also examined in rats made hyperalgesic or allodynic after carrageenan-induced inflammation. The rats were distributed into four groups (n = 5-9 per group), each group receiving topically either amethocaine microemulsion, amethocaine gel (Ametop), amethocaine subcutaneous infiltration or nothing (controls). In edematous paws, anti-hyperalgesic activity appeared at 4.2 and 13.8 min after application of amethocaine microemulsion and gel, respectively. These effects are lower than after 0.5% w/w amethocaine infiltration. Amethocaine microemulsion was the only topical formulation with an anti-allodynic effect, although this effect was less than with amethocaine infiltration. These results suggest that microemulsion could be a valuable formula for improving amethocaine permeation and thus bringing rapid pain relief.

Rapid skin anesthesia using a new topical amethocaine formulation: a preclinical study.

UNLABELLED: We developed a fast-acting topical amethocaine emulsion and tested its analgesic activity against heat or mechanically induced pain in a rat paw model. The first experiment was performed in rats made hyperalgesic or allodynic after carrageenan-induced inflammation. Rats were distributed in five subgroups, each receiving topically one of the following: amethocaine microemulsion, amethocaine gel (Ametopgel), EMLA (Eutectic Mixture of Local Anesthetics) cream, amethocaine infiltration, or nothing (controls). The second experiment was conducted on healthy, selected heat- or touch-hypersensitive rats, which were distributed as in the first experiment. Paw withdrawal time from a heat and a mechanical stimulus was used as a pain index. In the first experiment, antihyperalgesic activity appeared at 4.2, 13.8, and 14 min after amethocaine microemulsion, gel, or EMLA cream, respectively. Amethocaine microemulsion was the only topical formulation with an antiallodynic effects, although less than with amethocaine infiltration. In healthy rats (second experiment), all topical formulations produced similar analgesic effects in heat-induced pain of the ipsilateral paw. Activity in the contralateral paw appeared earlier with amethocaine microemulsion, which was also the only one that increased touch-induced withdrawal time in the ipsi- and contralateral paws. Therefore, the microemulsion could be valuable for improving amethocaine skin penetration and thus bringing rapid pain relief. IMPLICATIONS: Topical anesthetics are used in several painful clinical procedures, but they tend to have a slow onset time. A new amethocaine microemulsion with a faster onset of analgesia than commercial formulations was developed and its activity tested in pain states induced by heat or mechanical stimulus in inflamed and healthy rat paws.

Fenobarbital: farmacocinética, toxicología y monitorización por el Laboratorio / Phenobarbital: pharmacokinetics, toxicology and monitoring by clinical lanoboratory

El fenobarbital es un agente antiepiléptico muy utilizado en el tratamiento de las crisis tónico-clónicas parciales y generalizadas. Su estrecho rango terapéutico y su elevada capacidad depresora del sistema nervioso central junto con su capacidad de producir autoinducción enzimática hace que sea uno de los fármacos más frecuentemente monitorizados en el laboratorio clínico. En este trabajo revisamos la farmacología del fenobarbital, estudiando además la farmacocinética, las reacciones adversas debidas a la intoxicación, las indicaciones de su monitorización y los métodos empleados en el laboratorio para la medida de los niveles plasmáticos (AU)

Bacteremic cellulitis caused by Non-01, Non-0139 Vibrio cholerae: report of a case in a patient with hemochromatosis.

We report a case of bacteremia associated with hemorrhagic bullous skin lesions on the leg caused by non-01, non-0139 Vibrio cholerae in a 66-year-old man with hemochromatosis developed in an inland region. The organism was isolated from blood and bullae fluid. The patient was treated successfully with cefotaxime and doxycycline. This report emphasizes the potential of this organism to produce bacteremic cellulitis in people with underlying illness in the absence of usual epidemiological risk factors.

Influence of the formulation on the in vitro transdermal penetration of sodium diclofenac. Evaluation of the topical and systemic anti-inflammatory activity in the rat.

A study on the transdermal permeation through human skin was performed with a series of 6 semisolid formulations (A-F) containing 1% sodium diclofenac (CAS 15307-79-6) (w/w). A commercially available drug preparation was tested as a reference. Based on permeation characteristics, a study on the topical and systemic anti-inflammatory activities of three formulations (A, F and the reference formulation) was conducted using the model of erythema induced by UV radiation in hairless rats. This is expected, together with the index of topical anti-inflammatory activity to allow the selection of the most suitable formulation for dermal application. The following representative parameters were measured in the permeation study: amount of diclofenac permeated at 24 h, flow, lag time and amount of drug retained in skin at 24 h. Of the formulations tested, diclofenac formulated in the reference formulation showed the highest values of amount of diclofenac permeated at 24 h, amount of drug retained in skin at 24 and flow. As regards the skin inflammation test, no significant differences (p < 0.05) are seen between the topical and systemic anti-inflammatory activities of the three formulations tested. However, in absolute value, formulation F shows a lower systemic activity, which would prevent potential side effects of diclofenac. Since the topical anti-inflammatory index obtained for this formulation was > 1, it is concluded that a good therapeutic performance could be obtained in the treatment of local inflammation with diclofenac by using formulation F.

Influence of formulation on the in vitro transdermal penetration of flutrimazole.

Flutrimazole (1-[(2-fluorophenyl)(4-fluorophenyl)phenylmethyl]-1 H-imidazole, CAS 119006-77-8, UR-4056) is a new wide spectrum local imidazolic antifungal agent that has already been formulated as a dermal cream (FDC). A comparative study was carried out of the release of flutrimazole from two emulsions in which the drug has been incorporated differently: one dissolved in the oily phase (E24) and the other dispersed in the aqueous formulation phase (E25). Based on the E25 formulation, two more dermal creams were prepared, E27 with benzyl alcohol and E28 with diazolidinyl urea as preservative agents. A comparative study of transdermal penetration including E27, E28, FDC (reference 1% flutrimazole dermal cream) and 1% flutrimazole hydroalcoholic solution was also performed. An amount of the sample dosage form containing 10 mg of flutrimazole was applied to a Franz type cell. The penetration membrane used was cellulose acetate in the release studies and human skin provided by a plastic surgery clinic in the transdermal penetration study. The amount released after 7 h was 36.3 +/- 4.9 micrograms when flutrimazole was dissolved (E24) and 35.9 +/- 5.3 micrograms when flutrimazole was dispersed (E25). Although the differences were not significant, the cream with dispersed flutrimazole was selected for further penetration studies due to its better stability observed in previous studies. The amounts of drug penetrated after 44 h were 31.3, 41.5, 38.3 and 186.5 micrograms for E27, E28, FDC dermal creams and topical hydroalcoholic solution, respectively. The solution showed a statistically significant difference (p < 0.05) from the other formulations, however, no differences were observed between the dermal cream formulations. No differences were neither obtained between the different dermal creams when the amount of drug retained in the skin was compared. This allows to assert that the excipients used do not have different influences on transdermal penetration. In all cases, the mean quantity penetrated in relation to the dose applied was at most 0.5%. These results allow to infer that flutrimazole shows scarce transdermal penetration. Further, the amount of flutrimazole retained per gram of skin is more than 100 times the MIC per gram obtained in previous in vitro studies. It may be assumed that the topical application of the new formulations assayed would allow to obtain a good therapeutic response.

Brucellar osteomyelitis involving prosthetic extra-articular hardware.

We report the case of a patient with Brucella melitensis osteomyelitis involving non-joint prosthetic implant of the femur. This is the first case published of osteomyelitis by Brucella sp. in a patient with prosthetic implant in bone and the second one with both intra- or extra-articular prosthetic bone implant. Brucella melitensis is a rare organism which causes osteomyelitis in patients with prosthetic hardware, and should be added to the list of suspected organisms responsible for this disease, especially in endemic areas of brucellosis.

Structure-absorption relationships of a series of 6-fluoroquinolones.

The physicochemical constants and some structural parameters (topological, steric, and electronic) of eight third-generation monofluorate quinolones (six uncommercialized and two used clinically [ciprofloxacin and enrofloxacin]) were determined: pKa, intrinsic solubility (S0), chromatographic capacity factor, partition coefficient (P), valency molecular connectivity, molecular volume, molecular surface area, dipolar moment, and charges associated with each atom of the molecule. The apparent intestinal absorption rate constants (K(abs)) in rat (in vivo perfusion) and the MICs at which 90% of the isolates are inhibited (MIC90s) against 100 Escherichia coli strains were also determined. We sought to establish simple nonlinear and multiple linear correlations between K(abs), on the one hand, and lipophilic parameters and other physicochemical and structural parameters estimated. Of the nonlinear functions examined, the hyperbolic had the best correlation between K(abs) and P, which was in accordance with the Wagner-Sedman (J. G. Wagner and A. J. Sedman, J. Pharmacokinet. Biopharm. 1:23-50, 1973) equation, whereas, after application of the stepwise multiple linear regression method, a multiple linear correlation with some predictive value could be established only between K(abs) as a dependent variable and log P and log S0 as independent variables. In conclusion, the K(abs) and MIC90 of the quinolone CNV 8902 suggest that it is a sufficiently interesting compound to warrant the investigation of its potential therapeutic use orally.

A comparative study of the transdermal penetration of a series of nonsteroidal antiinflammatory drugs.

The transdermal absorption of a series of nonsteroidal antiinflammatory drugs (NSAIDs): indomethacin, ketoprofen, diclofenac, piroxicam, tenoxicam, ketorolac, and aceclofenac) was studied in vitro with human skin. The purpose of the study was to determine the permeation parameters (permeability rate constant, Kp; lag time, TL, and flux, J) as measures of the intrinsic transdermal permeabilities of these drugs to predict their potential for formulation in a transdermal therapeutic system (TTS). A linear correlation was established between the intrinsic log Kp values and the intrinsic partition coefficients (r = 0.863, p = 0.012, n = 7). Diclofenac had the highest value of in vitro transdermal penetration at approximately 0% ionization (Kp = 3.5 cm/h) and ketoprofen had the highest flux (J = 16 micrograms/h.cm2) of the NSAIDs assayed. Ketorolac would provide the plasma concentrations at steady state that would be nearest to the therapeutic concentration (Cr/Css = 26). Also, considering the whole permeation profile in vitro, ketorolac would be the most suitable candidate of the series studied to be formulated as a TTS.

Effect of d-limonene, alpha-pinene and cineole on in vitro transdermal human skin penetration of chlorpromazine and haloperidol.

The aim of this research is to carry out a comparative study of the ability to cross human skin of two neuroleptic drugs: chlorpromazine (CAS 50-53-3) and haloperidol (CAS 52-86-8), in the absence and in the presence of three terpenes (cineole, d-limonene and alpha-pinene) with the purpose of considering the possibility of improving their transdermal penetration profile. Franz diffusion cells were used, in conjunction with human skin as permeation membrane. The permeation parameters calculated were permeability constant (Kp), flux (J) and lag time (Tl) in the presence and in the absence of enhancers. None of the three enhancers assayed improved the penetration profile of chlorpromazine, and d-limonene even reduced the transdermal permeability (enhancement index, EI = 0.67) since its coefficient of relative activity was reduced, (Xr = 0.73). Cineole and d-limonene increased the permeation profile of haloperidol, giving EI values of 1.95 and 4.21, respectively, and leading to a fourfold increase in the flux value for both enhancers. alpha-Pinene did not modify the permeation profile of haloperidol. None of the three terpenes assayed had a significant effect on the lag time of chlorpromazine or haloperidol. In these experimental conditions the concentration values predicted at steady state of chlorpromazine formulated without enhancers are within the therapeutic range. In contrast, therapeutic levels of haloperidol cannot be predicted in the absence of enhancers such as d-limonene or cineole.

Influence of the chromatographic capacity factor (log k') as an index of lipophilicity in the antibacterial activity of a series of 6-fluoroquinolones. Relationship between physico-chemical and structural properties and their hydrophobicity.

The aim of this study was to establish the influence of lipophilicity on the antibacterial activity (log 1/MIC50) of 22 fluoroquinolones and to assess the influence of their electronic, steric and topological properties on their hydrophobicity. The lipophilicity of the compounds, expressed as the chromatographic capacity factor (log k'), was determined by ion-pair reversed-phase HPLC. On the basis of the mathematical models developed, an attempt was made to confirm the mechanism of interaction of the quinolones with DNA-gyrase proposed previously.