Pneumatosis intestinalis in children after allogeneic bone marrow transplantation

Four children, ages 3 to 8 years, developed pneumatosis intestinalis (PI) after allogeneic bone marrow transplantation (BMT) for acute leukemia or severe aplastic anemia. PI was detected at a median of 48 days (range, 10–63 days) after BMT and was associated with abdominal symptoms and clinical signs. All patients had severe systemic and/or high-grade cutaneous acute graft-versus-host disease (AGVHD) at some time after BMT and were receiving corticosteroids at the time of development of PI; however, PI was associated with concomitant severe AGVHD in only one patient. One patient with PI hadHafnia alvei bacteremia and another patient had gastroenteritis due to rotavirus and adenovirus. All patients were treated with supportive care and systemic broad-spectrum antibiotics, and PI resolved 2–16 days after onset. Two patients died with BMT-associated complications unrelated to PI. Multiple factors contribute to the development of PI after BMT, and the prognosis for recovery from PI is good with medical management alone. Overall survival in these patients is dependent on the frequency and severity of other conditions, such as AGVHD and opportunistic infections, after BMT. Presented in part at the 53rd Annual Meeting of the Society for Pediatric Research, San Francisco, California, 1–4 May 1984. Pediatr Res (1984) 18: 252A [Abstract])     

Lupus nephritis: a retrospective review of 78 cases from a single center

Lupus nephritis (LN) is a frequent and serious manifestation of systemic lupus erythematosus. However, the outcome has progressively improved in the last 3 decades and this was due to more efficient and early treatment of LN and comorbid situations. The aim of our study was to analyze our experience and outcome in LN, to evaluate clinicopathologic and clinicolaboratory correlations and to search for risk factors for renal and patient survival. PATIENTS AND METHODS: We conducted a retrospective study of 78 patients with biopsy-proven LN. RESULTS: Acute renal failure and subnephrotic proteinuria with microhematuria occurred each one in 39.7% of the patients, nephrotic syndrome in 16.7% and nephritic syndrome in 3.8%. The mean serum creatinine at presentation was 1.45 +/- 1.03 mg/dl and the creatinine clearance was 68.2 +/- 40.3 ml/min. Class IV LN existed in 71.8%, Class III in 20.5%, Class V in 6.4% and Class VI in 1.3%. The treatment included steroids and cytotoxic agents in 87.5% of the patients with proliferative LN. Hypertension, serum creatinine and acute renal failure at presentation, as well as significant chronicity on renal biopsy, were significantly correlated with the progression to chronic renal failure in our population. Males were more prone to develop renal flares. 3.8% of the patients died, 9% lost their renal function, 26.9% are in remission, 33.3% still have subnephrotic proteinuria and microhematuria, 7.7% have nephrotic syndrome and 19.2% have chronic renal failure. The mean global follow-up was 102 +/- 74 months and 96.2% of the patients survived. The actuarial renal survival was 96.1% in the first year; 89.9% at 5 years; and 83.7% at 10 and 20 years. CONCLUSION: We can say that hypertension, serum creatinine and acute renal failure at the onset and significant chronicity on renal biopsy, proved to be risk factors for chronic renal failure in our study population. Male gender was a risk factor for renal flares. The achieved global outcome can be considered a good result.     

One-trial tolerance to midazolam is due to enhancement of fear and reduction of anxiolytic-sensitive behaviors in the elevated plus-maze retest in the rat

The anxiolytic-like effects of benzodiazepines (BZDs) in rats is reduced after a single exposure to the elevated plus-maze test (EPM). Several hypotheses have been formulated but no conclusive explanation exists for this phenomenon called "one-trial tolerance." In this study, we examined this phenomenon further by carrying out an ethopharmacological analysis of the behavior of rats submitted to the EPM in two trials. Rats injected with saline before both trials (control), treated with 1.0 mg/kg of midazolam before both trials (MM), or only before Trial 2 (SM), were exposed to the EPM. The SM group did not differ from the controls in the Trial 1 and Trial 2 conditions. The MM group showed a clear anxioselective profile in Trial 1 and no anxiolytic-like effects in Trial 2. Whereas midazolam injected before the first trial caused no significant change in immobility, there was a pronounced increase in immobility during Trial 2 for all three conditions. These data suggest that the anxiolytic-like action of midazolam in the first trial gives way to the fear-related insensitive behaviors (phobic/avoidance responses) responsible for the one-trial tolerance to BZDs in Trial 2. Furthermore, an additional experiment showed that midazolam does not seem to affect the acquisition of the learned avoidance response since it is present upon retesting even after midazolam administration in Trial 1 (MS group). Rather, the present data suggest an emotional shift from Trial 1 to Trial 2, which leads to change in the responsiveness of the animals to BZDs.     

Kinetics of venom and antivenom serum and clinical parameters and treatment efficacy in Bothrops alternatus envenomed dogs

Dogs envenomed with non-lethal doses of Bothrops alternatus venom received standard antivenom therapy, im injections of flunixin meglumine, or topical treatmentwith aqueous Curcuma longa plant extract. Biodistribution of the venom and antivenom were determined by ELISA. There was no significant difference in the efficacy of antivenom and plant extract on local effects; flunixin treatment had lower efficacy. Distribution of the venom was similar with all 3 treatments. Serum levels of the antivenom reached maximum 2-4 h after administration and were not detected after the 5th d.     

Pharmacological treatment of obesity

The foundation on which the treatment of obesity rests is made up of the procedures aimed at unbalancing the equation of energy balance in favour of calorie consumption. Pharmacological treatment is aimed at favouring a reduction of calorie intake or stimulating calorie production. Depending on their mechanism of action, the drugs that are used in the treatment of obesity can be divided into appetite inhibitors, inhibitors of food intake or blockers of fat digestion and stimulators of thermogenesis. Amongst the appetite inhibitors, besides the adrenergic agents such as those of the amphetamine type, which are forbidden because of their addictive effect, are the serotonin uptake inhibitors such as dexfenfluramine (withdrawn in 1997) and fluoxetine. The recent commercialisation of sibutramine, a serotonin and norepinephrine reuptake inhibitor with an appetite inhibiting and thermogenesis stimulating effect, offer new perspectives in this field. Amongst inhibitors, mention is deserved by orlistat that inhibits the absorption of upto 30% of ingested fat without causing secondary effects of significance. In the area of thermogenic drugs there are the ephedrine-caffeine association, and the adrenergic beta antagonists, which are still being researched. There are numerous future perspectives amongst which are leptin, analogs of GLP-1 and cholecystokinin and neuropeptide Y antagonists. It is necessary to have reliable predictive elements that make it possible to know the most useful drugs, as well as the sort of patients who will benefit most from the different pharmacological treatments.     

The nicotinic allosteric potentiating ligand galantamine facilitates synaptic transmission in the mammalian central nervous system

In this study, the patch-clamp technique was used to determine the effects of galantamine, a cholinesterase inhibitor and a nicotinic allosteric potentiating ligand (APL) used for treatment of Alzheimer's disease, on synaptic transmission in brain slices. In rat hippocampal and human cerebral cortical slices, 1 microM galantamine, acting as a nicotinic APL, increased gamma-aminobutyric acid (GABA) release triggered by 10 microM acetylcholine (ACh). Likewise, 1 microM galantamine, acting as an APL on presynaptically located nicotinic receptors (nAChRs) that are tonically active, potentiated glutamatergic or GABA-ergic transmission between Schaffer collaterals and CA1 neurons in rat hippocampal slices. The cholinesterase inhibitors rivastigmine, donepezil, and metrifonate, which are devoid of nicotinic APL action, did not affect synaptic transmission. Exogenous application of ACh indicated that high and low levels of nAChR activation in the Schaffer collaterals inhibit and facilitate, respectively, glutamate release onto CA1 neurons. The finding then that the nAChR antagonists methyllycaconitine and dihydro-beta-erythroidine facilitated glutamatergic transmission between Schaffer collaterals and CA1 neurons indicated that in a single hippocampal slice, the inhibitory action of strongly, tonically activated nAChRs in some glutamatergic fibers prevails over the facilitatory action of weakly, tonically activated nAChRs in other glutamatergic fibers synapsing onto a given neuron. Galantamine is known to sensitize nAChRs to activation by low, but not high agonist concentrations. Therefore, at 1 microM, galantamine is likely to increase facilitation of synaptic transmission by weakly, tonically activated nAChRs just enough to override inhibition by strongly, tonically activated nAChRs. In conclusion, the nicotinic APL action can be an important determinant of the therapeutic effectiveness of galantamine.     

Interaction between human serum albumin and the felbamate metabolites 4-Hydroxy-5-phenyl-[1,3]oxazinan-2-one and 2-phenylpropenal

Felbamate is an anti-epileptic drug associated with hepatotoxicity and aplastic anemia. These toxicities are believed to be mediated by the formation of the reactive species 2-phenylpropenal. 4-Hydroxy-5-phenyl-[1,3]oxazinan-2-one is a metabolic precursor for 2-phenylpropenal. 4-Hydroxy-5-phenyl-[1,3]oxazinan-2-one exists in equilibrium with 3-oxo-2-phenylpropyl carbamate, which can undergo beta-elimination to form 2-phenylpropenal. The work presented here investigates the interaction between 4-hydroxy-5-phenyl-[1,3]oxazinan-2-one and human serum albumin (HSA). HSA (40 mg/mL) was found to decrease the half-life of 4-hydroxy-5-phenyl-[1,3]oxazinan-2-one from 4.57 +/- 0.44 h to 1.07 +/- 0.10 h at pH 7.4. This decrease in the half-life of 4-hydroxy-5-phenyl-[1,3]oxazinan-2-one was due to increased beta-elimination of 3-oxo-2-phenylpropyl carbamate, presumably through HSA-mediated general base catalysis. The k(cat) for HSA-catalyzed decomposition of 4-hydroxy-5-phenyl-[1,3]oxazinan-2-one was determined to be 12.04 min(-)(1) M(-)(1). Competitive binding assays using warfarin and ibuprofen showed that HSA-catalyzed decomposition of 4-hydroxy-5-phenyl-[1,3]oxazinan-2-one is dependent on the subdomain IIA binding site of HSA. LC/MS/MS analyses of trypsin digests of HSA incubations with either 4-hydroxy-5-phenyl-[1,3]oxazinan-2-one or 2-phenylpropenal identified HSA-2-phenylpropenal adducts formed specifically at residues His-242 and His-247. These HSA-2-phenylpropenal adducts were found to be slowly reversible, with a decrease in alkylation of 74.0 +/- 0.6% after extensive dialysis. Interestingly, only the bis-adduct (His-242 and His-247) could be identified after dialysis. These results demonstrate the first direct example of 2-phenylpropenal conjugation to a human protein in vitro and suggest the possibility that HSA may be involved in the development of felbamate toxicity either by antigen formation or as a route of detoxification of 2-phenylpropenal.     

Drugs that inhibit mycolic acid biosynthesis in Mycobacterium tuberculosis

Tuberculosis resurged in the late 1980s and now kills more than 2 million people a year. The reemergence of tuberculosis as a potential public health threat, the high susceptibility of human immunodeficiency virus-infected persons to the disease, and the proliferation of multi-drug-resistant (MDR) strains have created much scientific interest in developing new antimycobacterial agents to both treat Mycobacterium tuberculosis strains resistant to existing drugs, and shorten the duration of short-course treatment to improve patient compliance. Bacterial cell-wall biosynthesis is a proven target for new antibacterial drugs. Mycolic acids, which are key components of the mycobacterial cell wall, are alpha-alkyl, beta-hydroxy fatty acids, with a species-dependent saturated "short" arm of 20-26 carbon atoms and a "long" meromycolic acid arm of 50-60 carbon atoms. The latter arm is functionalized at regular intervals by cyclopropyl, alpha-methyl ketone, or alpha-methyl methylethers groups. The mycolic acid biosynthetic pathway has been proposed to involve five distinct stages: (i) synthesis of C20 to C26 straight-chain saturated fatty acids to provide the alpha-alkyl branch; (ii) synthesis of the meromycolic acid chain to provide the main carbon backbone, (iii) modification of this backbone to introduce other functional groups; (iv) the final Claisen-type condensation step followed by reduction; and (v) various mycolyltransferase processes to cellular lipids. The drugs shown to inhibit mycolic acid biosynthesis are isoniazid, ethionamide, isoxyl, thiolactomycin, and triclosan. In addition, pyrazinamide was shown to inhibit fatty acid synthase type I which, in turn, provides precursors for fatty acid elongation to long-chain mycolic acids by fatty acid synthase II. Here we review the biosynthesis of mycolic acids and the mechanism of action of antimicrobial agents that act upon this pathway. In addition, we describe molecular modeling studies on InhA, the bona-fide target for isoniazid, which should improve our understanding of the amino acid residues involved in the enzyme's mechanism of action and, accordingly, provide a rational approach to the design of new drugs.     

Pharmacotherapy of acute respiratory distress syndrome

To date, the only therapeutic option that has convincingly been shown to decrease mortality in acute respiratory distress syndrome (ARDS) has been to use a lung-protective strategy that minimises the iatrogenic consequences of providing adequate life support through the use of mechanical ventilation. In terms of the pharmacological options for ARDS, no single drug or treatment has been shown to be the magic bullet in this disease. The search for novel therapies and pharmacological agents is active and relentless. Important pathophysiological areas of focus are preventative therapy, supportive care and treatment of the underlying inflammatory process. In this paper we will review current and experimental approaches to the management of ARDS. In addition, the pathophysiological basis for their putative modes of action, the current state of the literature and the potential for future clinical development will be discussed.