4‐fluorotranylcypromine,a novel monoamine oxidase inhibitor: Neurochemical effects in rat brain after short‐ and long‐term administration

A series of acute and chronic experiments was conducted on 4‐fluorotranylcypromine (FTCP), an analog of the monoamine oxidase (MAO)‐inhibiting antidepressant tranylcypromine (TCP) in which the 4 position of the phenyl ring is protected from metabolism. These studies demonstrated that FTCP is a more potent inhibitor of MAO ex vivo than is the parent drug. Despite its similarity in structure to p‐chloroamphetamine, FTCP does not cause a depletion of brain levels of 5‐hydroxytryptamine (5‐HT) after chronic administration; in fact, it increases brain 5‐HT to levels similar to those produced by TCP. After chronic administration, FTCP produces a downregulation of β‐adrenergic and tryptamine receptors, in common with TCP and several other antidepressants. Pretreatment of rats with iprindole or trifluperazine, drugs known to block cytochrome P450‐mediated hydroxylation reactions and to elevate brain levels of TCP, had no effects on FTCP brain levels, suggesting that metabolic drug–drug interactions may be less of a concern with FTCP than with TCP. In vitro uptake experiments in prisms prepared from hypothalamus or striatum revealed that TCP and FTCP are both potent inhibitors of norepinephrine (NE) uptake; FTCP is a more potent inhibitor of 5‐HT uptake than is TCP. FTCP is a more potent releaser of 5‐HT than is TCP. Drug Dev. Res. 48:61–69, 1999. © 1999 Wiley‐Liss, Inc.     

Milnacipran for fibromyalgia: a useful addition to the treatment armamentarium

Kidney transplantation is the best treatment option in chronic kidney disease patients. Despite the new potent immunosuppressants, the long-term graft survival has not significantly improved. This is a rather complex issue with interrelationship between pretransplant donor–recipient variables, recipient post-transplant perioperative non/immunological factors, the combination/dose of maintenance immunosuppression and the general noncompliance of the patient. The recipients with an increased immunological risk should be maintained on triple therapy with steroids, preferably tacrolimus (Tac) or cyclosporine (CsA) plus mycophenolate mofetil (MMF). Eventual calcineurin inhibitor (CNI) minimization should be coupled with either protocol biopsies or frequent biochemistry monitoring including periodical assessment of anti-human leukocyte antigen and donor-specific antibodies. Recipients with standard immunological risks may be considered for as low as possible triple immunosuppression (steroids, Tac/CsA, MMF) after a period of 6 – 12 months. In cases of CNI minimization, a modification with a higher dose of the other two drugs in the triple therapy combination might be considered. The nonadherence to the prescribed maintenance therapy should be regularly checked-up. In conclusion, antibody induction, MMF, steroids and low-dose Tac/CsA should be the mainstream therapy in majority of patients. The short- and mid-term encouraging results for CNI minimization/withdrawal seem to correspond to recent findings of chronic antibody-mediated rejection, and long-term results need further evaluation.     

Cytotoxicity and proliferative capacity impairment induced on human brain cell cultures after short‐ and long‐term exposure to magnetite nanoparticles

Since magnetic iron oxide nanoparticles (IONP) as magnetite (Fe₃O₄NPs) have potential applications in life sciences, industrial fields and biomedical care, the risks for occupational, general population and patients rises correspondingly. Excessive IONP accumulation in central nervous system (CNS) cells can lead to a disruption of normal iron metabolism/homeostasis, which is a characteristic hallmark resembling that of several neurodegenerative disorders. Fe₃O₄NPs‐ versus Fe₃O₄ bulk‐induced toxic effects have been assessed in two human CNS cells namely astrocytes (D384) and neurons (SH‐SY5Y) after short‐term exposure (4–24‐48 h) to 1–100 μg ml⁻¹, and long‐term exposure to lower concentrations. Short‐term Fe₃O₄NPs induced significant concentration‐ and time‐dependent alterations of mitochondrial function in D384 (25–75% cell viability decrease): effects started at 25 μg ml⁻¹ after 4 h, and 1 μg ml⁻¹ after 48 h. SH‐SY5Y were less susceptible: cytotoxicity occurred after 48  h only with 35–45% mortality (10–100 μg ml⁻¹). Accordingly, a more marked intracellular iron accumulation was observed in astrocytes than neurons. Membrane integrity was unaltered in both CNS cell types. Lowering Fe₃O₄NP concentrations (0.05–10 μg ml⁻¹) and prolonging the exposure time (up to 10 days), D384 toxicity was again observed (colony number decrease at ≥0.05 μg ml⁻¹, morphology alterations and colony size reduction at ≥0.5 μg ml⁻¹). Effects on SH‐SY5Y appeared at the highest concentration only. Fe₃O₄ bulk was always remarkably toxic toward both cells. In summary, human cultured astrocytes were susceptible to both Fe₃O₄NP and bulk forms following short‐term and extended exposure to low concentrations, while neurons were more resistant to NPs. Cellular iron overload may trigger adverse responses by releasing iron ions (particularly in astrocytes) thus compromising the normal functions of CNS. Copyright © 2016 John Wiley & Sons, Ltd.     

Panic disorder. A long‐term treatment study: fluoxetine vs imipramine

This double‐blind study evaluates the efficacy and tolerability of fluoxetine and imipramine in the acute and long‐term treatment of panic disorder in 38 patients meeting DSM‐IV criteria for panic disorder with or without agoraphobia. On the basis of HRSA mean scores evaluation, fluoxetine was found to be quicker than imipramine in reducing generalized anxiety at the end of the first week of treatment. However, through PASS and CGI mean scores evaluation, no statistically significant differences were found at any time in the efficacy of fluoxetine and imipramine on the total number of panic attacks, anticipatory anxiety or phobia severity. Fluoxetine has also turned out to be better tolerated than imipramine and to be effective at dosages low enough to avoid the event of an activation syndrome. Long‐term evaluation has shown high rates of persistent remission with both drugs. Copyright © 1999 John Wiley & Sons, Ltd.     

Review article: permissive underfeeding in short‐term nutritional support

Aliment Pharmacol Ther 2010; 32: 628–636

Summary

Background The importance of adequate nutritional support in selected patient groups is well established. Traditionally, the amounts of macronutrients provided have been based on a perceived need to achieve, if not exceed, energy and protein balance. In recent years, there has been increasing interest in the concept of ‘permissive underfeeding’. Aim To determine whether or not there is evidence of benefit for permissive underfeeding in selected groups. Methods Studies were identified from MEDLINE, Embase and PubMed databases and the Cochrane collaboration. The search was limited from January 1950 to January 2010. Further searches were made from the references of original articles. The literature search revealed 591 abstracts of relevant studies. All abstracts were initially reviewed by the primary author (AO) and those that did not fulfil the inclusion criteria were discarded. The remaining articles were requested and were reviewed independently by two authors (AO, JM). Results Twelve studies were included in the final analysis. Eight of these were randomized interventional trials. Three were prospective cohort studies and one was a retrospective analysis. Conclusion This review suggests that permissive underfeeding may be associated with improved outcomes and reduced morbidity in patients requiring short‐term nutritional support.     

Meta‐analysis: pre‐operative infliximab treatment and short‐term post‐operative complications in patients with ulcerative colitis

Aliment Pharmacol Ther 31 , 486–492

Summary

Background Infliximab was approved for use in ulcerative colitis in recent years. It has been debated if infliximab increases the risk of post‐operative complications in patients with ulcerative colitis. Aim To perform a meta‐analysis that examines the relationship between preoperative infliximab treatment and short‐term post‐operative complications in patients with ulcerative colitis. Methods We searched the PubMed and MEDLINE databases to identify observational studies on the impact of pre‐operative infliximab use on short‐term post‐operative complications in ulcerative colitis. Infectious complications mainly included wound infection, sepsis and abscess, whereas non‐infectious complications included intestinal obstruction, thromboembolism and gastrointestinal haemorrhage. Pooled odds ratios (ORs) were calculated for each relationship. Results A total of 5 studies and 706 patients were included in our meta‐analysis. Overall, we did not find a strong association between pre‐operative treatment of infliximab and short‐term infectious [OR 2.24, 95% confidence interval (CI) 0.63–7.95] or non‐infectious (OR 0.85, 95% CI 0.50–1.45) post‐operative complications in ulcerative colitis patients. On the contrary, we discovered that pre‐operative infliximab use increased short‐term total post‐operative complications (OR 1.80, 95% CI 1.12–2.87). Conclusions Pre‐operative infliximab use increased the risk of short‐term post‐operative complications. Subgroup analysis is underpowered to assess the nature of these complications but shows a trend towards increased post‐operative infection.     

Short‐term and long‐term evaluation of selective serotonin reuptake inhibitors in the treatment of panic disorder: fluoxetine vs citalopram

This double‐blind study evaluates the efficacy and tolerability of fluoxetine and citalopram in the acute and long‐term treatment of panic disorder in 42 patients meeting DSM‐IV criteria for panic disorder with or without agoraphobia. Fluoxetine and citalopram showed similar efficacy in the treatment of panic disorder patients. On the basis of HRSA and PASS mean score evaluation, fluoxetine was more rapid than citalopram in reducing generalized anxiety symptoms, spontaneous panic attacks and anticipatory anxiety. Fluoxetine appeared to be effective at a dosage of 10 mg/day, while citalopram reached the same efficacy at a dosage of 30 mg/day. Long‐term evaluation has demonstrated high rates of persistent full remission with both drugs. Copyright © 1999 John Wiley & Sons, Ltd.