BACKGROUNDCritically ill patients suffer from physiological sleep deprivation and have reduced blood melatonin levels. This study was designed to determine whether nocturnal melatonin supplementation would reduce the need for sedation in patients with critical illness.METHODSA single-center, double-blind randomized placebo-controlled trial was carried out from July 2007 to December 2009, in a mixed medical-surgical Intensive Care Unit of a University hospital, without any form of external funding. Of 1158 patients admitted to ICU and treated with conscious enteral sedation, 82 critically-ill with mechanical ventilation >48 hours and Simplified Acute Physiology Score II>32 points were randomized 1:1 to receive, at eight p.m. and midnight, melatonin (3+3mg) or placebo, from the third ICU day until ICU discharge. Primary outcome was total amount of enteral hydroxyzine administered.RESULTSMelatonin treated patients received lower amount of enteral hydroxyzine. Other neurological indicators (amount of some neuroactive drugs, pain, agitation, anxiety, sleep observed by nurses, need for restraints, need for extra sedation, nurse evaluation of sedation adequacy) seemed improved, with reduced cost for neuroactive drugs. Post-traumatic stress disorder prevalence did not differ between groups, nor did ICU or hospital mortality. Study limitations include the differences between groups before intervention, the small sample size, and the single-center observation.CONCLUSIONLong-term enteral melatonin supplementation may result in a decreased need for sedation, with improved neurological indicators and cost reduction. Further multicenter evaluations are required to confirm these results with different sedation protocols.

Analgesic/sedative therapy is necessary in ICU patients; however, it presents important side effects. Critically ill patients have altered circadian rhythm, delirium and agitation often requiring additional sedation. The dramatically reduced endogenous blood melatonin level (basal and night peaks) could play a role in this context. We evaluated the effects of oral melatonin administration on the adaptation to critical illness and invasive procedures in high-risk critically ill patients [1] consciously sedated [2].

Oxygen (O2) is often thought of as a double-edged sword: all forms of life actually need O2 for survival as the terminal acceptor of electrons in oxidative phosphorylation, but excess O2 might increase formation of reactive O2 species (ROS). Whereas on one hand ROS trigger uncontrolled burst of free radicals that lead to potentially lethal injury, on the other hand they act as messengers that elicit cell protection and improve survival through a variety of mechanisms. Although one can easily expect a link of O2 with tumor growth and metastatic potential, there is no univocal role for O2 in cancer.

The pineal hormone melatonin is involved in physiological transduction of temporal information from the light dark cycle to circadian and seasonal behavioural rhythms, as well as possessing neuroprotective properties. Melatonin and its receptors MT1 and MT2, which belong to the family of G protein-coupled receptors, are impaired in Alzheimer's disease (AD) with severe consequences to neuropathology and clinical symptoms. The present data provides the first immunohistochemical evidence for the cellular localization of the both melatonin receptors in the human pineal gland and occipital cortex, and demonstrates their alterations in AD. We localized MT1 and MT2, in the pineal gland and occipital cortex of 7 elderly controls and 11 AD patients using immunohistochemistry with peroxidase-staining. In the pineal gland both MT1 and MT2, were localized to pinealocytes, whereas in the cortex both receptors were expressed in some pyramidal and non-pyramidal cells. In patients with AD, parallel to degenerative tissue changes, there was an overall decrease in the intensity of receptors in both brain regions. In line with our previous findings, melatonin receptor expression in AD is impaired in two additional brain areas, and may contribute to disease pathology.

PURPOSE: To investigate the tissue levels and distribution of amphotericin B in lung after i.v. administration of liposomal amphotericin B (L-AmB) in patients with lung cancer resected.

The aim of the present study was to identify the distribution of the second melatonin receptor (MT2) in the human hippocampus of elderly controls and Alzheimer's disease (AD) patients. This is the first report of immunohistochemical MT2 localization in the human hippocampus both in control and AD cases. The specificity of the MT2 antibody was ascertained by fluorescence microscopy using the anti-MT2 antibody in HEK 293 cells expressing recombinant MT2, in immunoblot experiments on membranes from MT2 expressing cells, and, finally, by immunoprecipitation experiments of the native MT2. MT2 immunoreactivity was studied in the hippocampus of 16 elderly control and 16 AD cases. In controls, MT2 was localized in pyramidal neurons of the hippocampal subfields CA1-4 and in some granular neurons of the stratum granulosum. The overall intensity of the MT2 staining was distinctly decreased in AD cases. The results indicate that MT2 may be involved in mediating the effects of melatonin in the human hippocampus, and this mechanism may be heavily impaired in AD.

The distribution of amphotericin B in lung tissue was studied in 18 patients with primary or secondary lung cancer who underwent thoracotomy and pulmonary resection. At different times before surgery the patients were treated with liposomal amphotericin B 1.5 mg/kg by i.v. infusion over 1h. Blood and lung tissue samples were collected during surgery (one subject for each collecting time) and assayed for amphotericin B levels by HPLC. Due to surgical requirements, it was possible to obtain data from the loth to the 25(th) h after the end of infusion. Plasma amphotericin B concentrations progressively decreased from 3.4 mu g/ml at the loth h to 1 mu g/ml at the 25(th) h after the end of intravenous infusion.In lung tissue samples the lowest amphotericin B concentration (about 1 mu/g) was observed at the loth h, then a progressive increase was observed with the highest value (2.5 mu g/g) determined at the 25(th) h.

Study Design. In vitro assays were performed with bone-forming cells isolated from 41 patients with adolescent idiopathic scoliosis and 17 control patients exhibiting another type of scoliosis or none.Objective. To determine whether a dysfunction of the melatonin-signaling pathway in tissues targeted by this hormone is involved in adolescent idiopathic scoliosis.Summary of Background Data. Pinealectomy in chicken has led to the formation of a scoliotic deformity, thereby suggesting that a melatonin deficiency may be at the source of adolescent idiopathic scoliosis. However, the relevance of melatonin in the etiopathogenesis of that condition is controversial because most studies have reported no significant change in circulating levels of melatonin in patients with adolescent idiopathic scoliosis.Methods. Primary osteoblast cultures prepared from bone specimens obtained intraoperatively during spine surgeries were used to test the ability of melatonin and Gpp(NH)p, a GTP analogue, to block cAMP accumulation induced by forskolin. In parallel, melatonin receptor and Gi protein functions were evaluated by immunohistochemistry and by coimmunoprecipitation experiments. Results. The cAMP assays demonstrated that melatonin signaling was impaired in osteoblasts isolated from adolescent idiopathic scoliosis patients to different degrees allowing their classification in 3 distinct groups based on their responsiveness to melatonin or Gpp( NH) p.Conclusion. Melatonin signaling is clearly impaired in osteoblasts of all patients with adolescent idiopathic scoliosis tested. Classification of patients with adolescent idiopathic scoliosis in 3 groups based on functional in vitro assays suggests the presence of distinct mutations interfering with the melatonin signal transduction. Posttranslational modifications affecting Gi protein function, such as serine residues phosphorylation, should be considered as one possible mechanism in the etiopathogenesis of AIS.

ABSTRACT The in vitro and in vivo antichlamydial activities of dexamethasone and beclomethasone alone and in combination with an antibiotic were tested. In vitro, dexamethasone and beclomethasone decreased the number of inclusion-forming units versus the control number ( P < 0.001). The combination of glucocorticoids with azithromycin, telithromycin, or levofloxacin was more active than antibiotics used alone ( P < 0.001). The combination, tested in a murine Chlamydophila pneumoniae infection model, produced similar results.

We studied absorption, efficacy, and tolerability in Parkinson's disease (PD) of a new preparation of apomorphine included in a microemulsion and administered by transdermal route (Apo‐MTD). Twenty‐one PD patients were treated with levodopa plus oral dopamine‐agonists (T0), with levodopa alone (T1), finally with levodopa plus Apo‐MTD (T2). Apo‐MTD provided therapeutic plasma levels for many hours, improved Unified Parkinson's Disease Rating Scale III scores, and reduced total duration of off periods compared to T0 and T1. We concluded that Apo‐MTD is absorbed and demonstrates clinical efficacy and long action. Therefore, it seems a promising add‐on treatment for uncontrolled prolonged off phases in PD patients, but chronic tolerability needs further study. © 2004 Movement Disorder Society

3738 Background: Oxaliplatin(OHP) and 5Fluorouracil(5FU) efficacy and toxicity strictly depend on circadian rhythms in cell cycle regulation, reduced glutathione content, dehydropyrimidine and thymidilate synthase activities, topoisomerase I activity, membrane permeability as well as liver and renal blood flow. Methods: From August 2002 to December 2003 (Tab.1) 27 untreated colorectal cancer patients(pt) were treated with OHP based chronomodulated delivery schedule using Melodie infusion system: OHP 25 mg / m2 /d1–4q14 (sinusoidal 12 hour infusion with flow rate peak at 4:00pm); 5FU 900 mg/m2 and L-Folinic Acid (LFA) 150 mg/m2 d1–4,q14 (sinusoidal 12 hour infusion with flow rate peak at 4:00am. Results: 147 cycles (6.11 average per pt.) were performed: average dose intensity was 48,21 mg/sqm/w, 319,28 mg/sqm/w 1630,41mg/sqm/w for OHP, LFA and 5FU respectively. Average dose according to body surface was 501mg/sqm, 3184,17mg/sqm, 16705,74mg/sqm respectively. No cycle was delayed due to toxicity. Haematological and hepatic toxicity weren't observed, neither was any gr. 4(WHO) toxicity. Radiological Objective Response evaluation has been performed in 23 pt (Tab.2). ORR was 65,22%. Median survival reached 13 months (only 3 pt died). Conclusions: These data seem confirm that FFL4/10 schedule has very interesting activity in metastatic colorectal cancer. Moreover, chronomodulated infusion is considerably less toxic than conventional flat or bolo infusion. No significant financial relationships to disclose.

Plasma concentrations of pirprofen and of its pyrrol metabolite were assessed in 9 elderly patients (3 males, 6 females; mean age 76 years) suffering from chronic degenerative disease. Pirprofen 400 mg in 4 ml was administered i.m. and the pharmacokinetic profile of the drug and the metabolite was calculated.

The pineal secretory product melatonin provides a circadian and seasonal signal in vertebrates regulating responses to changes in day length [1–3]. The biological clock in the suprachiasmatic nucleus (SCN), entrained by the light-dark cycle, controls the rhythm of melatonin synthesis in the pineal gland with the highest levels of melatonin production occurring during the night [1–5]. Melatonin provides a hormonal signal of darkness. The physiological effects of melatonin include retinal [6], antioxidative [7], neuroprotective [8, 9], vasoactive [10–12], immunological [13] and oncostatic [14] properties. In mammals melatonin acts through two specific highaffinity membrane receptors, MT1 (previously termed Mel1a) and MT2 (previously termed Mel1b), which have been cloned and characterized [15–18]. They share a common seven-transmembrane structure and transduce signals via G protein-coupling. Whereas MT1 is coupled to different G proteins that mediate adenylyl cyclase inhibition and phospholipase Cb activation, MT2 is also coupled to inhibition of adenylyl cyclase and additionally inhibits cyclic GMP levels via the soluble guanylyl cyclase pathway [5, 19]. A third melatonin receptor, Mel1c, was cloned from Xenopus [20] and birds [21] but is not found in mammals, so that of the family of three melatonin receptor subtypes in vertebrates, only two are present in mammals [5]. MT1 mRNA distribution has been studied in different mammalian brains including rodents [22] and humans [23, 24]. In human central nervous system (CNS) MT1 mRNA is expressed in SCN [23], cerebellum, occipital, parietal, frontal and temporal cortex, thalamus and hippocampus [24]. There is also immunohistochemical evidence for the presence of MT1 in human hippocampus [24], cerebrovascular tissue [11] and retina [25]. The presence of MT2 mRNA in CNS, on the other hand, has been shown in rodent SCN using in situ hybridization [26] and quantitative receptor autoradiography [27]. Thus far, in the human CNS, MT2 mRNA has been found in the cerebellum [28], and RT-PCR revealed MT2 expression in the hippocampus [15]. However, the exact cellular distribution of MT2 in human CNS is still not known. As specific antibodies against MT2 have been developed recently [29], we studied MT2 distribution in human hippocampus using immunohistochemistry. The results were compared with findings in the hippocampus of Alzheimer’s disease (AD) patients, because melatonin alterations may contribute to AD symptomatology and pathology, and hippocampus is a brain region highly implicated in AD-related neurodegeneration [3, 8, 9]. This study provides the first immunohistochemical description of MT2 distribution in human hippocampus and provides evidence for altered expression of MT2 in patients affected with AD.

Inflammation is crucial for the pathogenesis of both infectious and chronic obstructive pulmonary diseases. It is therefore important to modulate pulmonary inflammation in patients with these lung disorders. Macrolide antibiotics modulate inflammation in vitro and in in vivo by inhibiting the production of proinflammatory cytokines and prostaglandin E2, neutrophil chemotactic activity and elastase activity. This study evaluates the effect of clarithromycin (500 mg b.i.d. x 7 days) in comparison to amoxicillin (1 g t.i.d. x 7 days) in patients with community acquired pneumonia by testing plasma levels of IL-6, IFNgamma and IL-10 before starting therapy and at the 3rd and 7th days of therapy. Clarithromycin significantly decreased plasma levels of IL-6 and significantly increased those of IFNgamma and IL-10 at the 3rd and 7th day in comparison to basal levels. In patients treated with amoxicillin a significant decrease in IL-6 plasma levels was observed at the 7th day of therapy, probably in relation to the resolution of inflammatory symptoms. In the same patients IFNgamma plasma levels decreased during treatment while IL-10 plasma levels were unaffected.