Nadia Salem

• Managing Director at Sigma Tau Pharmaceuticals

Gimatecan is a lipophilic oral camptothecin analogue with preclinical activity in glioma models. We conducted a multicenter phase II trial to evaluate the efficacy of gimatecan in adults with recurrent glioblastoma. Eligibility criteria included ≤1 prior treatment for recurrent disease, age ≥18, Eastern Cooperative Oncology Group performance status...

A phase I study was conducted to determine the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) of gimatecan, a lipophilic camptothecin analogue, administered orally once a week for 3 weeks. Adult patients with advanced solid tumors with good performance status and adequate hematologic, hepatic, and renal function were eligible for t...

This study tested the hypothesis that the expression of uncoupling proteins (UCPs) and dopamine (DA) system genes is responsive to 3-nitropropionic acid (3-NPA) neurotoxic effects and to the neuroprotective effects of the mitochondrial enhancer, l-carnitine (LC), in the rat striatum. Inactivation of mitochondrial succinate dehydrogenase (SDH) by 3-...

Adult, male Sprague-Dawley rats were injected with 3-ni-tropropionic acid (3-NPA) at 30 mg/kg or methamphetamine (METH) at 20 mg/kg alone or following pretreatment with L-cartnitine (LC) at 100 mg/kg. Rectal temperature was measured before and 4 h following treatment. Animals were sacrificed at 4 h posttreatment. Monoamine neurotransmitters, dopami...

Introduction: Docosahexaenoic acid (22:6n3; DHA), an essential fatty acid (EFA), is a major component of the nervous system and is required for optimal neuronal function. Human infants can synthesize DHA from dietary alpha-linolenic acid (18:3n3;LNA) with eicosapentaenoate (20:5n3; EPA) and docosapentaenoate (22:5n3; DPA) as intermediates. It is of...

Hereditary sideroblastic anemia is a very rare disease recessive and X-linked that affect heme biosynthesis by deficit or decreased of delta aminolevulinic acid synthase (ALAS) activity. We report a case of a six-month-old boy, admitted in the hospital for anemic syndrome. The hemogram showed anemia (hemoglobin: 4.5 g/dL), frankly hypochronic micro...

A novel tracer technique is presented for the simultaneous and independent measurement of multiple stable isotopically labeled essential fatty acids. Gas chromatography/negative chemical ionization mass spectrometry was employed for high sensitivity detection of the following isotopes: deuterium-labeled-linolenate, carbon-13-U-labeled-eicosapentaen...

Neonatal listeriosis is an exceptional disease in Northern Africa. Hence, protocols for maternal-fetal infection treatment include only a third generation cephalosporin and an aminoside. This protocol does not take into account the possibility of Listeria monocytogenes infection. We report a fatal case of neonatal listeriosis in Tunisia. The use of...

The aim of the study was to explore nosocomial neonatal outbreak of Klebsiella pneumoniae producing extended-spectrum-betalactamase by macrorestriction genotyping. Over a 25 days period, a hospital neonatal outbreak due to Klebsiella pneumoniae producing extended-spectrum-betalactamase affected 14 newborn infants admitted to a university hospital i...

Background. – The aim of the study was to explore nosocomial neonatal outbreak of Klebsiella pneumoniae producing extended-spectrum-betalactamase by macrorestriction genotyping.Patients and methods. – Over a 25 days period, a hospital neonatal outbreak due to Klebsiella pneumoniae producing extended-spectrum-betalactamase affected 14 newborn infant...

The purpose of our study was to clarify the frequency of these causes. Retrospective study using reports of newborns in the neonatal unit in Sousse (Tunisia) from 1991 to 1996, hospitalized for hemorrhagic syndrome defined by bleeding, exteriorized or not, whatever its importance, severity, causes and the associated clinical and biological disorder...

The loss of docosahexaenoic acid (DHA) from the retina or brain has been associated with a loss in nervous-system function in experimental animals, as well as in human infants fed vegetable oil-based formulas. The reversibility of the loss of DHA and the compensation by an increase in the n-6 docosapentaenoic acid (DPAn-6) was studied in young adul...

Newborns hemorrhagic syndromes have multiple causes.Purpose. – The purpose of our study was to clarify the frequency of these causes.Patients and methods. – Retrospective study using reports of newborns in the neonatal unit in Sousse (Tunisia) from 1991 to 1996, hospitalized for hemorrhagic syndrome defined by bleeding, exteriorized or not, whateve...

Objectives The aim of the study was to identify the germ for neonatal septicemia and to propose the first-line antibiotherapy Material and methods A retrospective review was made of 202 cases of septicemia with positive blood culture in neonates admitted to a neonatal intensive care unit in Sousse (Tunisia) between 1991 and 1993 Results Two-third...

Neonatal alcaligenes xylosoxydans infection is characterized by a low incidence, possible nosocomial transmission, a severe infectious syndrome, diagnostic and therapeutic difficulties, and a grim prognosis. Two cases of nosocomial A. xylosoxydans meningitis caused in neonates by application of a contamined 2% aqueous eosin solution are reported. T...

Human adults are shown to be capable of conversion of linoleic acid (LA, 18:2 n-6) to arachidonic acid (AA, 20:4 n-6) in vivo. It is confirmed that they can also convert alpha-linolenic acid (LNA, 18:3 n-3) to eicosapentaenoic acid (EPA, 20:5 n-3) and to docosahexaenoic acid (DHA, 22:6 n-3) in vivo. The time course and the maximal response for thes...

Nosocomial infections, most notably those due to multidrug-resistant (MDR) organisms, are common in neonatal intensive care units. When they fail to respond to conventional antimicrobials, as is often the case, fluoroquinolone therapy should be considered. Ten cases of neonatal MDR infections (including nine due to nosocomial organisms) treated wit...

Without Abstract

Indirect evidence has suggested that long chain polyunsaturated fatty acids (LCPUFA) synthesis is insufficient for requirements in the newborn infant, and specially in the premature. We studied in vivo the elongation and desaturation of linoleic acid (LA) to arachidonic acid (ARA) and linoleic (LNA) to docosahexanoic acids (DHA). The infants receiv...

Rhesus monkeys that were maintained on a diet containing low, yet adequate, amounts of vitamins C and E and in which linoleate and linolenate represented 1.4% and 0.08% of the total caloric intake, respectively, developed liver fibrosis after consuming alcohol (mean, 2.6 g kg(-1) d[-1]) over a period of 3 years. In the liver, several polyunsaturate...

The elucidation of phospholipid molecular species composition provides detailed structural information concerning various lipids and thus offers descriptions of crucial determinants of membrane physical and biological properties. Various methods differing in labor intensity, mode of separation and detection, type of calibration, as well as other fa...

A study was carried out in domestic felines to determine whether corn oil-based maternal diets are an adequate source of essential fatty acids to support normal accumulation of long-chain polyunsaturated fatty acids in the brains and retinas of offspring and whether these diets have any subsequent effect on visual function. Female domestic felines...

A high-performance liquid chromatographic method with evaporative light-scattering detection was developed for the analysis of intact lipid classes in nervous tissue. The method had the ability to resolve plasmalogen-phosphatidyl-ethanolamine and diacyl-phosphatidylethanolamine along with other major phospholipid classes in a single run. This techn...

A study was carried out to determine whether corn oil-based diets devoid of arachidonic acid, 20:4(n-6), are capable of supporting feline reproduction. One group of four adult female felines were acclimated to a 10 weight% (wt%) fat diet consisting of 1 wt% corn oil and 9 wt% hydrogenated coconut oil for 1 mo before mating. One female produced two...

Background: Among an independent group of subjects selected for their history of violent, impulsive behaviors and nonviolent control subjects, we attempted to replicate the finding that plasma docosahexaenoic acid concentrations were negatively correlated with cerebrospinal fluid 5-hydroxyindoleacetic acid (CSF 5-HIAA) concentrations. Methods: CSF...

The omega-3 polyunsaturated fatty acid docosahexaenoic acid is highly enriched in neuronal membranes, and several studies suggest that DHA is critical for neuronal development. We have investigated the effects of exogenously applied DHA on voltage-gated K+ channels using patch-clamp techniques. DHA produced a concentration-dependent inhibition of t...

Anandamide has been identified in porcine brain as an endogenous cannabinoid receptor ligand and is believed to be a counterpart to the psychoactive component of marijuana, delta 9-tetrahydrocannabinol (delta 9-THC). Here we report that anandamide directly inhibits (IC50, 2.7 muM) Shaker-related Kv1.2 K+ channels that are found ubiquitously in the...

It is becoming clear that an adequate level of long-chain highly unsaturated fatty acids in the nervous system is required for optimal function and development; however, the ability of infants to biosynthesize long-chain fatty acids is unknown. This study explores the capacity of human infants to convert 18-carbon essential fatty acids to their elo...

A high-performance liquid Chromatographie method with the ability to resolve plasmalogen-phosphatidylethanolamine and diacyl phosphatidylethanolamine along with other major phospholipid classes of nervous tissue in a single run was developed. This method was employed for the investigation of the effects of chronic alcohol consumption on the membran...

Recent studies have both offered and contested the proposition that lowering plasma cholesterol by diet and medications increases suicide, homicide, and depression. Significant confounding factors include the quantity and distribution of dietary n-6 and n-3 polyunsaturated essential fatty acids that influence serum lipids and alter the biophysical...

Alcohol altered the fatty acyl composition of the liver, brain, and retina of domestic felines that were maintained on a diet having low, but adequate, amounts of essential fatty acids. For 8 mo, seven adult cats were provided a diet with 10% fat (by wt), consisting of 9:1 ratio of hydrogenated coconut oil:corn oil. During 6 of these 8 mo, four of...

Docosahexaenoic acid (22:6n3) acts at an extracellular site to produce a voltage- and time-dependent block of the delayed rectifier current (IK) similar to that classically described for intracellularly applied quaternary ammonia compounds. In dissociated cells from the pineal gland, some long-chain polyunsaturated fatty acids reduced both late sus...

Sub-micromolar levels of the lipoxygenase products of n-3 fatty acids specifically antagonize both the contractile effects of thromboxane (U46619) and its platelet aggregating effect. In addition, OH-22:6n3 inhibits thromboxane-induced decreases in cerebral blood flow of the rat. Analysis of binding parameters indicates these derivatives induce a m...

Although mammalian tissues contain high levels of polyunsaturated fatty acids, our knowledge of the effects of the degree of unsaturation and double-bond location upon bilayer organization is limited. Therefore, a series of mixed-chain unsaturated phosphatidylcholines (PC) comprised of 18:0 at the sn-1 position and various unsaturates at the sn-2 p...

A comparison was made between the liver and brain conversion of linoleic acid, 18:2n-6, and linolenic acid, 18:3n-3, to long chain polyunsaturated fatty acids in domestic felines. This report demonstrates that 6-desaturase activity does exist in the feline. The liver produced deuterium-labeled polyunsaturated fatty acids up to 22:4n-6 and 22:5n-3....

Mammalian platelets are capable of enzymatically producing a number of n-6 and n-3 hydroxy fatty acids. Human platelet suspensions produce two major docosahexaenoic acid (22:6n3) metabolites, namely, 11-OH and 14-OH-22:6n3. The hydroxy fatty acids which were formed by human platelets and purified by high performance liquid chromatography specifical...

Dietary supplementation with different classes of polyunsaturate fatty acids is known to result in their incorporation into cell membranes, but the effects of this on eicosanoid formation and other cell functions frequently does not correspond to the degree of alteration in total membrane fatty acids. This phenomenon may be related to the compartme...

Human platelet suspensions are capable of lipoxygenating docosahexaenoic acid (22:6n3) to an 11(S)-OH-, 14(S)-OH- or 17(S)-OH-22:6n3. The structure and stereochemical purity of these derivatives were confirmed by GC/MS and chiral phase LC analysis. The purified OH-22:6n3 positional isomers which are formed by human platelets were capable of inducin...

A sensitive negative chemical ionization (NCI) gas chromatography-mass spectrometry (GC-MS) method for the detection of pentafluorobenzyl (PFB) esters of deuterated fatty acids is described. Deuterated linoleic [18:2n-6 2H4-9,10,12,13] and linolenic [18:3n-3 2H5-17,17,18,18,18] acids were converted to chain-elongated and desaturated products during...

12-Hydroxyeicosatetraenoic acid (12-HETE) production from arachidonic acid by cerebral microvessels isolated from perfused adult murine brain was reduced by the lipoxygenase inhibitors baicalein, esculetin, gossypol, nordihydroguaiaretic acid, and quercetin. Except for quercetin and gossypol, the IC50 did not exceed 10 microM. Each inhibitor, excep...

A rapid and reliable method for the separation of lipid classes is described using aminopropyl disposable columns. This method is a modification to an existing procedure that allows the separation of both neutral and acidic phospholipid fractions and a high recovery of the latter. Acidic phospholipids were eluted with a mixture of hexane-2-propanol...

The stereochemical configuration of hydroxylated products of docosahexaenoic acid (22:6w3) formed by human platelets and rat brain homogenate were characterized for the first time. Chiral phase HPLC was employed along with autooxidized 22:6w3 as reference material. The 14- and 11-hydroxy 22:6w3 (HDHE) products produced by human platelets were in th...

The metabolism of docosahexaenoic acid (22:6w3) by 15-lipoxygenase activity of washed human platelets was investigated. Platelets produced 17-hydroxydocosahexaenoic acid (HDHE) when incubated with 22:6w3. Similarly, 15-hydroxyeicosatetraenoic acid (HETE) and 13- and 9-hydroxyoctadecadienoic acids (HODD) were produced when incubated with 20:4w6 and...

A new method is described for the separation of individual molecular species of the aminophospholipids, phosphatidylethanolamine and phosphatidylserine. Trinitrobenzene-sulfonic acid was used to derivatize both aminophospholipids and the derivatives were purified by thin-layer chromatography. A reversed-phase high performance liquid chromatography...

Conflicting results exist in the literature on the conversion of eicosapentaenoic acid (EPA) to trienoic prostaglandins and its influence on the formation of dienoic prostaglandins from arachidonic acid (AA). Tissues from animals fed fish oils produce little, if any, trienoic prostaglandins and reduced amounts of dienoic ones. Excretion of the majo...

A sensitive and selective assay for measuring prostaglandins in cerebrospinal fluid has been developed, based on the selected-ion-monitoring, electron-capture negative ionization GC/MS detection for the MO-PFB-TMS derivatives of prostaglandins E2, E1, F2 alpha, F1 alpha, and 6-keto-F1 alpha. Improvements over previously published assay procedures h...

A new method to determine the structure of lipoxygenase reaction products is presented. Thermospray mass spectra of hydroperoxy derivatives of polyunsaturates contain both molecular ion species and fragments reflecting the position of oxygenation. Data are presented for hydroperoxy-docosahexaenoic, eicosapentaenoic, arachidonic and linoleic acids i...

It has been previously reported that ethanol alters the level of polyunsaturated fatty acids, and this may be related to alteration of membrane physical properties. Therefore, developing a technique to efficiently analyze lipid molecular species is of value for alcohol research. A new technique which can provide detailed structural information for...

The principal features of the hypotheses presented here are presented in a model (Figure 8). Polyunsaturated phospholipids are preferentially localized on the cytosolic leaflet of the plasma membrane and around proteins. They influence the physical state of these microenvironments and thereby help to regulate cellular functions. Losses of these spe...

Washed platelets (10(8)cells/ml) are capable of metabolizing docosahexaenoic acid (22:6w3, DHE) to 12-lipoxygenase derivatives. The two major metabolites of the DHE thus formed were collected and derivatized for analysis by GC/MS/EI. The structures assigned were 14(S) and 11(S) hydroxy-docosahexenoate (HDHE). 12-lipoxygenase inhibitors such as ETYA...

It is known that alcohol exposure leads to a decline in brain docosahexaenoate (22:6w3). We hypothesized that alcohol could stimulate the metabolism of this polyunsaturated fatty acid to bioactive products. Several oxidized products of 22:6w3 were indeed observed when rat brain homogenate was incubated with 14C22:6w3 in vitro. A similar group of me...

Thermospray mass spectrometry has proven to be a useful technique for analyzing various biological compounds including eicosanoids and phospholipids. Molecular ions as well as fragment ions which reveal useful structural information are produced for underivatized eicosanoids and phospholipids using filament-off or filament-on thermospray mass spect...

The effect of free radicals, enzyme inhibitors, and free radical scavengers on docosahexaenoic acid (22: 6w3) metabolism by rat brain homogenate was studied in vitro. Rat brain homogenate was incubated with [14C]-22: 6w3 at 37°C for 15 min, and hydroxylated (1–3) 22: 6w3 compounds were separated by reversed-phase high-performance liquid chromatogra...

Inhalation chambers with a monitoring and control apparatus for ethanol vapor exposure of small animals were constructed. A thermal conductivity detector was employed for continuous measurement of inhalation chamber ethanol vapor concentration. The concentration was maintained within a very narrow range (± 1 mg/IHer) by incorporating into the desig...

Spontaneous 6-keto-PGF1 alpha and TXB2 levels in isolated rat aortic rings increased in a concentration dependent manner after a 0.5 hour incubation with moderate or high ethanol concentrations (11 mM to 218 mM). After a 1 hour incubation with moderate concentrations of ethanol less than or equal to 22 mM) spontaneous prostaglandin (PG) production...

The objective of this study was to determine if polyunsaturated fatty acid levels in rat tissues are altered by alcohol exposure. Therefore, rats were exposed to ethanol vapor using an inhalation system designed in their laboratory and capable of producing rats with blood ethanol concentrations (BEC) of 50-400 mg%, as desired. Mean BEC were determi...