Extracorporeal photochemotherapy: a safety and tolerability pilot study with preliminary efficacy results in refractory relapsing-remitting multiple sclerosis.

Extracorporeal photochemotherapy (ECP) is an immunomodulating procedure consisting of autologous reinfusion of peripheral blood mononuclear cells (PBMC) after direct exposure to 8-methoxy-psoralen and UV-A. It has been described as a successful treatment for different T-cell-mediated diseases and preliminary results suggest that ECP might be effective in the treatment of relapsing-remitting multiple sclerosis, but does not significantly alter the course of the progressive form of MS. In this study, we report the safety data and some preliminary efficacy evidence obtained using ECP in the treatment of five patients with refractory relapsing-remitting (RR) MS: in most cases ECP induced a reduction in the relapse rate and an EDSS stabilisation, with an apparent general MRI stabilisation. In conclusion, our results confirm ECP safety and tolerability and suggest that this treatment might be useful as a therapeutic alternative in the subgroup of RRMS patients not responsive to or not eligible for traditional immunomodulating or immunosuppressive treatments.

Extracorporeal photochemotherapy reduces the severity of Lewis rat experimental allergic encephalomyelitis through a modulation of the function of peripheral blood mononuclear cells.

Extra corporeal photochemotherapy (ECP) is an immunomodulating procedure used in several nonneurological diseases which, similarly to multiple sclerosis, are likely to be due to T-cell-mediated autoimmunity and it is probable that ECP can modulate the normal activity of peripheral blood mononuclear cells (PBMC). Using the Lewis rat experimental allergic encephalomyelitis (EAE) model of human multiple sclerosis (MS) we examined the effect of extracorporeal UV-A irradiation on psoralen-activated PBMC. In our experiment the comparison between the two groups of animals (ECP or sham-treatment) evidenced that the ECP treatment reduced the severity of EAE on clinical grounds and this result was confirmed by the pathological examination. The changes in the titers of anti-myelin antigen antibodies typical of EAE were also modulated by the procedure. Ex vivo examination evidenced a significant reduction in tumor-necrosis factor-alpha (TNF-alpha) released by PBMC after lipopolysaccharides (LPS) stimulation in culture. We conclude that ECP modifies the normal activity of PBMC during the course of EAE and it is possible that one of the anti-inflammatory mechanisms of action of ECP is correlated to a down-regulation of T-helper 1 lymphocytes activity.

Pixantrone (BBR2778) reduces the severity of experimental allergic encephalomyelitis.

Pixantrone is less cardiotoxic and is similarly effective to mitoxantrone (MTX) as an antineoplastic drug. In our study, pixantrone reduced the severity of acute and decreased the relapse rate of chronic relapsing experimental allergic encephalomyelitis (EAE) in rats. A marked and long-lasting decrease in CD3+, CD4+, CD8+ and CD45RA+ blood cells and reduced anti-MBP titers were observed with both pixantrone and MTX. In vitro mitogen- and antigen-induced T-cell proliferation tests of human and rodents cells evidenced that pixantrone was effective at concentrations which can be effectively obtained after i.v. administration in humans. Cardiotoxicity was present only in MTX-treated rats. The effectiveness and the favorable safety profile makes pixantrone a most promising immunosuppressant agent for clinical use in multiple sclerosis (MS).

Nerve growth factor and transforming growth factor-beta serum levels in acute stroke patients. Possible involvement of neurotrophins in cerebrovascular disease.

BACKGROUND AND PURPOSE: Experimental evidence indicates cytokine and neurotrophin production in brain tissue after stroke. Since neurotrophins may also be released from blood cells, we measured nerve growth factor (NGF) and transforming growth factor (TGF)-beta serum levels in 40 patients at various times after stroke and compared them to those in 20 healthy controls. METHODS: Venous blood was obtained 1, 4, 10, 30 and 90 days after stroke and NGF and TGF-beta serum levels were measured by commercial ELISA. Values at each time were correlated with stroke severity, assessed using the National Institute of Health Stroke Scale, and with lesion volume, calculated using Cavalieri's direct estimator on a computerized tomography scan performed 5 days after stroke. RESULTS AND CONCLUSIONS: Although no significant differences between the two groups were demonstrated, in stroke patients, serum neurotrophins were significantly associated with clinical and neuroradiological parameters of brain injury and positively correlated with each other in the acute phases of stroke, suggesting that stroke may modulate peripheral neurotrophin levels.

Increased glutamate in CSF and plasma of patients with HIV dementia.

BACKGROUND: Experimental evidence suggests that excitotoxicity might play a major role in HIV-induced neurodegeneration. However, few studies have investigated the role of endogenous glutamate in patients with HIV dementia. OBJECTIVE: To analyze CSF and plasma glutamate levels in 30 patients with AIDS with different dementia severity compared with 10 patients with other neurologic disorders, 11 healthy control subjects, and 10 patients with Alzheimer-type dementia. METHODS: CSF and plasma glutamate levels were measured by reverse-phase high-performance liquid chromatography followed by fluorometric analysis. RESULTS: Glutamate CSF levels were increased fivefold in the patients with HIV vs normal control subjects (p = 0.001), patients with Alzheimer-type dementia (p < 0.0001), and patients with other neurologic disorders (p < 0.01). CSF glutamate levels were also related to the degree of dementia (p < 0.02) and brain atrophy (p < 0.002). Plasma levels were also higher in the patients with HIV (p < 0.0001) but did not correlate with either clinical or imaging features. CONCLUSION: Increased CSF glutamate may originate within the CNS and may play a pathogenetic role in HIV dementia, thus supporting the treatment of these patients with glutamate receptor antagonists.

Recalcitrant organochlorine compounds in captive bottlenose dolphins (Tursiops truncatus): biomagnification or bioaccumulation?

Organochlorine residues were measured in the diet, blood, faeces and exhaled air of captive bottlenose dolphins (Tursiops truncatus) to evaluate the absorption efficiency from food and the eliminatory potential via faeces and exhaled air. Differences between air-breathing and water-breathing animals feeding on similar prey are briefly discussed. It is concluded that high concentrations of recalcitrant organochlorines currently found in marine mammals feeding on fish are essentially due to the lack of branchial elimination and not to their predator status.

Dolphin morbillivirus infection in different parts of the Mediterranean Sea.

Morbillivirus were isolated from Mediterranean striped dolphins (Stenella coeruleoalba) dying along the coasts of Italy and Greece in 1991. They were antigenically identical to the morbilliviruses isolated from striped dolphins in Spain in 1990.

Studies of chemical and biologic properties of a fraction of sulodexide, a heparin-like glycosaminoglycan.

The chemical composition and biologic properties of a fraction (f) of Sulodexide, a heparin-like GAG, were studied and compared with those of two sulfated GAG preparations and heparin from intestinal mucosa. f-Sulodexide and the sulfated GAG preparations were fractionated on a Dowex-1Cl- column and subsequently on an antithrombin III affinity column. Low affinity and high affinity fractions had similar chemical composition and lipoprotein lipase releasing ability, but they varied in anticoagulant activity. Low affinity fractions from f-Sulodexide had negligible anticoagulant activity while high affinity fractions had one-half the activity of mucosal heparin. When compared to heparin, both fractions had one third amount of lipoprotein lipase releasing activity. The low anticoagulant activity of f-Sulodexide suggests a suitability for long-term use as an antiatherogenic agent.

Naloxone does not interfere with the dopamine-induced decrease in gonadotropin secretion in women with polycystic ovarian disease.

Dopamine infusion 4 micrograms/kg/min over 4 h, administered to six subjects with diagnosis of polycystic ovarian disease laparoscopically confirmed, produced a significant decrease in serum LH, FSH and PRL, suggesting a reduced dopamine activity in these subjects. The addition of naloxone 4 mg iv bolus plus 4 mg/h over 2 h, a specific opiate antagonist, does not interfere with the well-established dopaminergic inhibitory influence on LH, FSH and PRL secretion. This suggests that opiatergic pathways are not directly involved in the dopamine-induced suppressive effect on LH secretion in subjects with LH-dependent polycystic ovarian disease.

Effect of SAS 650 (Furofenac) on malondialydehyde production by platelets.

The activity of SAS 650, a new anti-inflammatory drug, on ex vivo and in vitro MDA production by platelets was compared to that of aspirin. The drug induced dose-dependent inhibition of in vitro MDA production by rat and guinea-pig platelets and also had good activity after 30 second of incubation in rat platelets, quicker than aspirin. SAS 650 preincubation reduced the in vitro inhibitory effect of ASA, as shown also by ex vivo experiments. The results of the present study support the involvement of SAS 650 in the platelet cyclooxygenase pathway.

Rectal absorption of some glycosaminoglycan sulphates and heparin in rats.

A standardized extract of glycosaminoglycan sulphates containing heparin, with a low affinity for antithrombin III, and a commercial heparin were administered to rats, by the rectal route. When the glycosaminoglycan sulphates were given in oil emulsion with sodium laurylsarcosinate as surfactant, 1 mg kg-1 and 3 mg kg-1 were sufficient for the clearing and anticoagulant activities, respectively. The rectal absorption of glycosaminoglycans after dosing with a suitable 'promoter' produced dose-dependent effects and their kinetics were comparable to those obtained after intramuscular administration. The oil emulsion improved the bioavailability of glycosaminoglycan sulphates at least 20 times.

Synthesis and antibacterial activity of some derivatives of tolypomycinone. Relationship between structure and activity in ansamycins.

3-Aminotolypomycinoes and 3,16-diamino-16,17-dihydrotolypomycinones are formed by the addition of primary and secondary amines to tolypomycinone, obtained by mild hydrolysis of the antibiotic tolypomycin Y.3-Amino-16,17-dihydrotolypomycinones are formed by the addition of primary and secondary amines to 16,17-dihydrotolypomycinone. In vitro microbiological tests showed high antibacterial activity in compounds obtained by the addition of primary amines, which must be unbranched in the alpha position to the nitrogen atom to position 3 of the naphthoquinone ring. The relationship between structure and activity is described, and evidence is presented that hydrogen bonding between the amino NH bonded to C3 and the amide CO of tolypomycinone is very important for biological activity.