Species differences in the pharmacokinetics and metabolism of reparixin in rat and dog.

The pharmacokinetics and metabolism of reparixin (formerly repertaxin), a potent and specific inhibitor of the chemokine CXCL8, were investigated in rats and dogs after intravenous administration of [14C]-reparixin L-lysine salt. Protein binding of reparixin was investigated in vitro in rat, dog, rabbit, cynomolgus monkey and human plasma. Plasma protein binding of reparixin was >99% in the laboratory animals and humans up to 50 microg ml-1, but lower at higher concentrations. Although radioactivity was rapidly distributed into rat tissues, Vss was low (about 0.15 l kg-1) in both rat and dog. Nevertheless, reparixin was more rapidly eliminated in rats (t1/2 approximately 0.5 h) than in dogs (t1/2 approximately 10 h). Systemic exposure in dog was due primarily to parent drug, but metabolites played a more prominent role in rat. Oxidation of the isobutyl side-chain was the major metabolic pathway in rat, whereas hydrolysis of the amide bond predominated in dog. Urinary excretion, which accounted for 80-82% of the radioactive dose, was the major route of elimination in both species, and biotransformation of reparixin was complete before excretion.

Comparative bioavailability and tolerability study of two intramuscular formulations of thiocolchicoside in healthy volunteers.

The comparative bioavailability and tolerability of two intramuscular fomulations of thiocolchicoside (test, Thiocolchicoside, 4 mg ampoules, Dompé S.p.A.; reference, Muscoril, 4 mg ampoules, Inverni della Beffa S.p.A.) were investigated in twelve healthy volunteers according to a single dose (4 mg), cross-over, randomized design. Plasma thiocolchicoside concentrations were determined by using a validated specific HPLC/MS assay and local tolerability was investigated by assessing subjective pain intensity on a visual analogue scale (VAS), reddening at the injection site, and plasma creatinine phosphokinase (CPK) levels. Pharmacokinetic parameters after administration of the test formulation were similar to those observed after administration of the reference (Tmax 0.50 (0.25-1.00) vs 0.50 (0.25-1.00), median and range; Cmax 115.5 +/- 26.6 vs 113.2 +/- 40.4 ng/ml; AUC 291.6 +/- 77.7 vs 283.3 +/- 98.9 ng.h/ml, means +/- SD). Relative bioavailability (F) was 1.05 +/- 0.13. Statistical comparison of pain intensity, CPK levels and occurrence of redness at the injection site did not show statistically significant differences between formulations. It is concluded that the investigated test formulation is bioequivalent and equally well tolerated as the marketed reference formulation.

Neuro-urologic disorders in the patient with spinal cord injury after vertebral fracture: progress in the uro-rehabilitative approach between diagnosis and treatment.

The treatment of urinary disorders in post-traumatic myelic pathology must necessarily include the physiatrist involved in the rehabilitation of the patient with spinal cord injury. The approach to the disability consequent to a spinal cord injury, in fact, cannot be separated from the rehabilitative treatment of bladder-sphincter deficit that always accompanies the clinical course of this pathology: neurourologic disorders always negatively influence the quality of the person's life, they are the cause of severe complications, and, at times, they are resistant to any combined medical-surgical-rehabilitative treatment.

Effects of a new foam formulation of ketoprofen lysine salt in experimental models of inflammation and hyperalgesia.

The anti-inflammatory and analgesic profile of a new topical foam formulation of ketoprofen lysine salt (CAS 57469-78-0, Artrosilene Schiuma, KLS-foam) was characterized in comparison with marketed gel formulations containing KLS (KLS-gel) or diclofenac diethylammonium salt (DCF-gel). KLS-foam dose-dependently inhibited oedema formation and hyperalgesia induced by subplantar injection of carrageenan or substance P, being more potent than KLS-gel. At equieffective anti-inflammatory doses, KLS-foam provided a more pronounced analgesic effect than DCF-gel. KLS-foam also markedly inhibited exudate formation and prostaglandin production induced by subcutaneous implantation of carrageenan soaked sponges. In carrageenan induced paw inflammation, KLS-foam provided the same anti-inflammatory effect as orally administered KLS, but induced significantly less gastric damages. Oral administration of KLS resulted in sustained systemic absorption of ketoprofen, whereas after topical application of KLS-foam no appreciable ketoprofen plasma levels were detected. These data support the anti-inflammatory and particularly the analgesic effectiveness of the new foam formulation of KLS, a finding that, together with the high gastric tolerability, further emphasizes the usefulness of KLS-foam in the treatment of localized flogistic diseases and associated pain.

Heterogeneity of [3H]-mepyramine binding sites in guinea pig cerebellum and lung.

The nature of histamine receptors in peripheral tissues is still controversial. However, evidence of heterogeneous classes of binding sites for [3H]-mepyramine are reported in the literature. The aim of our study was, therefore, to investigate the nature of this heterogeneity by comparing [3H]-mepyramine binding in a central tissue (cerebellum) and in a peripheral tissue (lung) obtained from guinea pigs and to assess its dependence upon the temperature of incubation. The results revealed that the [3H]-mepyramine interaction in both tissues is temperature-dependent. At 25 degrees C, the interaction between [3H]-mepyramine and the receptors was biphasic in the lung while only a single class of binding site was found in the cerebellum. At 0 degrees C, [3H]-mepyramine interacted with three binding sites in the lung and two in the cerebellum. The behaviour of the reference compounds (clemastine, promethazine and histamine) also supported this temperature-dependence. Moreover, two new compounds (DF 11062 and DF 11113), synthesized in our laboratories and endowed with antihistamine activity, can differentiate between the low affinity site seen at 25 degrees C in the lung and that seen in the cerebellum at 0 degrees C.

Determination of nuvenzepine in human plasma by a sensitive [3H]pirenzepine radioreceptor binding assay.

A sensitive method for the quantitation of small amounts of nuvenzepine, a new M1-selective antimuscarinic drug, in plasma is described. The analytical method involves the use of a radioreceptor binding assay based on [3H]pirenzepine displacement in rat cerebral cortex homogenates; no previous extraction is required. The method is reliable, with an interassay CV ranging from 5 to 10%, and allows the analysis of greater than 100 samples/experiment. The limit of detection is approximately 0.1 ng/assay. Using this method we have determined the plasma levels of nuvenzepine in eight healthy volunteers treated PO with 15 or 25 mg of nuvenzepine.HCl. The pharmacokinetic parameters obtained were (for 15 and 25 mg): Cmax, 64 and 131 ng/mL; AUC0-infinity, 851 and 1379 ng.h/mL; t1/2, 8.6 and 7.2 h. These values are in good agreement with those obtained using an HPLC method. Therefore, this radioreceptor binding assay proved to be simple, rapid, and specific for the determination of low levels of nuvenzepine in human plasma.

Linearity of levodropropizine, a new antitussive drug, in the healthy volunteer.

The object of this study was to determine whether the pharmacokinetics of levodropropizine were linear. Twelve healthy adult male volunteers received oral doses use of 30, 60 and 90 mg of levodropropizine. A cross-over design was used. With the exception of Cmax, and AUC the pharmacokinetics of levodropropizine in the dose range studied are similar. The relationship between the doses and AUCs and the statistical comparison of AUCs (Anova test and Westlake test) confirm that in the range 30-90 mg the plasma pharmacokinetics of levodropropizine are linear.

[Clinical problems of neural lesions in the phase of rehabilitation. Their significance and importance in final success of rehabilitation therapy]. / Problemi clinici del neuroleso nella fase del suo recupero. Significato e importanza degli stessi ai fini del successo della terapia riabilitativa

The frequency and significance of associated diseases and clinical problems in patients with nerve injuries in the recovery stage was statistically assessed. A variety of clinical situations are observed in practically all such patients. Half of the symptoms and diseases encountered relate to the nervous system and cardiocirculatory apparatus, while there is also a high incidence of skeletal muscle and urinary affections. The significance of these signs as far as rehabilitation is concerned can be seen in the fact that psychological and micturition disturbances are observed, along with muscle hypertonia, fibromyositis, cystitis and arthrosis. These form the more common obstacles to the regular execution of a rehabilitation programme, whereas no such significance is possessed by such serious diseases as valvular cardiopathy, hypertension and neoplasia of the neuraxis.