alpha-Glycerophosphocholine in the mental recovery of cerebral ischemic attacks. An Italian multicenter clinical trial.

The clinical efficacy and the tolerability of alpha-glycerophosphocholine (alpha-GPC), a drug able to provide high levels of choline for the nervous cells of the brain and to protect their cell walls, have been tested in a clinical open multicenter trial on 2044 patients suffering from recent stroke or transient ischemic attacks. alpha-GPC was administered after the attack at the daily dose of 1000 mg im for 28 days and orally at the dose of 400 mg tid during the following 5 months after the first phase. The evaluation of the efficacy on the psychic recovery was done by the Mathew Scale (MS) during the period of im drug administration, and using the Mini Mental State Test (MMST), the Crichton Rating Scale (CRS), and the Global Deterioration Scale (GDS) during the following period of oral administration. The MS mean increased 15.9 points in 28 days in a statistically significant way (p < 0.001) from 58.7 to 74.6. At the end of the 5 month oral administration, the CRS mean significantly decreased 4.3 points, from 20.2 to 15.9 (p < 0.001); the MMST mean significantly increased (p < 0.001) from 21 to 24.3 at the end of the trial, reaching the "normality" score at the 3rd month assessment. The GDS score at the end of the trial corresponded to "no cognitive decline" or "forgetfulness" in 71% of the patients. Adverse events were complained of by 44 patients (2.14%); in 14 (0.7%) the investigator preferred to discontinue therapy. The most frequent complaints were heartburn (0.7%), nausea-vomit (0.5%), insomnia-excitation (0.4%), and headache (0.2%). The trial confirms the therapeutic role of alpha-GPC on the cognitive recovery of patients with acute stroke or TIA, and the low percentage of adverse events confirms its excellent tolerability.

[Effects of immunomodulation on antineoplastic radiotherapy. A controlled clinical study]. / Effetti dell'immunomodulazione nella radioterapia antineoplastica. Studio clinico controllato.

It is well known that thymic hormones can counteract immunodepression due to radiation therapy, preventing and reducing the severity and the number of myelotoxic and hematologic reactions. We tried to confirm these findings in a controlled multicenter clinical study involving 1,060 patients undergoing radiation therapy (580 treated with thymopentin 50 mg s.c. every other day, after irradiation and for at least 6 cycles of 4 weeks each, and 480 control patients). Highly statistically significant results (to the ANOVA test) were obtained in the protection against radiation-induced leukopenia in the treated group; furthermore, the treated patients had a marked reduction (p = 0.003 chi 2 test) in the early delayed reactions to irradiation, namely in the upper aero-digestive tract. In general, we observed a better, but not statistically significant recovery of the blood parameters, lymphocyte subsets and skin tests in the treated group versus the control group. Both of the treated groups showed the same trend for Karnofsky performance status and body weight. The local and general protection provided by thymopentin against the reactions to irradiation could be advantageously used for the administration of higher doses of radiation therapy.

The efficacy and safety of auranofin in the treatment of juvenile rheumatoid arthritis. A long-term open study.

The safety and efficacy of auranofin in the long-term treatment of children with juvenile rheumatoid arthritis was investigated in an open study of 14 patients. Twelve patients completed at least 12 months of treatment, and 7 patients completed 36 months of treatment. Classic parameters of disease activity showed improvement over baseline values after 6 months of treatment, and laboratory indices remained stable or improved throughout the study. Auranofin was well tolerated; the frequency of adverse effects was lower in these patients than has been previously reported in either adults or children whose arthritis has been treated with injectable gold.

Changes of immunological parameters during auranofin treatment in children affected with juvenile chronic arthritis.

Auranofin [S-triethylphosphine gold-2,3,4,6 tetra-O-acetyl-l-thio-beta-D-glucopyranoside) SK&F 39162) has been administered at 0.1-0.25 mg/kg/day as the sole remission-inducing drug to 46 children affected with juvenile chronic arthritis (JCA). There were 22 males and 24 females; 12 children were affected with pauciarticular onset JCA, 26 with polyarticular onset JCA and 8 with systemic onset JCA. Three sets of efficacy criteria were evaluated quarterly: eight clinical, (Ritchie Index, number of affected, swollen and limited joints, number of joint with increased temperature, morning stiffness, Steinbrocker functional class, physician's disease evaluation), three hematochemical and one therapeutical. In most patients a panel of immunological parameters was routinely performed inclusive of peripheral blood lymphocyte subsets, serum immunoglobulins and C3c-C4 complement components. Patients who showed a definite improvement of at least two out of the three orders of efficacy criteria were classified as responders to auranofin. Out of the 35 patients evaluable after at least six months of treatment there were 24 (68%) responders. Nonresponders had a basal higher level of serum IgA and a basal lower level of serum C4. Both responders and nonresponders presented a reduction of the T4/T8 ratio during auranofin treatment, while only in responders did the basal high levels of IgG and C3c show a definite decrease.

Mechanism of flavoxate antispasmodic activity comparative in vitro studies.

In order to clarify the pharmacological activity of flavoxate, its effect on the tone and spontaneous activity of the guinea-pig isolated ureter and of the muscle strip from rat urinary bladder were studied. Flavoxate, as well as papaverine, reduced all three parameters considered on the guinea-pig isolated ureter, namely: peristaltic motility, endoluminal pressure and longitudinal muscle contractility. In the same test, verapamil (a calcium antagonist), emepronium and atropine (both anticholinergic drugs) were used for comparison. Using strips of rat urinary bladder depolarized by KCl, flavoxate, papaverine and verapamil displayed a relaxant activity, while anticholinergic compounds such as atropine, hyoscine and emepronium failed to relax this tissue. In another series of experiments the effects of flavoxate and anticholinergic drugs on the contraction elicited by vagal electrical stimulation of the guinea-pig isolated stomach in toto were assayed. The results obtained suggest that the action of flavoxate is due to direct smooth muscle relaxation and does not involve anticholinergic activity.

Immunological evaluation in children with juvenile chronic arthritis treated with auranofin.

An immunological evaluation was performed before therapy and every four months during the first year of treatment with auranofin in 6 children with juvenile chronic arthritis. The immunological tests included: IgG, IgA, IgM, IgE and "natural" antibody serum levels, CH50 of the classical and alternative complement pathways, PWM-induced IgM production in vitro, and polymorphonuclear neutrophil functions. A reduction of the in vitro IgM synthesis and in the CH50 of the classical pathway of complement, and a normalization of impaired chemotaxis, occurred in patients who presented a clinically significant improvement during auranofin treatment.

Pharmacological studies on the mode of action of flavoxate.

Previous studies on the mode of action of flavoxate have shown that the drug exerts a selective and direct muscle relaxant activity. In order to study the mode of action of flavoxate, the following activities were investigated: calcium blocking, inhibition of cyclic AMP phosphodiesterase (PDE), local anaesthetic activity, the effects on the synthesis and release of prostaglandins. In the K+-depolarized guinea-pig taenia coli, contracted by CaCl2, flavoxate and papaverine showed a moderate calcium antagonistic activity. Anticholinergic drugs, such as atropine and emepronium, did not exert a similar action. The antispasmodic activity of a drug can be correlated with inhibition of cyclic AMP phosphodiesterase, and since papaverine is a potent PDE inhibitor, we tested flavoxate for this activity. Flavoxate exerted a PDE inhibitory activity about three and five times greater than that of aminophylline in tissues homogenates of guinea-pig ureter and urinary bladder, respectively. It also showed the same local anaesthetic activity of lidocaine. Finally, the synthesis and release of prostaglandins by urinary bladder muscle in vitro have been investigated before and after treatment with flavoxate. Myolytic activity of papaverine and flavoxate do not involve inhibition of prostaglandins synthesis in rat urinary bladder in vitro. Therefore, the mode of action of flavoxate can be related to a superimposition of myotropic, calcium antagonistic and local anaesthetic activity.