Optimizing CIGB-300 intralesional delivery in locally advanced cervical cancer.

BACKGROUND: We conducted a phase 1 trial in patients with locally advanced cervical cancer by injecting 0.5 ml of the CK2-antagonist CIGB-300 in two different sites on tumours to assess tumour uptake, safety, pharmacodynamic activity and identify the recommended dose. METHODS: Fourteen patients were treated with intralesional injections containing 35 or 70 mg of CIGB-300 in three alternate cycles of three consecutive days each before standard chemoradiotherapy. Tumour uptake was determined using (99)Tc-radiolabelled peptide. In situ B23/nucleophosmin was determined by immunohistochemistry. RESULTS: Maximum tumour uptake for CIGB-300 70-mg dose was significantly higher than the one observed for 35 mg: 16.1 ± 8.9 vs 31.3 ± 12.9 mg (P = 0.01). Both, AUC24h and biological half-life were also significantly higher using 70 mg of CIGB-300 (P < 0.001). Unincorporated CIGB-300 diffused rapidly to blood and was mainly distributed towards kidneys, and marginally in liver, lungs, heart and spleen. There was no DLT and moderate allergic-like reactions were the most common systemic side effect with strong correlation between unincorporated CIGB-300 and histamine levels in blood. CIGB-300, 70 mg, downregulated B23/nucleophosmin (P = 0.03) in tumour specimens. CONCLUSION: Intralesional injections of 70 mg CIGB-300 in two sites (0.5 ml per injection) and this treatment plan are recommended to be evaluated in phase 2 studies.

Recombinant streptokinase suppositories in the treatment of acute haemorrhoidal disease. Multicentre randomized double-blind placebo-controlled trial (THERESA-2).

AIM: A four-arm multicentre randomized double-blind placebo-controlled trial was undertaken to assess the effect and safety of suppositories containing recombinant streptokinase (rSK) at two dose levels (100,000 IU and 200,000 IU) with sodium salicylate (SS) compared with placebo and SS for the treatment of acute haemorrhoidal disease. METHOD: Patients with acute symptoms of haemorrhoids were randomized to four treatment groups: (I) placebo, (II) SS, (III) SS + rSK 100,000 IU and (IV) SS + rSK 200,000 IU per suppository. Inpatient treatment was by four suppositories given every 6 h to discharge at 24 h. Evaluations were made at the time of discharge (24 h) and at 3, 5 and 20 days later. The main end-point was the degree of relief of pain, oedema and reduction in the size of the lesion by 90% on day 5. Adverse events and the occurrence of anti-SK antibodies were also determined. RESULTS: Eighty patients were included. Respective response rates in the four groups were 16%, 30%, 25% and 52%. In the last group there was a significant difference (36.8%) compared with control (95% CI 7.0-58.4%). The time to response was significantly shorter (median 5 days) in the 200,000 IU rSK group with respect to the others. There were no adverse events attributable to the treatment. No increase in anti-SK antibodies was detected 20 days after treatment. CONCLUSION: Suppositories with 200,000 IU rSK showed a significant improvement in symptoms of acute haemorrhoids, with an adequate safety profile.

Treatment with type I interferons induces a regulatory T cell subset in peripheral blood mononuclear cells from multiple sclerosis patients.

Type I Interferon (IFN-alpha/beta) therapy has altered the natural course of multiple sclerosis. In this paper we evaluate the possible molecular mechanisms involved in the in vitro effects of IFN-alpha/beta on peripheral blood mononuclear cells from patients with clinically definite Relapsing-Remitting Multiple Sclerosis. The total RNA from IFN-alpha, IFN-beta treated cells and untreated cells was extracted and amplified for CD86, CD28, CTLA-4, TNF-alpha, IFN-gamma, CCL2, CCR5, IL-13, MMP-9, TIMP-1, CD25, TGF-beta, IL-10 and the transcriptional factor Foxp3 by Reverse Transcription-Polymerase Chain Reaction and the CD4+CD25high subset was evaluated using flow cytometry. In general, there were no significant differences concerning the modulation of the genes studied in the response to IFN-alpha and IFN-beta treatments, which suggest a similar mechanism of action for both interferons. However, we found a significant increment in IFN-gamma expression after IFN-alpha but not after IFN-beta treatments. The in vitro treatment of mononuclear cells from multiple sclerosis patients with both interferons significantly increased the CD25 mRNA. Furthermore, we observed a CD25/Foxp3 correlation and an increment of the CD4+CD25high subset, indicating that the induction of regulatory T cells could be a crucial mechanism involved in the type I interferon effects.

[Interferon alfa 2b treatment decreases histological activity in children with chronic hepatitis B]. / Tratamiento con alfa 2b interferón disminuye actividad histológica en niños con hepatitis crónica B.

Interferon alfa (IFN-alpha) is the only approved treatment for chronic hepatitis B (HBV) infection. In a non-controlled study 33 pediatric patients infected with HBV and in chronic phase of the disease were included and treated with 3 to 5 x 10(6) IU/m2 body surface of Interferon alpha 2b, 3 times per week, during 4 months. The objective was to evaluate the efficacy of the treatment in terms of the histological, biochemical and viral markers evolution of the patients. The patients were evaluated carrying out determinations of alanine aminotransferase (ALAT), HBsAg and HBeAg before treatment, at the end of the treatment and every 4 months during one year of follow-up. Liver biopsy and Knodell index determination were carried out at the beginning and upon concluding the follow-up. 39.3% of the patients concluded the treatment with normal ALAT values; 7% became HBsAg negative and 14.3% became HBsAg negative. These values ascended after follow-up to 51.5%, 11% and 37.5% respectively. The histological analysis evidenced a decrease of the Knodell index in 69% of the patients, an increase in 14.2%, and 13.8% did not show variation. Correlating the biochemical and histological responses, a favorable outcome was obtained in 36.4% of the patients, evidencing a remarkable reduction of the hepatic cytolysis. The treatment was well tolerated, being the fever the most frequent adverse events. The results confirm that interferon alfa seems to be an effective treatment for children with chronic hepatitis B.

Tratamiento con alfa 2b interferón disminuye actividad histológica en niños con hepatitis crónica B / Interferon alfa 2b treatment decreases histological activity in children with chronic hepatitis B

Interferon alfa (IFN-alpha) is the only approved treatment for chronic hepatitis B (HBV) infection. In a non-controlled study 33 pediatric patients infected with HBV and in chronic phase of the disease were included and treated with 3 to 5 x 10(6) IU/m2 body surface of Interferon alpha 2b, 3 times per week, during 4 months. The objective was to evaluate the efficacy of the treatment in terms of the histological, biochemical and viral markers evolution of the patients. The patients were evaluated carrying out determinations of alanine aminotransferase (ALAT), HBsAg and HBeAg before treatment, at the end of the treatment and every 4 months during one year of follow-up. Liver biopsy and Knodell index determination were carried out at the beginning and upon concluding the follow-up. 39.3% of the patients concluded the treatment with normal ALAT values; 7% became HBsAg negative and 14.3% became HBsAg negative. These values ascended after follow-up to 51.5%, 11% and 37.5% respectively. The histological analysis evidenced a decrease of the Knodell index in 69% of the patients, an increase in 14.2%, and 13.8% did not show variation. Correlating the biochemical and histological responses, a favorable outcome was obtained in 36.4% of the patients, evidencing a remarkable reduction of the hepatic cytolysis. The treatment was well tolerated, being the fever the most frequent adverse events. The results confirm that interferon alfa seems to be an effective treatment for children with chronic hepatitis B

Tratamiento con alfa 2b interferón disminuye actividad histológica en niños con hepatitis crónica B / Interferon alfa 2b treatment decreases histological activity in children with chronic hepatitis B

Interferon alfa (IFN-alpha) is the only approved treatment for chronic hepatitis B (HBV) infection. In a non-controlled study 33 pediatric patients infected with HBV and in chronic phase of the disease were included and treated with 3 to 5 x 10(6) IU/m2 body surface of Interferon alpha 2b, 3 times per week, during 4 months. The objective was to evaluate the efficacy of the treatment in terms of the histological, biochemical and viral markers evolution of the patients. The patients were evaluated carrying out determinations of alanine aminotransferase (ALAT), HBsAg and HBeAg before treatment, at the end of the treatment and every 4 months during one year of follow-up. Liver biopsy and Knodell index determination were carried out at the beginning and upon concluding the follow-up. 39.3% of the patients concluded the treatment with normal ALAT values; 7% became HBsAg negative and 14.3% became HBsAg negative. These values ascended after follow-up to 51.5%, 11% and 37.5% respectively. The histological analysis evidenced a decrease of the Knodell index in 69% of the patients, an increase in 14.2%, and 13.8% did not show variation. Correlating the biochemical and histological responses, a favorable outcome was obtained in 36.4% of the patients, evidencing a remarkable reduction of the hepatic cytolysis. The treatment was well tolerated, being the fever the most frequent adverse events. The results confirm that interferon alfa seems to be an effective treatment for children with chronic hepatitis B (AU)

Tratamiento con alfa 2b interferón disminuye actividad histológica en niños con hepatitis crónica B. / [Interferon alfa 2b treatment decreases histological activity in children with chronic hepatitis B]

Interferon alfa (IFN-alpha) is the only approved treatment for chronic hepatitis B (HBV) infection. In a non-controlled study 33 pediatric patients infected with HBV and in chronic phase of the disease were included and treated with 3 to 5 x 10(6) IU/m2 body surface of Interferon alpha 2b, 3 times per week, during 4 months. The objective was to evaluate the efficacy of the treatment in terms of the histological, biochemical and viral markers evolution of the patients. The patients were evaluated carrying out determinations of alanine aminotransferase (ALAT), HBsAg and HBeAg before treatment, at the end of the treatment and every 4 months during one year of follow-up. Liver biopsy and Knodell index determination were carried out at the beginning and upon concluding the follow-up. 39.3

of the patients concluded the treatment with normal ALAT values; 7

became HBsAg negative and 14.3

became HBsAg negative. These values ascended after follow-up to 51.5

, 11

and 37.5

respectively. The histological analysis evidenced a decrease of the Knodell index in 69

of the patients, an increase in 14.2

, and 13.8

did not show variation. Correlating the biochemical and histological responses, a favorable outcome was obtained in 36.4

of the patients, evidencing a remarkable reduction of the hepatic cytolysis. The treatment was well tolerated, being the fever the most frequent adverse events. The results confirm that interferon alfa seems to be an effective treatment for children with chronic hepatitis B.

In vitro interferon gamma regulation of CCR-3 mRNA expression in peripheral blood leukocytes from atopic asthmatics.

Interferon gamma (IFN-gamma) exerts major pro-inflammatory, regulatory, and anti-inflammatory actions in immune defense responses. In asthma the infiltration of eosinophils, neutrophils, and lymphocytes is a critical event. Chemokines stimulate the migration of the susceptible subset of inflammatory cells. The chemokine receptors CCR-3 are mainly expressed in eosinophils, basophils, and Th2 cells. More recently it has been demonstrated that the IFN-gamma downregulates the expression of some chemokine receptors. IgE determinations were performed using an ELISA for total IgE Peripheral blood leukocytes from patients and controls were isolated by Ficoll-Hypaque gradient. The cells were incubated in the absence or presence of 500 IU/ml of recombinant human IFN-gamma for different times. After incubation the cells were washed and lyzed for reverse transcription-polymerase chain reaction (RT-PCR) analysis. RT-PCR was performed using a Perkin-Elmer kit. The amplified bands were run in 2% agarose gels and quantified. The basal levels of CCR-3 in asthmatic patients with IgE > 150 IU/ml tend to be higher than in controls. IFN-gamma down-regulates the expression of CCR-3 in peripheral blood leukocytes from asthmatics with IgE >150 IU/ml, when compared with the basal levels of expression. In conclusions, through the modification of the expression of CCR-3 in peripheral blood leukocytes from atopic asthmatics, IFN-gamma could exert a beneficial effect in patients with asthma, regulating the migration of some inflammatory cells involved in the pathogenesis of the disease.

Regression of infancy hemangiomas with recombinant IFN-alpha 2b.

Interferon-alpha (IFN-alpha) has antitumor and antiangiogenic effects. The purpose of this work was to evaluate its efficacy and safety in the treatment of infancy hemangioma and to monitor the appearance of anti-IFN antibodies in these patients. Thirty-nine children (29 girls) aged 1.5-158 months, with 19 younger than 1 year and 9 older than 5, were treated with 3 x 10(6) IU/m(2) IFN-alpha 2b, subcutaneously (s.c.) daily. Inclusion criteria were life-threatening or life-limiting hemangioma and parents' informed consent. Regression was considered if tumor size diminished by 50% or more. Of the 38 patients who completed 6 months of treatment, 27 (71.1%) had regression and 11 (28.9%) had stable disease. No patient experienced progression. Regression was more frequent (100%) among patients between 1 and 5 years old, but it was particularly important (68%) among those under 1 year old, when spontaneous regression is rare. The main side effects were the IFN-related flulike syndrome (79%), increase in serum alanine aminotransferase (ALT) (28%), anorexia (19%), and mild inflammation at the injection site (19%). There was no effect on psychomotor or physical development. On the contrary, 1 patient with neurologic symptoms improved remarkably, including seizure disappearance. Eight patients developed anti-IFN-alpha 2 neutralizing antibodies, and 7 of them responded to IFN treatment. IFN-alpha 2b is a safe and efficacious treatment of infancy hemangioma. Further work should look for other treatment schedules and ways of administration and carefully monitor anti-IFN neutralizing antibodies, which does not seem to interfere with response.

Epidermal growth factor reduces multiorgan failure induced by thioacetamide.

BACKGROUND: Multiorgan failure is a severe life threatening state where present therapeutic approaches are suboptimal. Epidermal growth factor (EGF) is a potent stimulant of repair in in vitro and in vivo models. We therefore examined its potential beneficial effect in reducing mortality and injury induced by the noxious agent thioacetamide (TAA). METHODS: Mice (20 per group) were fasted overnight and received a single intraperitoneal dose of human recombinant EGF at 10 or 30 microg/kg or saline (control). Either 30 minutes before or after EGF, all animals also received TAA (40 mg/kg intraperitoneally). Twenty four hours later, surviving animals were killed, tissues collected, and degree of organ injury assessed. RESULTS: Fifty per cent (10/20) of control animals died within the first 24 hour period. Mortality was almost completely prevented by the higher dose of EGF whether given before or after TAA (p<0.01) and was reduced by about 50% with the lower dose of EGF. In control animals, the entire length of the jejunum and ileum had necrosis with or without mucosal denudation. In contrast, necrosis affected only about 10-20% of the total length in EGF treated groups (both p<0.01 v control). Control animals showed marked glomerular tuft collapse, interstitial haemorrhage, and increased plasma creatinine levels. These effects were significantly reduced in animals given EGF (30 microg/kg; p<0.01). All groups showed similar changes in liver histology (centrilobular necrosis) and alanine transaminase levels (10-fold increase). CONCLUSIONS: Although EGF did not prevent the hepatotoxicity associated with TAA, it reduced mortality, renal injury, and gastrointestinal damage. These studies provide preliminary evidence that EGF may be a novel approach for the prevention and/or treatment of multiorgan failure.

A multicenter, randomized, double-blind clinical trial examining the effect of oral human recombinant epidermal growth factor on the healing of duodenal ulcers.

BACKGROUND: Our aim was to study the efficacy of oral human recombinant epidermal growth factor (EGF) in the treatment of duodenal ulcers, on the basis of its repairing actions in the gastrointestinal tract. METHODS: A placebo-controlled, multicenter, randomized, and double-blind study was conducted. Treatment groups were A) placebo solution, B) 10 microg/ml of human recombinant (hr)-EGF, and C) 50 microg/ml of hr-EGF, three times daily during 6 weeks. Patients, 15-65 years old, with a duodenal ulcer >4 mm, who gave their written informed consent to participate were eligible. Exclusion criteria were gastric ulcer and more than one duodenal ulcer, ulcer-related complications, and previous treatment with oral EGF or other specific anti-ulcer drugs in the previous 2 weeks. The main outcome variable was ulcer healing, evaluated by endoscopy after the 2nd, 4th, and 6th week. RESULTS: One hundred and three patients were included. The groups were comparable with regard to age, sex, toxic habits, antecedents of ulcerous disease, initial size and depth or the ulcer, initial symptoms, and positivity for Helicobacter pylori. The ulcers were healed in a larger proportion of patients treated with hr-EGF at the highest dose (70.6% in group C versus 40.0% and 35.3% in placebo and low-dose groups, respectively (P = 0.007)). The difference was significant from week 4 on. Groups A and B did not differ. Eighty-eight percent of group C patients were cured or improved versus 57% and 56% in groups A and B, respectively. No adverse reactions were reported. CONCLUSIONS: Oral hr-EGF was effective in the treatment of duodenal ulcer at a 50-microg/ml dose every 8 h but not at 10 microg/ml.

Impaired angiogenic balance and suppression of tumorigenicity in HeLa cells chronically exposed to interferon-alpha.

We have previously reported that IFNalpha-chronic treatment for 41 days induced a partial phenotype reversion on HeLa cells along with a down-regulation of HPV18 mRNA levels. However, tumorigenicity of these cells in nude mice was unchanged. Interestingly, after 1 year of IFNalpha-chronic exposition, HeLa cells failed to induce s.c. tumors when injected into nude mice. In such experimental conditions both HPV18 DNA integration pattern and viral DNA copy number present in HeLa cells remained intact in the nontumorigenic phenotype cells. As result of the treatment with IFNalpha, HeLa cells rendered more resistant to lysis mediated by activated natural killer cells in vitro. Furthermore, IFNalpha-chronic treatment was able to induce VEGF and decrease bFGF mRNA expression, suggesting a potential effect on the angiogenic behavior of these tumoral cells. Thus, long-term treatment of HeLa cells with IFNalpha can accomplish a reversion of the malignant phenotype by a sequential multistep mechanism, in which the antiangiogenic effect of IFNalpha could be one of the contributing events.

Intralesional recombinant interferon alpha-2b in Peyronie's disease.

OBJECTIVE: To evaluate interferon alpha-2b (IFN) in the treatment of Peyronie's disease (PD) since IFN exerts antifibrotic action through collagen synthesis inhibition and fibrolysis stimulation. METHODS: The study comprised 34 patients, aged 31 to 63, with clinical and ultrasonographic (US) diagnosis of PD, who gave their consent to enter the study. They had the disease for 10.1 +/- 5.6 (2-22) months. Ten million IU of IFN were injected intralesionally, twice weekly for 14 weeks or less if there was complete remission. Clinical evaluation included penis angle at erection, sexual dysfunction (pain, possibility of intercourse) and palpable plaque. Plaque size was evaluated by US. Systemic and local adverse reactions, and anti-IFN antibodies were monitored as well. RESULTS: Sexual dysfunction disappeared in 19/24 (79.2%) patients with this disorder, palpable lesions in 21/34 (62%), angle at erection in 15/32 (47%), and pain in 16/17 (94%). Complete clinical response was achieved in 16/34 patients (47%). Ultrasonographic response rate was 88%, (53% complete). Plaque size decreased from 56.7 +/- 42.9 (median: 35.4) before treatment to 12.7 +/- 22.6 mm2 (median: 0) (p < 0.00001; Wilcoxon's paired test). Clinical and US responses correlated. No patient showed progression. Eight of 9 patients in whom other treatments had failed responded to IFN therapy (5 complete). The main systemic adverse reaction in most patients (mild or moderate) was the flu-like syndrome expected for IFN. Local reactions, more related to the administration procedure than to IFN itself, were small hematoma (10 patients), edema (3), cysts that were excised surgically (2), and venous leak (1). No patient developed anti-IFN antibodies. CONCLUSIONS: IFN treatment can be a suitable option for the management of PD. The results appear to be better than those achieved with other procedures. Further work should include comparative studies, long-term follow-up of treated patients, and alternative ways of administration.

[Alpha interferon and Alzheimer's disease]. / Interferón alfa y enfermedad de Alzheimer.

INTRODUCTION: Alzheimer's disease (AD) is the commonest cause of dementia; its aetiology is unknown and there is non-specific treatment to detain the course of the disease. The interferons (IFN) are proteins which have antiviral, antiproliferative and immuno-modulating effects, and in the central nervous system these effects are mediated through the opiate receptors and the dopaminergic system. There is evidence that AD may be related to certain prion diseases and certain viruses, and that the IFN system has become deteriorated in this condition. OBJECTIVE: We present a review of patients with AD treated with alpha interferon. DEVELOPMENT: The first known case in the literature was that of a 69 year old man with definite AD (NINCDS-ADRDA) who was given alpha leucocytic IFN intrathecally and who initially was suspected of having Creutzfeldt-Jakob disease; after his treatment with IFN-alpha, his neurological signs were observed to have stabilized. Subsequently, the results of a controlled, randomized, clinical trial were analyzed for 16 patients with probable EA (NINCDS-ADRDA) treated with recombinant IFN-alpha 2b intramuscularly, in whom no changes in clinical and neurophysiological assessment were observed after a year of treatment. However, there was a significant improvement in one of the variables used to measure quality of life, together with a certain reduction in mortality in the patients treated with IFN-alpha. CONCLUSION: These results should be investigated in future studies in the light of current findings concerning the fact that, in the neurophysiological changes in AD, the pro-inflammatory cytokines, of which some of their numerous actions are blocked by IFN-alpha, may produce a deleterious effect on the course of AD.

Interferón alfa y enfermedad de Alzheimer / Alpha interferon and Alzheimer's disease

Introducción. La enfermedad de Alzheimer (EA) es la causa más frecuente de demencia. Su etiología es desconocida y carece de tratamiento específico para detener el curso de la enfermedad. Los interferones (IFN) son proteínas que tienen efecto antivírico, antiproliferativo e inmunomodulador, y en el sistema nervioso central ejercen sus acciones a través de los receptores opiáceos y el sistema dopaminérgico. Existen evidencias de que la EA podría relacionarse con las enfermedades priónicas y con determinados virus, así como que el sistema de IFN se encuentra deteriorado en esta entidad. Objetivo. Se presenta una revisión de los pacientes con EA tratados con IFNa. Desarrollo. El primer caso conocido en la literatura fue el de un varón de 69 años con EA definida (NINCDS-ADRDA), a quien se le administró IFN-a leucocitario por vía intratecal y cuya sospecha clínica inicial fue de enfermedad de Creutzfeldt-Jakob; tras concluir el tratamiento con IFN-alfa, se observó en dicho paciente estabilización de los signos neurológicos. Posteriormente, se analizan los resultados de un ensayo clínico, aleatorizado y controlado, en 16 pacientes con EA probable (NINCDS-ADRDA) tratados con IFN-alfa2b recombinante por vía intramuscular y en los que no se observaron cambios en las evaluaciones clínicas y neuropsicológicas tras un año de tratamiento. Sin embargo, se apreció una mejoría significativa en una de las variables que midieron la calidad de vida, así como cierta tendencia a una menor mortalidad en los pacientes tratados con IFN-alfa. Conclusión. Estos resultados deben investigarse en futuros estudios a la luz de los hallazgos actuales sobre el hecho que, en las alteraciones neuropatológicas en la EA, las citocinas proinflamatorias, algunas de cuyas numerosas acciones son contrarrestadas por el IFN-alfa, pueden producir un efecto deletéreo en la evolución de la EA (AU)

[Alpha interferon in the treatment of multiple sclerosis. Update and experience in Cuba]. / Interferón alfa en el tratamiento de la esclerosis múltiple. Actualización y experiencia en Cuba.

OBJECTIVES: We present an update of specific treatment for multiple sclerosis (MS), especially the form with a clinical course of exacerbation-remission (ER), in which we consider the benefits of beta interferons, copolymer 1 and intravenous immunoglobulin. We discuss the properties of alpha interferon and its modes of action which are very similar to those of beta interferon. The main clinical trials in which various subtypes of alpha interferons were used are summarized. PATIENTS AND METHODS: We establish the elements which justify interest in studying this substance and present the main trials carried out in Cuba. These consist in an initial trial in 9 patients, with encouraging results in the clinical course ER-MS and following this, the findings of a preliminary study of the first 17 patients of a randomized, double-blind National Clinical Trial, in which a placebo was used for control. CONCLUSIONS: In view of these results we recommend that the study being carried out in Cuba to confirm the efficacy of alpha interferon in the ER-MS form be continued.

[Recent advances in the treatment the nervous system disorders with interferon-alpha]. / Actualización del tratamiento con interferón alfa en las enfermedades del sistema nervioso.

INTRODUCTION: The interferons (IFN) have had considerable effect on the course of relapses and the natural course of the disability of patients with multiple sclerosis (MS). However, the effects of IFN in other neurological disorders are little known. OBJECTIVES: To review the literature on the experimental and clinical applications of the IFN in disorders of the nervous system excluding MS. DEVELOPMENT: We reviewed studies of the applications of the IFN in viral diseases (experimental and human rabies, herpes zoster, herpes virus, non-herpetic meningoencephalitic viruses, HTLV-I myelopathy, arbovirus in animals, subacute sclerosing panencephalitis (SSPE), progressive multifocal leukoencephalopathy); supposedly viral diseases (Reye's syndrome), continuous partial epilepsy (Kojewnikoff's syndrome); prion diseases (Creutzfeldt-Jakob disease); degenerative-hereditary diseases (amyotrophic lateral sclerosis, Alzheimer's disease, schizophrenia, Sturge-Weber-Dimitri syndrome); immuno-allergic disorders (experimental myasthenia gravis, chronic inflammatory demyelinating polyneuropathy-CIDP-); Landry-Guillain-Barré-Strohl syndrome, polyneuropathy associated with IgM monoclonal gammapathy; tumour disorders (benign and malignant primary tumours of the brain, metastatic tumours, meningeal carcinomatosis, extra-intracranial haemangiomas, meningiomas), and other causes (cuban epidemic neuropathy, neuro-Becçet). CONCLUSIONS: Disorders of the nervous system in which IFN may be used in a clinical trial include: herpes zoster and herpes simplex infections, HTLV-I myelopathy; subacute sclerosing leukoencephalopathy, continuous partial epilepsy (Kojewnicoff's syndrome), intra-extracranial haemangiomas, CIDP, polyneuropathy associated with IgM gamma monoclonal disorder, malignant primary tumours, recurrent meningiomas, some cerebral metastases, Behçet's disease and schizophrenia.