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Biomedical subjects

R E Gonsette

Publications and source records attributed to R E Gonsette.

At least 19 recordsLinked to original sources
PubMed2004

Pixantrone (BBR2778): a new immunosuppressant in multiple sclerosis with a low cardiotoxicity.

Mitoxantrone (MX) has been approved by the Food and Drug Administration for the treatment of rapidly progressive multiple sclerosis (MS). Unfortunately, its long-term administration is prevented by the cardiotoxicity. Pixantrone (PIX) is an analogue of MX devoid of toxic effects on cardiac tissue and was developed as a replacement for other anthracenediones in cancer patients. With a view to an application in MS patients, experimental data demonstrated that PIX is as potent as MX in preventing acute experimental allergic encephalomyelitis development as well as the occurrence of relapses in the chronic model. Safety data from animal studies and from phase II trials in cancer patients confirm a very weak cardiotoxicity, if any. A phase I trial with PIX in patients with a rapidly progressive MS seems thus warranted.

Animals↗
PubMed2004

New immunosuppressants with potential implication in multiple sclerosis.

New immunosuppressants are consistently developed to treat autoimmune diseases and some of them might have implications in multiple sclerosis (MS). A new antiproliferative agent, pixantrone, an analogue of mitoxantrone (MX), has a much lower cardiotoxicity and exerts the same potent immunosuppressive effects in experimental allergic encephalomyelitis (EAE). A phase I trial in MS patients is planned in the next future. New monoclonal antibodies (mAb) and other biological constructs containing foreign proteins are developed but their potential immunogenicity is a considerable drawback to their long-term administration. In addition, their beneficial effects in MS are not evident so far. Small molecules targeting the voltage-gated Kv1.3K+ channel regulating CA2+ signaling in T lymphocytes, specifically target activated, pathogenic T cells. Already found effective in EAE, those agents would be easier to handle than T-cell vaccination. Two new immunosuppressants with a unique mechanism of action (FTY720 and Epomycine M) selectively impair autoreactive T-cell homing, without affecting the other components of the immune response. The potent protective effect of TRY720 has been demonstrated in EAE and a phase I trial in MS appears warranted. Finally, a new concept about immunosuppressive treatments in organ transplantation, "tolerogenic immunosuppression", may have potential in MS.

Animals↗
PubMed2004

Combination therapy for multiple sclerosis.

To improve the partial benefit of approved monotherapies in multiple sclerosis (MS), over 25 combined therapies have been tested in recent years, either as fixed-dose or sequential combination regimes. The main therapeutic targets for combination therapy in MS are the same as for monotherapy: the immune-mediated inflammatory cascade, oxidative toxicity and excitotoxicity. There are numerous reasons to consider combination therapy in MS, including to improve the benefit and/or tolerance in patients responding to approved treatments, stop frequent disabling relapses and/or rapid progression in patients who do not respond to approved therapies, and maintain the benefit of immunosuppressive treatments. Preliminary clinical trials suggest that combination therapy in MS does not increase the side-effects of approved monotherapy; its efficacy over monotherapy should therefore be tested. Statistically robust trials would need to involve many patients for each combination, so the first step in determining the efficacy of combination therapy should be to perform safety studies, followed by proof-of-concept efficacy studies.

Clinical Trials as Topic↗
PubMed2003

Mitoxantrone in progressive multiple sclerosis: when and how to treat?

Mitoxantrone (MX) has been approved by the Food and Drug Administration (FDA) for the treatment of patients with worsening relapsing-remitting (RR) or secondary progressive (SP) multiple sclerosis (MS). However, indications should be refined and mitoxantrone reserved as a rescue therapy to: (1) patients in the relapsing-remitting phase with frequent and disabling exacerbations likely leading to permanent severe disability and (2) to patients in the secondary progressive phase whose disability progression rate increases by one EDSS point or more per year and who do not respond to other current therapies. An induction phase with the monthly intravenous administration of 12 mg/m(2) followed by a maintenance phase with 12 mg/m(2) every 3 months for 2 years seems the most effective and safe treatment regimen, not exceeding the maximum cumulative dose of 140 mg/m(2). Given the potent myelosuppressive activity of mitoxantrone, dosage should be carefully adapted to the body surface and hematological changes. Long-term toxicities (amenorrhoea and therapy-related leukemia) seem acceptable but a valid evaluation will need a longer follow-up in more patients. Cardiotoxicity, the major long-term toxicity, is clearly dose-dependent and is a strict treatment duration limiting factor. To reduce the risk of cardiac events, the drug should be administered by slow infusion (over 30 min). Analogs of mitoxantrone with a much lower cardiotoxicity are currently investigated in animal experimental models.

Disability Evaluation↗
PubMed2002

Cardiac adverse effects associated with mitoxantrone (Novantrone) therapy in patients with MS.

BACKGROUND: Mitoxantrone (MITO) is associated with dose-related cardiotoxicity when administered concomitantly with other cytotoxic agents with or without radiotherapy for leukemia and solid tumors. OBJECTIVE: To review observed cardiotoxicity of single-agent MITO therapy for MS. METHODS: Records of 1,378 patients from three clinical trials of MITO treatment for MS were reviewed for signs and symptoms of cardiac dysfunction and left ventricular ejection fraction (LVEF) results. Duration of follow-up was a median of 29 months (4,084 patient-years). RESULTS: No patients experienced congestive heart failure (CHF) before treatment. Cumulative MITO doses ranged from 2 to 183 mg/m(2) (mean 60.5 mg/m(2), median 62.5 mg/m(2)), and 141 patients received >100 mg/m(2). Two of 1,378 patients experienced CHF after initiating MITO therapy. Of 1,378 patients, 779 completed baseline and scheduled follow-up LVEF testing. Baseline LVEF was >50% in all 779 patients. Seventeen of 779 patients had asymptomatic LVEF of <50% (incidence proportion = 2.18%, 95% CI = 1.28 to 3.47%). Although the incidence of asymptomatic LVEF of <50% was not significantly related to monthly versus 3-monthly therapy, duration of therapy, age, or gender, asymptomatic LVEF of <50% trended higher with a cumulative dose of >/=100 mg/m(2) (5.0%) than with <100 mg/m(2) (1.8%) (p = 0.06). CONCLUSIONS: The observed incidence of CHF in patients with MS who received a mean cumulative dose of 60.5 mg/m(2) MITO was <0.20%. Continued monitoring of patients with MS who are receiving MITO is needed to determine whether the incidence of CHF increases with higher cumulative MITO doses and prolonged follow-up.

Adolescent↗
PubMed2002

A study of therapy-related acute leukaemia after mitoxantrone therapy for multiple sclerosis.

To evaluate the incidence of therapy-related acute leukaemia (t-AL) after single-agent mitoxantrone (MITO) treatment, we reviewed medical records of patients in three studies of single-agent MITO therapy for multiple sclerosis (MS) and existing literature on MITO therapy in MS, leukaemia, and solid tumors. Of 1378 MITO recipients in the three MS studies (mean cumulative dose of 60 mg/m2 and mean follow-up of 36 months), one patient had t-AL, an observed incidence proportion of 0.07% [95% confidence interval (CI) = 0.00-0.40%]. There were no cases of t-AL in published reports of nine additional studies of single-agent MITO therapy for MS. There was one published case report of acute promyelocytic leukoemia detected five years after initiating MITO therapy for MS. The observed incidence proportion of t-AL is very low in patients who received MITO as single-agent therapy for MS. Although these observations provide preliminary reassurance, extended follow-up of these patients and those who receive higher cumulative doses of MITO is required to define the long-term risk of t-AL after MITO therapy for MS.

Acute Disease↗
PubMed1996

Introductory remarks: immunosuppressive and immunomodulating drugs, where and how do they act?

Immunotherapies used in multiple sclerosis are reviewed. The mechanisms of action supporting their clinical application are described according to our current understanding. Immune treatments can be divided into three groups: (1) cytostatic and cytotoxic immunosuppressants which block the cell cycle of immunocompetent cells and/or provoke their deletion; (2) immunomodulators which specifically interfere in cellular or humoral immune mechanisms; (3) immunoregulators which restore immunodeficient states but have also immunosuppressive properties at the same time. Numerous attempts have been made to correct almost all abnormal immune mechanisms underlying disease progression. The results of those clinical trials are reviewed. Recent studies have demonstrated that a severe, unspecific and sustained immunosuppression markedly downregulates the clinical and pathological activity of the disease. Unfortunately, serious delayed adverse effects prevent a long-term administration. Recent specific immunomodulators with an acceptable toxicity have provided modest but unquestionable benefit on the attack rate and MRI lesion burden. No clear effect on progression has been demonstrated to date. There is still much work to be done to improve the efficacy of our current therapies on the attack rate and particularly on the progression. Several promising new compounds are already under evaluation. Another approach is combination therapies which will certainly become critical in MS like in other autoimmune diseases.

Adjuvants, Immunologic↗
PubMed1996

Mitoxantrone immunotherapy in multiple sclerosis.

Mitoxantrone, a cytotoxic agent recently developed, was subsequently found a very potent immunosuppressor. Experimental data in experimental allergic encephaloymyelitis demonstrated a dramatic suppression of both active and passive forms. Immune effects concern cellular and humoral components and are particularly persistent. B cell subset is preferentially deleted. Suppressor cells are relatively spared and suppression becomes dominant. In cancer therapy, the main advantages of mitoxantrone are a definitely better immediate tolerance and very low delayed adverse reactions (carcinogenicity, teratogenicity, impact on reproductive organs). Given its major immunosuppressive activity and its better tolerance, mitoxantrone was a potential candidate for multiple sclerosis therapy. Several clinical trials have confirmed the remarkable efficacy of mitoxantrone to reduce both attack and progression rates. Unfortunately the cardiotoxicity was found more frequent than expected and limits the maximum cumulative dose to 120 mg/m2. Mitoxantrone, when employed properly, may be useful in patients with frequent and disabling excerbations and/or rapidly progressing disability. It must be kept in mind that multiple sclerosis is a chronic disease, and that the benefit is limited to the period of administration of any treatment.

Antineoplastic Agents↗
PubMed1989

Homolateral disappearance of essential tremor after cerebellar stroke.

The case of a patient with essential tremor in whom tremor disappeared on the right side after a homolateral cerebellar infarct is reported. The pathophysiology of essential tremor remains unknown. Vascular and surgical lesions of dentorubrothalamic pathway have been reported to improve various kinds of tremor including essential tremor. In this patient, a lesion of this pathway related to the cerebellar infarct probably explains the homolateral cessation of essential tremor.

Aged↗
PubMed1986

Rupture of the arterial wall in two cases of recent cerebral embolism: morphological expression of cerebral vasospasm?

Previously undescribed morphological changes are reported in two cases of recent, non-septic cerebral embolism. These consisted of an arterial rupture involving the whole thickness of the wall. A direct tear by a sharp embolus seems unlikely but, as proposed by Villaret et al. in 1937, the arterial spasm may have occurred at the time of cerebral embolism. The embolic occlusion would prevent narrowing of the vascular lumen, so that focal spasm would rupture the arterial wall even at the level of a healthy and relatively thick media.

Arteries↗
PubMed1985

[Meningoradiculitis caused by a spirochete (Borrelia burgdorferi) after arthropod bite].

Eight cases of meningoradiculitis (Garin-Bujadoux-Bannwarth's syndrome) are presented; the first case followed an "unidentified insect" bite and erythema chronicum migrans, whereas the second and third cases were not preceded by any documented insect bite or erythema; they occurred during summer in 1984 and 1985 and were characterized by cranial or radicular neuritis, lymphocytic meningitis, positive serology by immunofluorescence against Borrelia Burgdorferi and a good response to Penicillin (20 000 000 U during 14 days I.V.). Five other cases were observed in the same area as the first and second cases (Walloon Brabant) during the preceding summers; in two, serological proof of Borrelia Burgdorferi infection was obtained retrospectively. Lyme disease and Garin-Bujadoux-Bannwarth syndrome are both tick-born spirochetosis, due to two slightly different subtypes of Borrelia Burgdorferi. Their early neurological manifestations differ mainly by focalised pain on the bitten region in Garin-Bujadoux-Bannwarth's syndromes. This could be due to direct aggression of the peripheral nerve in Garin-Bujadoux-Bannwarth syndrome.

Antibodies, Bacterial↗
PubMed1984

[Infarction of the olivary area of the medulla oblongata].

The two first cases of an infarct involving the arterial olivary territory of the medulla oblongata are reported. In the first one, an old infarct of the medial territory and a recent infarct involving the whole inferior olivary nucleus at its middle third level were associated. Rostrally this infarct was reduced to the medial reticular formation and internal half of the olive. Caudally it was reduced to its external half. In the second case the infarct involved only the external half of the right olive, but involved also the external half of the left olive with the lateral territory. From these two cases and from the anatomic, pathologic and clinical data reviewed in the literature, the authors propose as "total" olivary territory a triangular area including all the inferior olivary nucleus, the dorsal accessory olivary nucleus and partly the medial reticular formation, and as "minimum" olivary territory the external half of the olive. The many important medial, lateral and cranio-caudal arteries which supply the olivary territory account for these "total" and "minimum" territories, as well as for some cases in the literature. They account also for the pyramid-like cranio-caudal extension of the olivary territory infarction. The olivary territory is likely to be supplied by two short circumferential arterial groups, i.e. inferior bulbar and superior medullo-pontine. Nevertheless, the cause of the olivary territory infarction is an occlusion of the vertebral artery.

Arteries↗
PubMed1982

Modulation of immunity in multiple sclerosis: a double-blind levamisole-placebo controlled study in 85 patients.

Levamisole seems to regulate cell-mediated immunity by restoring T-cell function. Since a deficiency of T lymphocytes has been described by various authors in multiple sclerosis patients. Of the 85 patients involved in the trial, evaluation of functional and neurological scores was possible in 54 (32 with placebo and 22 with levamisole). The mean follow-up period was 2 years. This double-blind controlled study indicates that both neurological function and disability significantly deteriorated in the placebo-treated patients, but remained fairly stable in the levamisole-treated group. Since the difference between both groups was not significant, no levamisole effect was demonstrated on progression in multiple sclerosis. With the exception of one case of granulocytopenia (which had no clinical effect), no drug-related changes could be demonstrated. This contrasts with the general impression that this immunomodulator agent might be harmful to patients with multiple sclerosis. The fact that during this blind study both annual relapse rate and disability score remained more stable in treated patients with severe disability suggests that, while waiting for a more effective treatment, long-term levamisole therapy could be useful in patients with multiple sclerosis.

Adolescent↗