Efficacy of a comfrey root extract ointment in comparison to a diclofenac gel in the treatment of ankle distortions: results of an observer-blind, randomized, multicenter study.

In the treatment of minor blunt injuries several topical drugs are known to have anti-inflammatory and analgesic properties. They represent, however, two fundamentally different major pharmacological therapy approaches: the "chemical-synthetical" and the "phytotherapeutical" approach. The main objective of this trial (CODEC_2004) was to compare the efficacy and tolerability of an ointment of Comfrey extract (Extr. Rad. Symphyti) with that of a Diclofenac gel in the treatment of acute unilateral ankle sprain (distortion). In a single-blind, controlled, randomized, parallel-group, multicenter and confirmatory clinical trial outpatients with acute unilateral ankle sprains (n=164, mean age 29.0 years, 47.6% female) received either a 6 cm long ointment layer of Kytta-Salbe f (Comfrey extract) (n=82) or of Diclofenac gel containing 1.16 g of diclofenac diethylamine salt (n=82) for 7 +/- 1 days, four times a day. Primary variable was the area-under-the-curve (AUC) of the pain reaction to pressure on the injured area measured by a calibrated caliper (tonometer). Secondary variables were the circumference of the joint (swelling; figure-of-eight method), the individual spontaneous pain sensation at rest and at movement according to a Visual Analogue Scale (VAS), the judgment of impaired movements of the injured joint by the method of "neutral-zero", consumption of rescue medication (paracetamol), as well as the global efficacy evaluation and the global assessment of tolerability (both by physician and patient, 4 ranks). In this study the primary variable was also to be validated prospectively. It was confirmatorily shown that Comfrey extract is non-inferior to diclofenac. The 95% confidence interval for the AUC (Comfrey extract minus Diclofenac gel) was 19.01-103.09h*N/cm2 and was completely above the margin of non-inferiority. Moreover, the results of the primary and secondary variables indicate that Comfrey extract may be superior to Diclofenac gel.

Efficacy and tolerance of a comfrey root extract (Extr. Rad. Symphyti) in the treatment of ankle distorsions: results of a multicenter, randomized, placebo-controlled, double-blind study.

Comfrey (Symphytum officinale L.) is a medicinal plant with anti-inflammatory, analgesic and tissue regenerating properties. In a double-blind, multicenter, randomized, placebo-controlled, group comparison study on patients suffering from unilateral acute ankle sprains (n = 142, mean age 31.8 years, 78.9% male), the percutaneous efficacy of an ointment of comfrey extract (Kytta-Salbe f, four treatments per day for 8 days) was confirmed decisively. Compared to placebo, the active treatment was clearly superior regarding the reduction of pain (tonometric measurement, p<0.0001, as the primary efficacy variable) and ankle edema (figure-of-eight method, p = 0.0001). Statistically significant differences between active treatment and placebo could also be shown for ankle mobility (neutral zero method), and global efficacy. Under active treatment, no adverse drug reactions were reported. The good local and global tolerance of the trial medication could also be confirmed. The study results are consistent with the known pre-clinical and clinical data concerning comfrey.

Diclofenac patch for topical treatment of acute impact injuries: a randomised, double blind, placebo controlled, multicentre study.

OBJECTIVES: To investigate the clinical efficacy and safety of a newly developed diclofenac patch in the topical treatment of blunt impact injuries. METHODS: This was a randomised, placebo controlled, double blind, multicentre study in 120 patients with traumatic blunt soft tissue injury. Within 3 h of the injury participants of sport competitions and training camps were enrolled and treated twice daily with the diclofenac or a placebo patch over a period of 7 days. Patients were randomised (1:1) to two parallel groups. Tenderness produced by pressure was measured twice daily during the first 3 days after enrollment as well as at day 7. Tenderness was defined as the amount of pressure (measured by a calibrated caliper at the centre of the injury) that first produced a pain reaction as reported by the patient. RESULTS: The primary efficacy variable was the area under the curve for tenderness over the first 3 days. The diclofenac patch was significantly more effective than placebo (p<0.0001). The treatment effect was 64.7 kp h/cm2 (95% confidence interval 48.7 to 80.9) between diclofenac and placebo patches. These results were supported by all secondary efficacy variables. The diclofenac patch produced rapid pain relief as reflected by the time to reach resolution of pain at the injured site which was significantly shorter compared to placebo (p<0.0001). The diclofenac patch was well tolerated. The most frequently observed adverse events were local cutaneous adverse reactions (pruritus, rash) of minor severity occurring with the same frequency as in the placebo group. CONCLUSIONS: A newly developed diclofenac patch is effective and safe for the treatment of blunt impact injuries.

Sludge treatment by ozonation--evaluation of full-scale results.

Ozonation of industrial and sewage sludge is a suitable process for minimizing the sludge production of activated sludge processes. The ozonation has the advantage for complete oxidation of volatile suspended solids (VSS) of combining partial sludge oxidation with subsequent biological oxidation. This paper describes the evaluation of two full-scale sewage sludge ozonation investigations for subsequent aerobic stabilisation as well as for subsequent anaerobic stabilisation compared to different sludge treatment processes. For both the anaerobic and aerobic application, sludge liquefying by release of 110 and 160 mg COD per g total suspended solids (TSS) has been reached at specific ozone consumption of 0.03 and 0.06 kg O3 per kg TSS, respectively. The subsequent biological treatment has reached a mass reduction of 20-35% for the aerobic and 19% for the anaerobic stabilisation. For both applications the specific ozone consumption was about 0.05 kgO3 per kg TSS to be treated. A comparison with mechanical and thermo-chemical sludge mass reduction methods shows that the mass reduction potential of ozonation is presently higher. Even though costs for sludge ozonation are higher compared to other methods, the optimisation potential for cost reduction of sludge ozonation is obvious from the results presented in this paper.

Lack of apolipoprotein-E exacerbates experimental allergic encephalomyelitis.

Experimental autoimmune encephalomyelitis (EAE) was found to have a chronic and significantly worse course in apolipoprotein-E (apoE) deficient female mice when compared with matched controls. Disease measures compared included incidence of EAE (64% versus 31%, P < 0.05, chi2 test), maximal clinical score (average +/- SD 2.81 +/- 2.5 versus 0.75 +/- 1.1, P < 0.01, Mann-Whitney test) and mortality (27.3% versus 0%, P = 0.02, Mann-Whitney test and chi2 test). ApoE deficient mice had significantly increased lymphocyte proliferation responses to both myelin antigens and mitogens and significantly more infiltrating lesions in the central nervous system (CNS) in histopathology. Defective neuronal repair mechanisms and enhanced immune reactivity in apoE deficient mice may explain our findings. Clinical implications for MS are discussed.

RheoSorb: a specific adsorber for fibrinogen elimination in clinical situations with impaired rheology.

A functional microcirculation is crucial for the normal function of an organism. In many physiopathological situations, impaired microcirculation may contribute to the development or progress of diseases. Microcirculation is closely interrelated with blood and especially plasma rheology. Thus, improvement of plasma viscosity has beneficial effects on rheology, microcirculation, and the related tissue microenvironment. However, at best tools that only have a minor influence on plasma viscosity exist so far. Fibrinogen is known to be the major contributor to plasma viscosity, making it an interesting target for therapeutic intervention. An adsorber specific for fibrinogen was developed on the basis of the TheraSorb technology. The TheraSorb technology (PlasmaSelect AG, Teterow, Germany) allows the selective removal of components from human blood plasma by means of an affinity chromatography column. A ligand specific for a defined plasma component is coupled to a solid matrix (sepharose) thus binding and eliminating the target molecule from plasma. Using a fibrinogen specific pentapeptide as ligand, selective removal of fibrinogen, fibrin, and degradation products, containing the target sequence of these molecules, can be obtained. The LIFE-18, a state-of-the-art integrated plasma therapy instrument, is used to perform the treatment. The procedure improves plasma and whole blood viscosity in a dose dependent manner as shown in Phase 1 and 2 clinical trials. This article describes the first clinical experience in patients with diabetic foot syndrome and provides an outlook for further clinical and scientific investigations related to this promising new procedure.

[Therapeutic characteristance and tolerance of topical comfrey preparations. Results of an observational study of patients]. / Therapeutische Eigenschaften und Verträglichkeit topischer Beinwellzubereitungen. Ergebnisse einer Beobachtungsstudie an Patienten.

AIM: To analyze the anti-inflammatory and analgetic properties of the topical comfrey, preparations Kytta-Salbe f, Kytta-Plasma f and Kytta-Balsam f applied to bruises, sprains and distortions and painful conditions of the muscles and joints. METHOD: A prospective open multicentric observational study complying with paragraph 67(6) of the AMG and involving 162 general practitioners. During the two-week period of observation, the patients received an average of one to three applications of the comfrey preparation per day. All 492 questionnaires were evaluated. Efficacy and tolerability were assessed by both physician and patient. RESULTS: Pain at rest and on movement, as also tenderness, improved in the overall observation group by an average of 45-47%. The duration of morning joint stiffness decreased from 20 minutes initially to 3 minutes. During the course of treatment with comfrey, more than two-thirds of the patients were able to reduce or even discontinue their intake of non-steroidal anti-inflammatory drugs and other specific concomitant medication. In most of the cases, both effectiveness and tolerability were assessed to be excellent or good. CONCLUSION: The results of the study confirm the effectiveness and tolerability of the topical comfrey preparation investigated in the treatment of bruises, sprains and distortions as well as painful conditions affecting muscles and joints.

The Ras-pathway inhibitor, S-trans-trans-farnesylthiosalicylic acid, suppresses experimental allergic encephalomyelitis.

AIM: To evaluate the effects of the synthetic Ras-pathway inhibitor, S-trans-trans-farnesylthiosalicylic acid (FTS) on acute and chronic experimental autoimmune encephalomyelitis (EAE and CR-EAE). BACKGROUND: Treatment of EAE and MS is based on immunosuppression aiming at downregulation of the proliferating myelin-reactive lymphocytes. One of the pathways of lymphocyte activation involves the GTP-binding protein Ras. FTS destabilizes the attachment of Ras to the cell membrane, resulting in an inhibition of the Ras-mediated signal transduction pathways. MATERIALS AND METHODS: EAE was induced in SJL/J mice by immunization with spinal cord homogenate (MSCH) in adjuvant and two i.v. boosts of pertussis antigen and CR-EAE with passive transfer of proteolipid protein (PLP)-activated lymphocytes. Animals were treated daily starting either from the day of EAE-induction (or cell transfer) or at a later stage, with i.p. injections of FTS (5 mg/kg/day). The clinical severity of the disease was evaluated daily and scored using a 0-6 scale. RESULTS: In six separate experiments, 27 of the 38 (71.7%) vehicle-treated animals developed clinical signs of EAE compared to 17/38 (44.7%) of the FTS-treated mice (p=0.02, t-test). The maximal average score in the control group was 2.94+/-2.2, whereas in the FTS group it was significantly lower (1.63+/-2.2, p=0.01). Mortality was 26.3% and 10.5% in the two groups, respectively (p=0.03). When treatment was initiated at a later stage, just before the onset of the clinical signs, the protective effect was even more pronounced. A significant suppression of clinical signs was also observed in the CR-EAE model (p=0.02). Lymphocyte proliferation assays demonstrated a more than twofold decrease in the reactivity to myelin antigens (MBP and PLP) and downregulation of the activated lymphocytes (expressing the CD62L, and IA-k-MHC Class I markers and the Vb17 T-cell receptor) in the FTS-treated group; in vitro FTS suppressed the Ras activity of lymphocytes and inhibited the proliferative ability of the lymphocytes in a dose-dependent manner. CONCLUSIONS: FTS suppresses EAE by downregulation of myelin-reactive activated T-lymphocytes. Since FTS did not induce generalized immunosuppressive effects, it may offer significant advantages over the broad immunosuppressive modalities and may be a candidate treatment for autoimmune diseases, such as MS.

Linomide downregulates autoimmunity through induction of TH2 cytokine production by lymphocytes.

Linomide is a synthetic immunomodulator that has been shown to protect animals against a wide range of spontaneously developing or induced autoimmune diseases. We have previously reported that Linomide blocks both the clinical and the histopathological manifestations of experimental autoimmune encephalomyelitis (EAE) in various animal models. In this study, in an effort to elucidate the mechanisms by which Linomide suppresses EAE, and autoimmunity in general, we investigated the in vivo effects of this drug on the TH1/TH2 lymphocyte balance, which is important for the induction or inhibition of autoireactivity. Naive SJL/J mice were treated orally for 15 days with Linomide (80 mg/kg/day). Spleen cells were obtained at various time points during the treatment period and were stimulated in vitro with concanavalin A. Interleukins IL-4, IL-10 and IL-12, transforming growth factor-beta (TGFbeta) and interferon-gamma (IFNgamma) cytokine production was evaluated both by means of detection of the cytokines in the medium (by ELISA technique) and by detection of the cytokine mRNA production, using a semiquantitative reverse transcriptase polymerase chain reaction method. A significant upregulation of IL-4, IL-10 and TGFbeta was observed following treatment with Linomide, which peaked at day 10 (IL-10) or day 15 (IL-4). On the other hand, IL-12 and IFNgamma production were either unchanged or decreased. It seems therefore that Linomide induces in vivo a shift towards TH2 lymphocytes which may be one of the mechanisms of downregulation of the autoimmune reactivity in EAE. Our observations indicate that downregulation of TH1 cytokines (especially IL-12) and enhancement of TH2 cytokine production may play an important role in the control of T-cell-mediated autoimmunity. These data may contribute to the design of new immunomodulating treatments for a group of autoimmune diseases.

Acute/relapsing experimental autoimmune encephalomyelitis: induction of long lasting, antigen-specific tolerance by syngeneic bone marrow transplantation.

Experimental autoimmune encephalomyelitis (EAE) is an inducible autoimmune disease widely used as a model of the acute/relapsing stage of multiple sclerosis. We have previously shown that treatment of EAE-mice with high doses of cyclophosphamide (CY) (350 mg kg), followed by syngeneic bone marrow transplantation (SBMT), completely abrogates the clinical paralytic signs and even prevents the appearance of new relapses in the chronic-relapsing model of the disease. In the present study we examined whether this treatment protocol induces long term tolerance and whether this tolerance is antigen-specific. EAE was induced by immunization with spinal cord homogenate (MSCH) in complete Freund's adjuvant (CFA). The treatment with CY and SBMT was performed on day 6 post immunization. Treated and untreated mice were rechallenged with MSCH, or a non-relevant antigen (OVA) in CFA at various stages after the first paralytic attack. In contrast to previous data showing that animals recovering from acute EAE are usually refractory to re-induction of the disease, repeated injections of MSCH at different sites from the initial immunization, followed by i.v. injection of inactivated Bordetella bacteria, 2, 4 and 6 months after the initial EAE-induction, caused a severe and usually lethal relapse in all the untreated, control animals. Mice treated with CY and SBMT were resistant to all rechallenges with the same encephalitogenic inoculum. Following the second rechallenge, peripheral lymph node cells were examined in vitro for their proliferative responses to myelin antigens or to OVA. Lymphocytes obtained from CY+SBMT treated mice did not proliferate in vitro in response to myelin basic protein (MBP), but proliferated against OVA, when immunized with this antigen, after SBMT. Adoptive transfer of lymphocytes from tolerant mice to naive recipients did not transfer resistance to EAE-induction. Our results indicate that high doses of CY, followed by SBMT, induce long term antigen-specific tolerance presumably by a mechanism of clonal deletion or anergy.

Linomide induces apoptotic death of cortical CD4/CD8 double positive thymocytes and thymic atrophy by a corticosteroid-independent pathway.

Linomide is a synthetic immunomodulator which was shown to protect animals against a wide range of experimental autoimmune diseases. In this study we have investigated the effects of Linomide on the thymus in an effort to elucidate the mechanisms by which this immunomodulator suppresses autoimmune reactivity. Normal or adrenalectomized SJL/J mice were treated orally for 10 days with linomide (80 mg/kg/day). Thymocytes were tested by FACS for the analysis of the CD4 and CD8 markers and TCR expression on their surface. Thymuses from these animals were examined for size and cellularity and immunohistopathologically for the detection of apoptosis and for the expression of the markers CD4 and CD8. A significant reduction in the thymus size and cellularity was observed in mice treated with Linomide, starting from day 3 after treatment, accompanied by an enhanced apoptotic death of cortical thymocytes, which was first noted on day 1 of treatment and peaked on day 3. FACS analysis and immunohistochemistry revealed a significant depletion of the CD4(+)/CD8(+) (double positive) cells with a parallel relative increase of the more mature, medullar, single positive, lymphocytes. These effects on the thymus were not mediated through a corticosteroid-dependent pathway, and were also observed in adrenalectomized and Linomide-treated animals. These observations may be of importance for the clarification of the role of thymus in autoimmunity and the possible ways for immune intervention with immunomodulators like Linomide at this level.

Inhibition of experimental autoimmune neuritis by the immunomodulator linomide.

Experimental autoimmune neuritis (EAN) is an animal model that shares clinical, pathological and electrophysiological features with the human disease Guillain-Barre syndrome. The synthetic immunomodulatory substance linomide has been successfully used to prevent the development of several experimental autoimmune models in laboratory animals and has been proved to be beneficial in modulating the course of multiple sclerosis in humans. In the present study we demonstrate that oral administration of linomide prevents the development of clinical and histopathological signs of EAN in Lewis rats, inoculated with the P2 (60-70) synthetic peptide. The immunomodulatory effect of linomide on this experimental model of disease was associated with marked apoptosis of lymphocytes in thymus and spleen early after starting the treatment. Furthermore, a downregulation of the endothelial expression of the adhesion molecules ICAM-1 at the target site and LFA-1 on lymphocytes could also contribute to the absence of inflammatory cells in the neuraxis.

Antihuman immunoglobulin affinity immunoadsorption strongly decreases proteinuria in patients with relapsing nephrotic syndrome.

Approximately 20 to 30% of patients with idiopathic nephrotic syndrome and focal glomerulosclerosis experience a relapse of their nephrotic syndrome after transplantation. Previously, it has been shown that ex vivo immunoadsorption on protein A strongly (although transiently) reduces proteinuria in relapsing patients. To investigate whether the factor(s) that give rise to albuminuria are bound directly to protein A in the immunoadsorption procedure or are part of a complex with Ig, four patients with relapse of focal glomerulosclerosis presenting as nephrotic syndrome after transplantation were treated, sequentially, using a (non-protein A) anti-Ig affinity column and a protein A column. This study reports that the effect on proteinuria of immunoadsorption using an anti-Ig immunoaffinity column is comparable in its magnitude and kinetics to that of immunoadsorption on protein A. The two procedures were also equally effective in depleting the relapsing patients' plasma of a factor capable of altering the albumin permselectivity of isolated glomeruli in vitro. This study demonstrates for the first time that immunoglobulins have a role in the nephrotic syndrome. In addition, the fact that the two different immunoadsorption procedures both resulted in the removal of the same putative albuminuric factor in these patients and that no autoreactivity of eluted immunoglobulins was observed on human tissues strongly suggests that the factor or factors that may be responsible for immediate nephrotic syndrome after transplantation are bound to an immunoglobulin. However, no firm evidence can be yet provided against a direct role of immunoglobulins.

Course of islet autoantibody titers during Ig-immunoadsorption in a patient with newly diagnosed type 1 diabetes.

The purpose of this study was to determine whether and to what extent diabetes-specific autoantibodies can be removed from the plasma by Ig-immunoadsorption therapy. We followed the course of islet cell antibodies (ICA), insulin antibodies (I[A]A), glutamic acid decarboxylase antibodies (GADA) and antibodies to the protein tyrosine phosphatase IA-2 (IA2A) in a patient with newly diagnosed insulin-dependent diabetes mellitus (IDDM) under multiple immunoadsorption treatments over 6 months. Autoantibodies were not removed from the plasma as efficiently as expected when compared to the removal of total immunoglobulin (IgG). Whereas IgG levels were lowered by 70-90% through each immunoadsorption treatment, antibodies to insulin were reduced by an average of 83%, IA2A by 36% and GADA by only 9% directly after treatment. ICA were > 320 JDF U at diabetes onset and remained above this level. During the 6 months of multiple immunoadsorption therapies, I[A]A levels showed a 24-fold increase due to stimulation of insulin antibody production by exogenous insulin substitution, IA2A levels remained unchanged (average 6% increase), and GADA levels were reduced by an average of 39% compared to antibody titers at onset. All four antibodies were highly positive in the eluate from the immunoadsorption columns. We showed that antibodies to pancreatic islet cells can be reduced by immunoadsorption, but as for plasmapheresis the effect is incomplete and transient for most of the antibodies. If there is clinical benefit through immunoadsorption therapy--as has been shown for newly diagnosed IDDM patients treated with plasmapheresis--our data suggest that this may be due to factors other than the sufficient removal of antibodies.

LDL-Therasorb immunoadsorption for the treatment of severe hypercholesterolemia refractory to conventional therapy.

The role of severe hypercholesterolemia (SH) as a major risk factor for coronary heart disease has been well established. Not all patients with SH can be treated sufficiently with diet and drugs. In such circumstances, extracorporeal removal of low-density lipoprotein (LDL) cholesterol is required in patients with existing atherosclerosis. The chronic regular application of extracorporeal cholesterol removal demands an efficient and selective method not influencing other plasma components. Several methods have been developed for the extracorporeal reduction of LDL cholesterol using different approaches to achieve selectivity. Today the most selective approach is the use of specific antibodies directed against apolipoprotein B-100. For 17 years, this method has been used in the therapy of patients with SH. Numerous publications demonstrate the safety and efficacy of immunoadsorption (IA) with the LDL-Therasorb System. Within an IA treatment, LDL cholesterol is reduced by 60-70%. The system, however, allows for any desired reduction in the cholesterol levels because the double column system can be alternately loaded and regenerated to enable virtually unlimited treatment of plasma. The treatable plasma quantity is not limited by the nonspecific removal of other plasma components, e.g., coagulation factors, fibrinogen, plasminogen, or immunoglobulins. In long-term studies, the influence of LDL-Therasorb IA on coronary and peripheral atherosclerotic disease has been shown to have a favorable influence on the development of stenoses. In the majority of patients, a stop of progression and even a regression of stenoses could be demonstrated.

Ig-Therasorb immunoadsorption for selective removal of human immunoglobulins in diseases associated with pathogenic antibodies of all classes and IgG subclasses, immune complexes, and fragments of immunoglobulins.

Therasorb immunoadsorption (IA), by selectively eliminating pathogenic substances from the circulation, allows for successful therapy of previously insufficiently treatable diseases. Molecules (specific polyclonal sheep antibodies) coupled to a matrix (Sepharose CL 4B) selectively bind plasma components in extracorporeal circulation. This procedure has been established in the treatment of various diseases. Examples are familial hypercholesterolemia (LDL-Therasorb) and selected autoimmune diseases (Ig-Therasorb). Ig-Therasorb IA has been performed in a variety of clinical indications, primarily in the treatment of autoimmune diseases. In most cases, Ig-Therasorb IA has been applied in patients who have failed to respond to conventional therapy with a high rate of clinical improvement. In defined groups of patients with autoimmune diseases and alloantibodies, immunoadsorption can now be considered an established therapeutic means. The fast and efficient removal of immunoglobulins obviously exceeds the efficiency of conventional plasma exchange by far. Autoimmune diseases could be induced by balanced and nonbalanced immunity. The importance of autoantibodies remains unclear, but the efficacy of Ig-Therasorb IA suggests a key role for them. In addition to the established indications for removal of immunoglobulins, there may be a number of promising new indications.

Inhibition of the progression of multiple sclerosis by linomide is associated with upregulation of CD4+/CD45RA+ cells and downregulation of CD4+/CD45RO+ cells.

In a recent double-blind, phase II study, conducted in our department, we showed that Linomide-treated MS patients had significantly less active lesions (in serial monthly MRI tests) and a tendency for clinical stabilization. Here we present the immunological evaluation of the patients who participated in this study and propose a novel mechanism by which Linomide downregulates autoreactivity. Peripheral blood leukocytes (PBLs), serum, and CSF samples were obtained at two to four time points over the 6 months of the trial. Flow cytometric analysis (FACS) of the CD5/CD19, CD4/CD8, CD14/CD3, CD16/CD3, CD45RA/CD4, and CD45RO/CD4 surface markers on PBLs was performed and the levels of the IL-1beta, IL-2, IL-4, IL-6, IL-10, TNF-alpha, IFN-gamma, and IL-2R were also examined. White blood counts of Linomide-treated patients were consistently elevated throughout the treatment period (P = 0.002-0.04). Cytokines levels in serum and CSF were highly fluctuating and we could not detect any clear trend as a result of Linomide treatment. FACS analysis showed that Linomide treatment significantly increased the percentage of the CD4+/CD45RA+ cells (from 35.5% at baseline to 42.3% at week 24; P = 0.02), and decreased CD4+/CD45RO+ lymphocytes (62.6% at baseline vs 53.7% at week 24, P = 0.02). Linomide also induced a transient increase in the NK-cells, the NK 1.1 cells, and the CD5 B-cells (P = 0.02). Upregulation of naive CD45RA T-lymphocytes and parallel downregulation of memory CD45RO cells seems to be one of the main mechanisms by which Linomide inhibits MS activity and may represent an alternative immunomodulating approach for the treatment of MS and autoimmunity in general.

Immunomodulation of autoimmunity by linomide: inhibition of antigen presentation through down regulation of macrophage activity in the model of experimental autoimmune encephalomyelitis.

Linomide (quinoline-3-carboxamide, LS-2616), a synthetic immunomodulator, protects animals against a variety of experimental autoimmune diseases. In experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis (MS), linomide blocks both the clinical and histological signs of the disease, without inducing generalized immunosuppression. In the first clinical trial in patients with MS, linomide was shown to inhibit the progression of the disease. In the present study we investigated several aspects of the mechanisms of action of this immunomodulator. We found that linomide can inhibit acute EAE even when given as pretreatment, prior to induction of disease (days - 10 to 0). This inhibitory effect was reversed by adoptive transfer of naive spleen cells. A short course (7 days) of linomide treatment also inhibited EAE, especially when administered immediately after disease induction. Spleen cells from linomide-treated mice failed to present myelin antigens to T-cell lines in vitro. The defective antigen presentation was normalized by anti-oxidants such as 2-mercaptoethanol. The proportion of Mac1+ cells in the spleens of linomide-treated mice was significantly reduced and macrophage growth was inhibited in long term cultures of spleen cells derived from linomide-treated animals. Our findings suggest that the effect of linomide on EAE may be attributed, at least in part, to inactivation of antigen presenting cells, possibly following a short period of over-stimulation and increased oxidant production. This mechanism may play a universal role in the regulation of autoimmune reactivity and merits further investigation.

Noncorneal astigmatism related to poly(methyl methacrylate) and plate-haptic silicone intraocular lenses.

PURPOSE: To evaluate noncorneal astigmatism after implantation of a one-piece, plate-haptic silicone or one-piece poly(methyl methacrylate) PMMA intraocular lens (IOL). SETTING: Klinik und Poliklinik für Augenheilkunde der Universität Regensburg, Germany. METHODS: After a follow-up of at least 3 months, the degree of postoperative noncorneal astigmatism was calculated using the data from an auto refractometer. Sixty patients were evaluated: 30 with silicone IOLs (Group A) and 30 with PMMA lenses (Group B). RESULTS: Mean noncorneal astigmatism in Group A was 0.78 diopter (D) +/- 0.51 (SD), which was statistically significantly higher than that in Group B (0.51 +/- 0.27 D) (P = .013). The highest noncorneal astigmatism, 2.32 D, occurred in Group A. CONCLUSIONS: Based on these findings, we recommend noncorneal astigmatism be considered in eyes with a one-piece, plate-haptic silicone IOL and postoperative astigmatism. A prospective study with a standardized capsulorhexis size is needed to ascertain whether this IOL-related noncorneal astigmatism is caused by capsular shrinkage, which may then be treatable with a laser capsulotomy of the anterior capsule.

[Lens astigmatism in connection with implantation of a foldable one-piece silicone lens in a patient]. / Das Auftreten von Linsenastigmatismus in Zusammenhang mit Implantation einer faltbaren One-piece-Siliconlinse bei einem Patienten.

BACKGROUND: The use of one-piece plate-haptic Silicon lenses has become more frequent especially in combination with small incision cataract surgery. Different complications as before are to be expected. CASE REPORT: Six weeks after cataract surgery and implantation of a one-piece plate-haptic Silicon lens a lens astigmatism of 3.5 dpt was noted. The astigmatism occurred after successfully performed retinal detachment surgery in this eye. The development of the astigmatism was considered to be due to a capsular shrinkage of the anterior capsular ring. The retinal detachment surgery was performed with the use of SF6 gas, which is known as a factor for increasing inflammation. After a Nd: YAG incision of the anterior capsule the astigmatism disappeared immediately. CONCLUSION: Capsular shrinkage can induce a significant lens astigmatism in combination with soft one-piece plate-haptic Silicon lenses. Intraocular inflammation seems to play an important role. Astigmatism after implantation of one-piece plate-haptic Silicon lenses in combination with signs of capsular shrinkage can be explained by lens astigmatism only.