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Selected AbstractsMycophenolate Mofetil Monotherapy for Severe Side Effects of Calcineurin Inhibitors Following Liver TransplantationAMERICAN JOURNAL OF TRANSPLANTATION, Issue 3 2009S. Dharancy Withdrawal of calcineurin inhibitors (CNI) followed by mycophenolate mofetil (MMF) monotherapy after liver transplantation (LT) remains controversial due to the increased risk of acute rejection and graft loss. The aim of the present study, performed in a large cohort of liver-transplanted patients with severe CNI-induced side effects, was to assess renal function recovery, and safety in terms of liver function, of complete CNI withdrawal and replacement by MMF monotherapy. Fifty-two patients treated with MMF monotherapy for CNI-induced toxicity were analyzed. Mean estimated glomerular filtration rate (eGFR) increased significantly during the period of MMF monotherapy, from 37 ± 10 to 44.7 ± 15 mL/min/1.73 m2 at 6 months (p = 0.001) corresponding to a benefit of +17.4% in renal function. eGFR stabilized or improved in 86.5%, 81% and 79% of cases, and chronic renal dysfunction worsened in 13.5%, 19% and 21% of cases, at 6, 12 and 24 months after CNI withdrawal, respectively. Only two patients experienced acute rejection. MMF monotherapy may be efficient at reversing/stabilizing CRD, and appears relatively safe in terms of liver graft function in long-term liver-transplanted patients. However, clinicians must bear in mind the potential risk of rejection and graft loss, and should be very cautious in the management of such ,difficult-to-treat patients'. [source] Use of aminoglutethimide in the treatment of pituitary-dependent hyperadrenocorticism in the dogJOURNAL OF SMALL ANIMAL PRACTICE, Issue 3 2002M. D. Pérez Alenza The aim of this study was to evaluate the efficacy and safety of aminoglutethimide in the treatment of dogs with pituitary-dependent hyperadrenocorticism (PDH). Ten dogs were diagnosed with PDH based on clinical and laboratory data, adrenal function tests (adrenocorticotropic hormone [ACTH] stimulation test and urinary cortisol/creatinine ratio [UCCR] combined with a high dose oral dexamethasone suppression test) and ultrasonographic evaluation of the adrenal glands. Aminoglutethimide was administered daily at a dose of 15 mg/kg bodyweight for one month. Median basal cortisol concentration and post-ACTH cortisol concentration one month after treatment were significantly lower than pretreatment values. Complete response was achieved in one dog, and partial response was obtained in three dogs. Severe side effects of anorexia, vomiting and weakness occurred in one dog and medication was withdrawn. Two further dogs developed decompensations of concurrent diseases and medication was stopped in these animals as well. Mild toxicity occurred in four dogs. Moderate to severe elevations in liver enzymes occurred in all dogs. The efficacy of this drug is lower than that observed using mitotane and ketoconazole, and adverse effects limit its use. Aminoglutethimide, using the protocol described, cannot be recommended for long-term management of PDH in the dog. [source] Low-Density Lipoprotein Apheresis: Clinical Results with Different MethodsARTIFICIAL ORGANS, Issue 2 2002Rolf Bambauer Abstract: In 40 patients (22 women, 18 men) suffering from familial hypercholesterolemia resistant to diet and lipid lowering drugs, low-density lipoprotein (LDL) apheresis was performed over 84.9 ± 43.2 months. Four different systems (Liposorber, 28 of 40, Kaneka, Osaka, Japan; Therasorb, 6 of 40, Baxter, Munich, Germany; Lipopak, 2 of 40, Pocard, Moscow, Russia; and Dali, 4 of 40, Fresenius, St. Wendel, Germany) were used. With all methods, average reductions of 50.6% for total cholesterol, 52.2% for LDL, 64.3% for lipoprotein (a) (Lp[a]), and 43.1% for triglycerides, and an average increase of 10.3% for high-density lipoprotein (HDL) were reached. Severe side effects such as shock or allergic reactions were very rare (0.5%) in all methods. In the course of treatment, an improvement in general well being and increased performance were experienced by 39 of 40 patients. Assessing the different apheresis systems used, at the end of the trial, there were no significant differences with respect to the clinical outcome experienced with the patients' total cholesterol, LDL, HDL, and triglyceride concentrations. However, to reduce high Lp(a) levels, the immunoadsorption method with special Lp(a) columns (Lipopak) seems to be most effective: ,59% versus ,25% (Kaneka) , (Baxter), and ,29% (Dali). The present data demonstrate that treatment with LDL apheresis of patients suffering from familial hypercholesterolemia resistant to maximum conservative therapy is very effective and safe even in long-term application. [source] Peptide-doxorubicin conjugates specifically degraded by matrix metalloproteinases expressed from tumorDRUG DEVELOPMENT RESEARCH, Issue 5 2006Gee Young Lee Abstract Specific peptide-doxorubicin conjugates were developed for targeting matrix metalloproteinases (MMPs) expressed from tumors. The peptide-doxorubicin conjugates were designed to be cleaved by MMP-2 and MMP-9 in order that doxorubicin or the active form that acts as an anticancer agent was released free from the peptide fragment at the tumor site. Three types of peptide-doxorubicin conjugates were synthesized using the peptides: GPLG (Gly-Pro-Leu-Gly), GPLGV (Gly-Pro-Leu-Gly-Val), and GPLGPAG (Gly-Pro-Leu-Gly-Pro-Ala-Gly). The synthesized peptide-doxorubicin conjugates were characterized for their degradation behavior and bioactivity in vitro, and their antitumoral activity was assessed using the Lewis lung carcinoma (LLC) model, which expresses MMP-2 and MMP-9. After incubation with active MMP-2 for 24,h, GPLG-doxorubicin was barely degraded, whereas GPLGV-doxorubicin and GPLGPAG-doxorubicin were considerably degraded by active MMP-2. Consequently, all peptide-doxorubicin conjugates had significantly low cytotoxicity compared to doxorubicin, but tumor growth suppression was exhibited only by GPLGV-doxorubicin and GPLGPAG-doxorubicin. The tumor growth suppression by the two conjugates was higher compared to control, although it did not exceed the suppression level shown by doxorubicin. The low toxicity exhibited by peptide-doxorubicin conjugates resulted in only slight body weight loss in mice, whereas doxorubicin greatly reduced body weight and induced severe side effects. Therefore, we propose MMPs-specific peptide-doxorubicin conjugates in targeting anti-cancer drug delivery that could reduce systemic toxicities. Drug Dev. Res. 67:438,447, 2006. © 2006 Wiley-Liss, Inc. [source] Model of cryptogenic infantile spasms after prenatal corticosteroid primingEPILEPSIA, Issue 2010Libor Velí Summary Infantile spasms (IS) is a devastating epilepsy syndrome of childhood. IS occurs in 3,12-month-old infants and is characterized by spasms, interictal electroencephalography (EEG) hypsarrhythmia, and profound mental retardation. Hormonal therapy [adrenocorticotropic hormone (ACTH), corticosteroids] is frequently used, but its efficacy is tainted by severe side effects. For research of novel therapies, a validated animal model of IS is required. We propose the model of spastic seizures triggered by N -methyl- d -aspartate (NMDA) in infant rats prenatally exposed to betamethasone. The spasms have remarkable similarity to human IS, including motor flexion spasms, ictal EEG electrodecrement, and responsiveness to ACTH. Interestingly, the spasms do not involve the hippocampus. Autoradiographic metabolic mapping as well as tagging of the areas of neuronal excitation with c-fos indicates a strong involvement of hypothalamic structures such as the arcuate nucleus, which has significant bilateral connections with other hypothalamic nuclei as well as with the brainstem. [source] Type 1 diabetes and epilepsy: Efficacy and safety of the ketogenic dietEPILEPSIA, Issue 6 2010Anastasia Dressler Summary Diabetes type 1 seems to be more prevalent in epilepsy, and low-carbohydrate diets improve glycemic control in diabetes type 2, but data on the use of the classic ketogenic diet (KD) in epilepsy and diabetes are scarce. We present 15 months of follow-up of a 3 years and 6 months old girl with diabetes type 1 (on the KD), right-sided hemiparesis, and focal epilepsy due to a malformation of cortical development. Although epileptiform activity on electroencephalography (EEG) persisted (especially during sleep), clinically overt seizures have not been reported since the KD. An improved activity level and significant developmental achievements were noticed. Glycosylated hemoglobin (HbA1c) levels improved, and glycemic control was excellent, without severe side effects. Our experience indicates that diabetes does not preclude the use of the KD. [source] Comparison of adefovir and tenofovir in the treatment of lamivudine-resistant hepatitis B virus infection,HEPATOLOGY, Issue 6 2004Florian van Bömmel Adefovir dipivoxil was recently approved for the treatment of wild-type and lamivudine-resistant hepatitis B virus (HBV) infection. Tenofovir disoproxil fumarate, a congender of adefovir that is used in the treatment of HIV infected patients, has recently been shown to also be effective in patients with lamivudine-resistant HBV infection. We therefore compared the two substances in a study of 53 patients defined by high HBV DNA (>6 log10 copies/mL) levels and genotypic evidence of lamivudine resistance. Thirty-five patients received tenofovir for 72 to 130 weeks, and 18 received adefovir for 60 to 80 weeks. Changes in HBV DNA levels were followed for the complete period of 48 weeks. Early viral kinetics were compared on matched subgroups of 5 patients each. Individually, all tenofovir-treated patients showed a strong and early suppression of HBV DNA within a few weeks whether they were coinfected with HIV or were without comorbidity. In contrast, considerable individual variations in HBV DNA decline were observed in the adefovir group. Thus at week 48, only 44% of these patients had HBV DNA levels below 105 copies/mL in contrast to 100% of the tenofovir-treated patients (P = .001). No severe side effects were noticed in either group. No evidence of phenotypic viral resistance could be demonstrated in the tenofovir-treated patients in the long term (up to 130 weeks). In conclusion, tenofovir may become an effective alternative for the treatment of patients with lamivudine-resistant HBV infection. (HEPATOLOGY 2004;40:1421,1425.) [source] Controlled application and removal of liposomal therapeutics: Effective elimination of pegylated liposomal doxorubicin by double-filtration plasmapheresis in vitroJOURNAL OF CLINICAL APHERESIS, Issue 2 2010Gerhard Pütz Abstract Introduction: Nanoscale particle-based drug delivery systems like long circulating liposomal doxorubicin show unique pharmacokinetic properties and improved toxicity profiles. Liposomal doxorubicin accumulates in tumor tissue due to the enhanced permeation and retention effect, but only a small fraction of a total dose reaches the tumor site. Accumulation of liposomal doxorubicin is much faster in tumor sites than in certain organs where dose limiting adverse effects occur. Finding a way to detoxify the predominant part of a given dose, circulating in the blood after accumulation is completed, will presumably reduce severe side effects during chemotherapy. Methods: Elimination properties of therapeutic used pegylated liposomal doxorubicin (Doxil®/Caelyx®) and therapeutic used double-filtration plasmapheresis systems were evaluated in vitro and in reconstituted human blood. Results: Liposomes can be filtered by appropriate membranes without leakage of doxorubicin up to a pressure of 1 bar. At higher pressures, liposomes (,85 nm) may squeeze through much smaller pores without significant leakage of doxorubicin, whereas decreasing pore size to ,8 nm leads to increased leakage of doxorubicin. With therapeutic used apheresis systems, liposomal doxorubicin can be efficiently eliminated out of buffer medium and reconstituted human blood. No leakage of doxorubicin was detected, even when liposomes were circulating for 48 h in human plasma before apheresis. Conclusions: Convenient apheresis techniques are capable of a safe and efficient elimination of therapeutic used liposomal doxorubicin in an experimental model system. J. Clin. Apheresis, 2010. © 2010 Wiley-Liss, Inc. [source] Sustained low-dose growth hormone therapy optimizes bioactive insulin-like growth factor-I level and may enhance CD4 T-cell number in HIV infectionJOURNAL OF MEDICAL VIROLOGY, Issue 2 2010Ove Andersen Abstract High-dose recombinant human growth hormone (rhGH) (2,6,mg/day) regimes may facilitate T-cell restoration in patients infected with human immunodeficiency virus (HIV) on highly active antiretroviral therapy (HAART). However, high-dose rhGH regimens increase insulin-like growth factor-I (IGF-I) to supra-physiological levels associated with severe side effects. The present study investigated whether lower doses of rhGH may improve T-cell restoration in patients infected with HIV following an expedient response of total and bioactive (i.e., free) IGF-I. A previous 16-week pilot-study included six HIV-infected patients on stable HAART to receive rhGH 0.7,mg/day, which increased total (+117%, P,<,0.01) and free (+155%, P,<,0.01) IGF-I levels. The study was extended to examine whether continuous use of low-dose rhGH (0.7,mg/day until week 60; 0.4,mg/day from week 60 to week 140) would maintain expedient IGF-I levels and improve CD4 T-cell response. Total and free IGF-I increased at week 36 (+97%, P,<,0.01 and +125%, P,<,0.01, respectively) and week 60 (+77%, P,=,0.01 and +125%, P,<,0.01) compared to baseline levels (161,±,15 and 0.75,±,0.11,µg/L). CD4 T-cell number increased at week 36 (+15%, P,<,0.05) and week 60 (+31%, P,=,0.01) compared to baseline levels (456,±,55,cells/µL). Following rhGH dose reduction, total IGF-I and CD4 T-cell number remained increased at week 88 (+44%, P,=,0.01 and +33%, P,<,0.01) and week 140 (+46%, P,=,0.07 and +36%, P,=,0.02) compared to baseline levels. These data support the notion that low-dose rhGH regimens may increase expediently total and bioactive IGF-I and improve T-cell restoration in patients infected with HIV on HAART. J. Med. Virol. 82:197,205, 2010. © 2009 Wiley-Liss, Inc. [source] Abnormal alterations in the metabolic patterns of patients on valproate therapyJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 7 2002U. Kreher Four cases of abnormal metabolic patterns which were obtained from three infantile patients and one adult on valproate (valproic acid; 2-n-propyl-pentanoic acid) therapy are reported. Serum levels of valproate and 15 metabolites were measured by gas chromatography/mass spectrometry. A mentally retarded, 11-month-old boy developed an extremely altered metabolic profile after having been treated with valproate polytherapy for 3 months. The altered pattern included strongly elevated serum levels of the 4-ene as well as of the x-/x 1-metabolites, with the b-metabolites (2-ene; 2,3,-diene) being diminished. Two samples obtained previously had shown a common pattern. The infant died 3 weeks after the last sample had been taken. Two boys of the same age showed similar but less intense deviations in their metabolic profiles at the onset of valproate therapy. Within a few weeks they approached, in a step-wise fashion, the average pattern common for children under 3 years of age. The striking alterations were paralleled by the metabolic profiles of an adult patient who suffered from intrahepatic metastasis and renal insufficiency. From the close resemblance of the abnormal metabolic patterns it was concluded that liver dysfunction results in alteration of the whole metabolic system. Regular inspection of the entire profile of an individual might help to recognize conspicuous alterations in time to avoid severe side effects. [source] Photodynamic therapy of cervical intraepithelial neoplasia with hexaminolevulinate,LASERS IN SURGERY AND MEDICINE, Issue 9 2008Philipp Soergel MD Abstract Background and Objective CIN is a disease of women in their reproductive years, and treatment includes excisional techniques with increased risk of preterm deliveries. Photodynamic therapy (PDT) using topical precursor of photoactive porphyrins may be a non-invasive alternative with minimal side effects. This study assessed the feasibility and response rate of PDT with hexaminolevulinate (HAL) in cervical intraepithelial neoplasia (CIN) and human papillomavirus (HPV) infection. Study Design/Materials and Methods Twenty four patients with a CIN 2 or 3 or a persistent CIN 1 and a positive high-risk HPV-DNA test were included. Each patient had gynaecologic examination including cervical cytology, HPV DNA testing, colposcopy and biopsy. Ten milliliters of HAL-thermogel (10 mM) were topically applied to the cervix for 3,5 hours, followed by 1,000 seconds of illumination of both ecto- and endocervical canal with red coherent light (wave length 633 nm) using a PDT laser and a special light catheter. Follow-up examinations were carried out after 3 (cytology, colposcopy, HPV DNA testing, and if needed re-PDT) and 6 months. Results Seven, 10, and 7 patients had a CIN 1, 2, or 3, respectively. Treatment could be accomplished in all cases and no severe side effects were encountered. Fifteen out of the 24 patients had a complete response (15/24,=,63%) and a HPV remission 6 months after 1,3 treatments. The remission rates were 71%, 50%, and 71% for CIN 1, 2 and 3. Conclusion HAL PDT seems to be a non-invasive, repeatable procedure for CIN and cervical HPV infection with minimal side effects which can be easily performed on outpatient basis. Lesers Surg. Med. 40:611,615, 2008. © 2008 Wiley-Liss, Inc. [source] Treatment of early rheumatoid arthritis: A randomized magnetic resonance imaging study comparing the effects of methotrexate alone, methotrexate in combination with infliximab, and methotrexate in combination with intravenous pulse methylprednisolone,ARTHRITIS & RHEUMATISM, Issue 12 2007Patrick Durez Objective To compare the effects of methotrexate (MTX), alone or in combination with intravenous (IV) methylprednisolone (MP) or infliximab, on magnetic resonance imaging (MRI),detected synovitis, bone edema, and erosive changes in patients with early rheumatoid arthritis (RA). Methods Forty-four patients with early RA were randomized to receive MTX alone (MTX group), MTX plus IV MP (IV MP group), or MTX plus infliximab (infliximab group), infused on day 0 and weeks 2, 6, 14, 22, 30, 38, and 46. Gadolinium-enhanced MRI scans of the metacarpophalangeal joints, wrists, and metatarsophalangeal joints were performed at baseline, week 18, and week 52. Results Scores for MRI-detected synovitis and bone edema improved over time in the 3 groups, with significantly lower synovitis scores in the infliximab group compared with the MTX group and significantly lower bone edema scores in the infliximab group compared with the MTX and the IV MP groups. Scores for MRI-detected erosion significantly increased over time in all groups. There were no differences in erosion scores between the MTX group and the other groups. It is of note that patients treated with IV MP showed more significant progression in MRI-detected erosions compared with patients treated with infliximab. At week 22, response rates according to the American College of Rheumatology 20% improvement criteria (ACR20), the ACR50, and the ACR70 were significantly higher in both the IV MP group and the infliximab group compared with the MTX group. At week 52, remission was achieved in 40% of patients in the MTX group and in 70% of patients in the IV MP and infliximab groups. Health Assessment Questionnaire scores improved significantly over time in all groups, with patients receiving IV MP experiencing significantly more improvement compared with patients treated with MTX alone. No severe side effects were observed, except 1 case of MTX-related pneumonitis. Conclusion The combination of MTX and infliximab is superior to MTX alone for reducing MRI-detected signs of synovitis and bone edema in patients with early RA. Progression of MRI-detected erosion was greater in patients treated with MTX plus IV MP compared with that in patients who received MTX plus infliximab. [source] Structure of Helicobacter pyloril -asparaginase at 1.4,Ĺ resolutionACTA CRYSTALLOGRAPHICA SECTION D, Issue 12 2009Prathusha Dhavala Bacterial l -asparaginases have been used in the treatment of childhood acute lymphoblastic leukaemia for over 30,years. Their therapeutic effect is based on their ability to catalyze the conversion of l -asparagine, an essential amino acid in certain tumours, to l -aspartic acid and ammonia. Two l -asparaginases, one from Escherichia coli and the other from Erwinia chrysanthemi, have been widely employed in clinical practice as anti-leukaemia drugs. However, l -asparaginases are also able to cause severe side effects owing to their intrinsic glutaminase activity. Helicobacter pyloril -asparaginase (HpA) has been reported to have negligible glutaminase activity. To gain insight into the properties of HpA, its crystal structure in the presence of l -aspartate was determined to 1.4,Ĺ resolution, which is one of the highest resolutions obtained for an l -asparaginase structure. The final structure has an Rcryst of 12.6% (Rfree = 16.9%) with good stereochemistry. A detailed analysis of the active site showed major differences in the active-site flexible loop and in the 286,297 loop from the second subunit, which is involved in active-site formation. Accordingly, Glu289, Asn255 and Gln63 are suggested to play roles in modulating the accessibility of the active site. Overall, the structural comparison revealed that HpA has greater structural similarity to E. colil -asparaginase than to any other l -asparaginase, including Er. carotovoral -asparaginase, despite the fact that the latter is also characterized by low glutaminase activity. [source] Conversion to Sirolimus in Renal Transplant Recipients: A Single-Center ExperienceARTIFICIAL ORGANS, Issue 8 2010Berna Yelken Abstract Maintenance immunosuppression with calcineurin inhibitors (CNI) following renal transplantation is associated with nephrotoxicity and accelerated graft loss. Sirolimus (SRL) is a nonnephrotoxic immunosuppressive agent. We retrospectively analyzed our experience with kidney transplant recipients who were converted from CNI to SRL. A total of 58 renal transplant recipients were converted from CNI to SRL. SRL was started at a dose of 0.075 mg/kg and, at the same time, CNI dose was reduced by 50% daily for 3 days. SRL trough levels were targeted between 8 and 12 ng/mL. When target trough levels were achieved, CNI was withdrawn. The main indications for switching were posttransplant malignancies (n = 32) and chronic allograft nephropathy (CAN) (n = 10). The mean time from transplantation to conversion was 84 ± 71 months. Mean serum creatinine level was 1.63 ± 0.52 mg/dL before conversion. Serum creatinine levels at the 1, 3, 6 months, and 1, 2, 3 years after conversion were 1.64 ± 0.58 mg/dL (P = 0.67), 1.52 ± 0.53 mg/dL (P = 0.414), 1.62 ± 0.62 mg/dL (P = 0.734), and 1.48 ± 0.58 mg/dL (P = 0.065), 1.58 ± 0.53 mg/dL (P = 0.854), 1.88 ± 0.77 mg/dL (P = 0.083), respectively. Daily proteinuria levels increased from 0.04 ± 0.11 g/day at baseline to 0.55 ± 1.33 g/day (P = 0.037) after conversion, in the responders group. In the nonresponders group, baseline proteinuria was 0.13 ± 0.25 g/day, and increased to 1.44 ± 2.44 g/day after conversion (P = 0.008). SRL was discontinued in 16 patients (31%) because of the occurrence of severe side effects. The proportion of patients remaining on SRL therapy over time was 43.1% at 1 year, 15.5% at 2 years after conversion, and 10.3% at 3 years after conversion. SRL conversion may be very useful in patients suffering from neoplasia; however, frequent side effects related with this intervention should be considered, and routine conversion from CNI to SRL to reduce nephrotoxicity should be discouraged. [source] Rapid determination method of caffeine and application to monitoring of caffeine-assisted chemotherapyBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 2 2004Masami Kawahara Abstract Caffeine-assisted chemotherapy for bone and soft tissue tumours is very effective. However, high serum caffeine concentrations cause severe side effects, so monitoring of the serum level during therapy is important. For this purpose, a rapid determination method was established by high-performance liquid chromatography after solid-phase extraction. This method can measure caffeine and its three major metabolites in serum samples within 8 min. The mean serum caffeine concentrations of patients were 34.6±7.8, 54.5±11.9 and 73.0±12.8 ,g/ml at 24, 48 and 72 h, respectively, after the start of a 1500 mg/m2/day continuous infusion for 72 h. The distribution volume of caffeine was 0.65±0.23 l/kg, and the total body clearance was 0.025±0.011 l/h/kg, which was one-third of the reported low dose clearance. The appropriate infusion rate was calculated to avoid severe side effects in the final phase of the infusion by using a one-compartment constant infusion model based on the serum levels measured at 24 and 48 h. Caffeine clearance did not correlate with the metabolite/caffeine ratio in serum at any time. It is concluded that individual monitoring with this method for the purpose of dose adjustment is useful for avoiding the side effects of caffeine-assisted chemotherapy. Copyright © 2004 John Wiley & Sons, Ltd. [source] Can we face the challenge of expanding use of intravenous immunoglobulin in neurology?ACTA NEUROLOGICA SCANDINAVICA, Issue 5 2010I. Elovaara Elovaara I, Hietaharju A. Can we face the challenge of expanding use of intravenous immunoglobulin in neurology? Acta Neurol Scand: 2010: 122: 309,315. © 2010 The Authors Journal compilation © 2010 Blackwell Munksgaard. The use of high-dose polyclonal intravenous immunoglobulin (IVIG) in the treatment of autoimmune neurological diseases has expanded over the last decade. Based on controlled clinical trials IVIG can be considered currently as the first-line treatment in Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy, and it may be used as a rescue therapy in worsening myasthenia gravis. IVIG is a second-line therapy in dermatomyositis, stiff-person syndrome and pregnancy-associated or postpartum relapses of multiple sclerosis. Although the biological efficacy of IVIG is due to multiple effects on the immune system, many mechanisms are still unknown. The awareness of risks and complications of IVIG therapy has increased, but severe side effects are still considered rare. Due to increasing costs of this treatment, careful selection of patients who will benefit from IVIG is extremely important. [source] Antitumor activity of sequence-specific alkylating agents: Pyrolle-imidazole CBI conjugates with indole linkerCANCER SCIENCE, Issue 3 2006Ken-ichi Shinohara DNA-targeting agents, including cisplatin, bleomycin and mitomycin C, are used routinely in cancer treatments. However, these drugs are extremely toxic, attacking normal cells and causing severe side effects. One important question to consider in designing anticancer agents is whether the introduction of sequence selectivity to DNA-targeting agents can improve their efficacy as anticancer agents. In the present study, the growth inhibition activities of an indole-seco 1,2,9,9a-tetrahydrocyclopropa[1,2-c]benz[1,2-e]indol-4-one (CBI) (1) and five conjugates with hairpin pyrrole-imidazole polyamides (2,6), which have different sequence specificities for DNA alkylation, were compared using 10 different cell lines. The average values of , log GI50 (50% growth inhibition concentration) for compounds 1,6 against the 10 cell lines were 8.33, 8.56, 8.29, 8.04, 8.23 and 8.83, showing that all of these compounds strongly inhibit cell growth. Interestingly, each alkylating agent caused significantly different growth inhibition patterns with each cell line. In particular, the correlation coefficients between the , log GI50 of compound 1 and its conjugates 2,6 showed extremely low values (R < 0). These results suggest that differences in the sequence specificity of DNA alkylation lead to marked differences in biological activity. Comparison of the correlation coefficients between compounds 6 and 7, with the same sequence specificity as 6, and MS-247, with sequence specificity different from 6, when used against a panel of 37 human cancer cell lines further confirmed the above hypothesis. (Cancer Sci 2006; 97: 219,225) [source] Prostanoids in the Therapy of GlaucomaCARDIOVASCULAR THERAPEUTICS, Issue 1 2006Naruhiro Ishida ABSTRACT Elevated intraocular pressure (IOP) is one of the most important risk factors for the development of glaucoma, which is a progressive optic neuropathy. Lowering IOP is currently the only therapeutic approach to the therapy of glaucoma. Since the use of pilocarpine eye drops for glaucoma treatment was reported in the late 1870s, academic researchers and pharmaceutical companies attempted to discover new drugs with more potent, prolonged, and safer IOP-reducing effects. These persistent efforts finally paid off, and prostanoids with FP-receptor agonist activity were found to be very potent IOP-lowering agents. To date, three prostanoids (latanoprost, travoprost and bimatoprost) have been launched in many countries, and now a new FP-receptor agonist, tafluprost, is entering clinical development. All of these prostanoids are superior to the ,-adrenoceptor antagonists in their IOP-lowering efficacy, and no severe side effects have been reported in their long-term clinical use. In addition, tafluprost may be expected to improve ocular blood flow. Hence, prostanoids currently occupy center stage among glaucoma medications. It cannot be denied that in terms of efficacy, safety, patient compliance, and medical economy prostanoids are currently the first-line medicines among ocular antihypertensive drugs. [source] 4234: Glaucoma considerations in OOKPACTA OPHTHALMOLOGICA, Issue 2010N AL RAQQAD Purpose To study the incidence and prognosis of glaucoma in OOKP eyes and to evaluate methods for detection and treatment of glaucoma following osteo-odonto-keratoprosthesis surgery. Methods Retrospective analysis of 49 consecutive patients treated at the national OOKP referral centre in Brighton, UK between November 1996 and September 2009. Data were collected over a 3 month period from December 2009 giving a minimum of 6 months follow up (range: 6 months to 13 years). Data collected include: age at surgery, primary diagnosis, previous surgical procedures (corneal grafts), family history of glaucoma, serial post-operative cup-disc ratios and visual fields, glaucoma procedures at any stage, and any OOKP complications. Results A total of 49 patients were included in the study with age ranging from 19 to 88 years (mean 53.5). 14 (28.5%) patients had pre-existing glaucoma, 25(51%) patients had glaucoma by the end of the study. 12(24.5%) patients developed de novo increase in intraocular pressure. Of the 49 patients, 5 underwent cyclodialysis ,4 had cyclodiode laser treatment, 4 underwent ECP, 5 had a glaucoma tube inserted and 4 had detachment and reattachment of their recti muscles (VRDR ± MRDR). All patients were treated with oral acetozolamide 250mg once daily (except one who is allergic). Sublingual timolol was used in three patients, one of experienced severe side effects and the treatment had to be stopped. Systemic betablockers were used in 3 patients. Conclusion Glaucoma is one of the major complications of osteo-odonto-keratoprosthesis. It is difficult to monitor and treat in the OOKP eye. Various treatment modalities have been used. Many patients require long term oral medications and many are not adequately controlled and should have surgical treatment the results of which are not satisfactory. VRDR might represent a safer surgical method to control glaucoma in OOKP eyes. [source] KP1019, A New Redox-Active Anticancer Agent , Preclinical Development and Results of a Clinical Phase I Study in Tumor PatientsCHEMISTRY & BIODIVERSITY, Issue 10 2008Christian Abstract The promising drug candidate indazolium trans -[tetrachlorobis(1H -indazole)ruthenate(III)] (KP1019) is the second Ru-based anticancer agent to enter clinical trials. In this review, which is an update of a paper from 2006 (Hartinger et,al., J. Inorg. Biochem.2006, 100, 891,904), the experimental evidence for the proposed mode of action of this coordination compound is discussed, including transport into the cell via the transferrin cycle and activation by reduction. The results of the early clinical development of KP1019 are summarized in which five out of six evaluated patients experienced disease stabilization with no severe side effects. [source] GR Ligands: Can We Improve the Established Drugs?CHEMMEDCHEM, Issue 8 2006Hartmut Rehwinkel Dr. Glucocorticoids (GCs) represent the most effective therapy for acute and chronic inflammatory disorders, yet they can elicit severe side effects. New classes of GC receptor ligands appear to have all of the benefits and fewer side effects and have prompted new research into an old drug target. Compound,A (shown) is the latest addition to this exciting development. [source] | |||||||||||||