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Long-term Therapy (long-term + therapy)
Selected AbstractsNon-invasive assessment of liver fibrosis progression in hepatitis C patients retreated for 96 weeks with antiviral therapy: a randomized studyLIVER INTERNATIONAL, Issue 7 2010Jean-Pierre Zarski Abstract Background: The efficacy of a maintenance therapy in non-responder patients with chronic hepatitis C has been essentially evaluated by histological semiquantitative scores. Aim: The aim was to evaluate the efficiency of 2 years of treatment with peginterferon ,-2a vs ,-tocopherol in these patients by histology, morphometry and blood markers of fibrosis. Method: Hundred and five HCV patients with a Metavir fibrosis score,2 were randomized to receive peginterferon ,-2a 180 ,g/week (PEG) (n=55) or ,-tocopherol (TOCO) 1000 mg/day (n=50) for 96 weeks. The primary endpoint was improvement or stabilization of the Metavir fibrosis score by biopsy performed at week 96. Secondary endpoints included a quantitative assessment of fibrosis by morphometry and changes in blood markers of fibrosis. Results: There was no difference at baseline between PEG and TOCO according to the metavir (83.3 vs 86.8%, P=0.751) stage. The median fibrosis rate, measured with morphometry was 2.72 and 2.86% at day 0, and 3.66 and 2.82% at week 96, in the PEG and TOCO groups (P=0.90) respectively. However, the percentage of patients with metavir activity grade improvement was significantly higher in the PEG group vs the TOCO group (52.8 vs 23.7%, P=0.016). Non-invasive markers analysis did not show any significant change in both groups. Conclusion: Long-term therapy with peginterferon ,-2a did not reduce liver fibrosis degree assessed by morphometry and blood tests as compared with ,-tocopherol. Blood tests could be useful to assess liver fibrosis changes in clinical trials. [source] Oral insulin , a review of current statusDIABETES OBESITY & METABOLISM, Issue 3 2010Harish Iyer Oral insulin is one of the most exciting areas of development in the treatment of diabetes because of its potential benefit in patient convenience, rapid insulinization of liver, adequate insulin delivery avoiding peripheral hyperinsulinaemia while potentially avoiding adverse effects of weight gain and hypoglycaemia. Growing evidence that earlier initiation of intensive insulin therapy produces sustained tight glycaemic control resulting in substantial delay in complications makes an effective oral insulin product even more vital for the management of patients with diabetes. Despite knowledge of this unmet medical need, oral delivery of insulin has been unsuccessful because of several barriers. For several decades, researchers have tried to develop oral insulin using various technologies without much clinical or commercial success. This review summarizes the development status of oral insulins which are publicly reported to be undergoing clinical studies. Currently, two oral insulin products are in an advanced stage of clinical development and first data from long-term therapy are expected to be available in the second half of 2010. [source] Insulino-mimetic and anti-diabetic effects of vanadium compoundsDIABETIC MEDICINE, Issue 1 2005A. K. Srivastava Abstract Compounds of the trace element vanadium exert various insulin-like effects in in vitro and in vivo systems. These include their ability to improve glucose homeostasis and insulin resistance in animal models of Type 1 and Type 2 diabetes mellitus. In addition to animal studies, several reports have documented improvements in liver and muscle insulin sensitivity in a limited number of patients with Type 2 diabetes. These effects are, however, not as dramatic as those observed in animal experiments, probably because lower doses of vanadium were used and the duration of therapy was short in human studies as compared with animal work. The ability of these compounds to stimulate glucose uptake, glycogen and lipid synthesis in muscle, adipose and hepatic tissues and to inhibit gluconeogenesis, and the activities of the gluconeogenic enzymes: phosphoenol pyruvate carboxykinase and glucose-6-phosphatase in the liver and kidney as well as lipolysis in fat cells contributes as potential mechanisms to their anti-diabetic insulin-like effects. At the cellular level, vanadium activates several key elements of the insulin signal transduction pathway, such as the tyrosine phosphorylation of insulin receptor substrate-1, and extracellular signal-regulated kinase 1 and 2, phosphatidylinositol 3-kinase and protein kinase B activation. These pathways are believed to mediate the metabolic actions of insulin. Because protein tyrosine phosphatases (PTPases) are considered to be negative regulators of the insulin-signalling pathway, it is suggested that vanadium can enhance insulin signalling and action by virtue of its capacity to inhibit PTPase activity and increase tyrosine phosphorylation of substrate proteins. There are some concerns about the potential toxicity of available inorganic vanadium salts at higher doses and during long-term therapy. Therefore, new organo-vanadium compounds with higher potency and less toxicity need to be evaluated for their efficacy as potential treatment of human diabetes. [source] The effects of discontinuing pioglitazone in patients with nonalcoholic steatohepatitis,HEPATOLOGY, Issue 2 2007Glen Lutchman A pilot study of a 48-week course of pioglitazone demonstrated significant improvements in the biochemical and histological features of nonalcoholic steatohepatitis (NASH). The aim of the study was to assess the effects of stopping pioglitazone. Twenty-one patients with NASH were treated with pioglitazone (30 mg/day) for 48 weeks and underwent baseline and end-of-treatment evaluation including liver biopsy. Thirteen patients were followed for at least 48 weeks after stopping therapy and 9 underwent repeat liver biopsy. Statistical comparisons were made to evaluate whether discontinuation of pioglitazone resulted in a reversal of improvements seen on therapy. Stopping pioglitazone was associated with subsequent elevation in serum alanine aminotransferase levels (from 34 ± 13 to 70 ± 39 IU/l), decrease in adiponectin (from 9.7 ± 9.1 to 5.1 ± 4.5 ,g/ml), worsening insulin sensitivity (HOMA Index: from 2.9 ± 1.8 to 5.5 ± 5.4), and increase in total hepatic fat (from 30% ± 32% to 71% ± 33%) despite no change in average body weight compared to the end of treatment. Repeat liver biopsy in 9 patients revealed significant worsening of parenchymal inflammation (from 1.2 ± 0.7 to 2.9 ± 1.1) and steatosis (from 0.9 ± 0.6 to 2.1 ± 1.3) but no change in fibrosis (from 1.1 ± 1.2 to 1.2 ± 1.3). NASH was again present on liver biopsy in 7 patients. Conclusion: These findings suggest that long-term therapy with pioglitazone may be necessary to maintain improvements in disease activity in patients with NASH, although weight gain during treatment may ultimately limit its beneficial effects. (HEPATOLOGY 2007.) [source] Raloxifene, conjugated oestrogen and endothelial function in postmenopausal womenJOURNAL OF INTERNAL MEDICINE, Issue 1 2003E. J. J. Duschek Abstract., Duschek EJJ, Stehouwer CDA, de Valk-de Roo GW, Schalkwijk CG, Lambert J, Netelenbos C (VU University Medical Center, Amsterdam; Sophia Hospital, Zwolle; The Netherlands). Raloxifene, conjugated oestrogen and endothelial function in postmenopausal women. J Intern Med 2003; 254: 85,94. Objectives., To study the long-term effects of raloxifene, a potential designer oestrogen, and oestrogen monotherapy on endothelial function in healthy postmenopausal women. Design., A 2-year double-blind, randomized and placebo-controlled study in an Academic Medical Center. Fifty-six hysterectomized but otherwise healthy postmenopausal women randomly received raloxifene hydrochloride 60 mg day,1 (n = 15) or 150 mg day,1 (n = 13), conjugated equine oestrogen (CEE) 0.625 mg day,1 (n = 15), or placebo (n = 13). Main outcome measures., Endothelial function as estimated from brachial artery flow-mediated, endothelium-dependent vasodilation and nitroglycerine-induced endothelium-independent vasodilation, and plasma levels of the endothelium-derived regulatory proteins, von Willebrand factor (vWF) and endothelin (ET). Results., Raloxifene 60 mg did not significantly affect endothelial function. As compared with placebo, at 6 months of therapy, raloxifene 150 mg and CEE were associated with a mean increase in vWF of 25.5% point (95% CI 3.6,47.3) and 26.6% point (95% CI 6.9,46.3), respectively. At 24 months of therapy, raloxifene 150 mg was associated with a mean decrease in ET of 0.96 pg mL,1 (95% CI ,1.57 to ,0.36). Raloxifene nor CEE significantly affected endothelium-dependent and/or -independent vasodilation. Conclusions., Our results suggest that long-term therapy with raloxifene or oral CEE does not affect endothelium-dependent vasodilation in healthy postmenopausal women. Raloxifene 150 mg day,1 might have both positive and negative effects on endothelium. The clinical significance of these findings remains to be investigated. [source] Liver fibrosis attributed to lipid lowering medications: two casesJOURNAL OF INTERNAL MEDICINE, Issue 3 2001Z. Punthakee Abstract. Punthakee Z, Scully LJ, Guindi MM, Ooi TC (Department of Medicine, Division of Gastroenterology, Department of Pathology and the Laboratory of Medicine and the Division of Endocrinology and Metabolism, The Ottawa Hospital , Civic Campus, University of Ottawa, Ottawa, Canada). Liver fibrosis attributed to lipid lowering medications: two cases (Case Report). J Intern Med 2001; 250: 249,254. We identified two cases of chronic active hepatitis with liver fibrosis induced by lipid lowering drugs of the statin and fibrate classes despite regular monitoring of transaminases. There are few reports of clinically significant hepatitis induced by these drugs and even fewer cases of fibrosis. Given the growing use of these drugs, there are implications for monitoring patients on long-term therapy for liver damage. [source] 5,-reductase inhibition for men with enlarged prostateJOURNAL OF THE AMERICAN ACADEMY OF NURSE PRACTITIONERS, Issue 8 2007MBA (Associate Professor of Urology), Muta M. Issa MD Abstract Purpose: Increasingly, men with lower urinary tract symptoms (LUTS) are seeking treatment in the primary care setting. This article reviews the use of ,-blockers and 5,-reductase inhibitors (5ARIs) in the management of LUTS and enlarged prostate. Data sources: Information is based on a critical review of the published literature. Relevant studies were identified using MEDLINE and review of reference lists of published studies. Conclusions: Enlargement of the prostate is a common occurrence among aging men. Nurse practitioners (NPs) are in a unique, frontline position to evaluate symptoms and bother and to recommend appropriate treatment of patients with enlarged prostate. Both ,-blockers and 5ARIs are effective at reducing symptoms in the short term. However, only the 5ARIs impact disease progression and maintain improvement in symptoms in the long term. Implications for practice: NPs play an important role in assessing and treating LUTS in men with enlarged prostate. When treating men with LUTS, assess the severity of symptoms and the extent of prostate enlargement. For symptomatic men with enlarged prostate, long-term therapy with 5ARIs should be considered to treat symptoms as well as address the disease progression. [source] Current topical and systemic approaches to treatment of rosaceaJOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY & VENEREOLOGY, Issue 8 2009HC Korting Abstract Rosacea is a common, often overlooked, chronic facial dermatosis characterized by intermittent periods of exacerbation and remission. Clinical subtypes and grading of the disease have been defined in the literature. On the basis of a genetic predisposition, there are several intrinsic and extrinsic factors possibly correlating with the phenotypic expression of the disease. Although rosacea cannot be cured, there are several recommended treatment strategies appropriate to control the corresponding symptoms/signs. In addition to adequate skin care, these include topical and systemic medications particularly suitable for the papulopustular subtype of rosacea with moderate to severe intensity. The most commonly used and most established therapeutic regimens are topical metronidazole and topical azelaic acid as well as oral doxycycline. Conventionally, 100,200 mg per day have been used. Today also a controlled release formulation is available, delivering 40 mg per day using non-antibiotic, anti-inflammatory activities of the drug. Anti-inflammatory dose doxycycline in particular allows for a safe and effective short- and long-term therapy of rosacea. Topical metronidazole and topical azelaic acid also appear to be safe and effective for short-term use. There are indications that a combined therapy of anti-inflammatory dose doxycycline and topical metronidazole could possibly have synergy effects. Further interesting therapy options for the short- and long-term therapy of rosacea could be low-dose minocycline and isotretinoin; however, too little data are available with regard to the effectiveness, safety, optimal dosage and appropriate length of treatment for these medications to draw final conclusions. Conflicts of interest None declared. [source] Consistent control of psoriasis by continuous long-term therapy: the promise of biological treatmentsJOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY & VENEREOLOGY, Issue 6 2006PCM Van De Kerkhof Abstract Psoriasis is a chronic, incurable disease that frequently requires long-term treatment. Although many patients benefit from effective traditional systemic therapies, namely methotrexate, cyclosporin, retinoids and fumaric acid esters, and some patients achieve long-term disease control, unrestricted long-term administration is not recommended due to the potential for cumulative toxicity. In order to diminish the risk of toxicity, physicians have adopted various treatment approaches (e.g. rotational, sequential, intermittent, and combination). However, these approaches may not provide continuous disease control or a stable treatment regimen. The recent advent of targeted biological therapeutics such as etanercept, infliximab, adalimumab, alefacept and efalizumab may offer physicians and their patients treatment options with improved safety profiles that may permit continuous disease control. [source] Changes of gastric histology in patients with erosive oesophagitis receiving long-term lansoprazole maintenance therapyALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 1 2010M. M. Haber Aliment Pharmacol Ther 2010; 32: 83,96 Summary Background, Changes in gastric histology associated with long-term maintenance therapy with lansoprazole for erosive oesophagitis have not been well described. Aim, To evaluate the effect on gastric histology of long-term dose-titrated lansoprazole administered as maintenance therapy for up to 82 months in patients with erosive oesophagitis. Methods, Sequential gastric biopsy specimens were obtained for evaluation of histological changes and Helicobacter pylori infection status. Results, Active and chronic inflammation improved from baseline to final visit in a majority of patients receiving long-term therapy with lansoprazole, irrespective of baseline H. pylori infection status. Reductions in active inflammation in the gastric body and antrum were seen in 53% (17/32) and 67% (20/30) of H. pylori -positive patients, respectively, and in 88% (7/8) and 86% (12/14) of H. pylori -negative patients, respectively. Reductions in chronic inflammation in the gastric body and antrum were seen in 38% (12/32) and 47% (15/32) of H. pylori -positive patients, respectively, and in 58% (70/121) and 57% (68/120) of H. pylori -negative patients, respectively. No clinically meaningful increases in hyperplasia, dysplasia, neoplasia, intestinal metaplasia or atrophy were observed during the follow-up period. Conclusions, Lansoprazole administered as maintenance therapy for up to 6 years in patients with erosive oesophagitis demonstrated gastric mucosal safety and was well tolerated. [source] The borderline syndrome in psychosomatic dermatology Overview and case reportJOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY & VENEREOLOGY, Issue 4 2004W Harth ABSTRACT The borderline syndrome is one of the most severe disturbances of psychosomatic dermatology. Patients with borderline syndrome are situated ,on the border' of psychosis, neurosis and personality disorders. The skin as a borderline organ carries a symbolic role. The clinical picture includes artefactual skin diseases due to self-mutilation by conscious or unconscious cutting, and rubbing, scratching or para-artefactual manipulations of pre-existing dermatoses. Leading symptoms of the borderline syndrome are poor impulse control, emotional instability and poor ego strength with low frustration tolerance and unstable personal relationships. We present the case of a 38-year-old female patient with borderline syndrome suffering from para-artefactual skin diseases of the face and a massive hyperhidrosis of the hands and feet. Within 9 months she was treated in four acute psychiatric hospitals and by 12 psychiatrists and psychotherapists. Early and accurate diagnosis and high-quality, sophisticated long-term therapy are necessary. [source] Role of cytokine gene polymorphisms in acute rejection and renal impairment after liver transplantationLIVER TRANSPLANTATION, Issue 3 2001Julie R. Jonsson Although immunosuppressive regimens are effective, rejection occurs in up to 50% of patients after orthotopic liver transplantation (OLT), and there is concern about side effects from long-term therapy. Knowledge of clinical and immunogenetic variables may allow tailoring of immunosuppressive therapy to patients according to their potential risks. We studied the association between transforming growth factor-,, interleukin-10, and tumor necrosis factor , (TNF-,) gene polymorphisms and graft rejection and renal impairment in 121 white liver transplant recipients. Clinical variables were collected retrospectively, and creatinine clearance was estimated using the formula of Cockcroft and Gault. Biallelic polymorphisms were detected using polymerase chain reaction-based methods. Thirty-seven of 121 patients (30.6%) developed at least 1 episode of rejection. Multivariate analysis showed that Child-Pugh score (P = .001), immune-mediated liver disease (P = .018), normal pre-OLT creatinine clearance (P = .037), and fewer HLA class 1 mismatches (P = .038) were independently associated with rejection. Renal impairment occurred in 80% of patients and was moderate or severe in 39%. Clinical variables independently associated with renal impairment were female sex (P = .001), pre-OLT renal dysfunction (P = .0001), and a diagnosis of viral hepatitis (P = .0008). There was a significant difference in the frequency of TNF-,-308 alleles among the primary liver diseases. After adjustment for potential confounders and a Bonferroni correction, the association between the TNF-,-308 polymorphism and graft rejection approached significance (P = .06). Recipient cytokine genotypes do not have a major independent role in graft rejection or renal impairment after OLT. Additional studies of immunogenetic factors require analysis of large numbers of patients with appropriate phenotypic information to avoid population stratification, which may lead to inappropriate conclusions. [source] Oral tacrolimus long-term therapy in patients with Crohn's disease and steroid resistanceALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 3 2001E. Ierardi To report the results of a prospective, open-label, uncontrolled study in 13 patients affected by Crohn's disease with resistance to steroids. Methods: The patients were treated long-term with oral tacrolimus, aiming to both resolve acute attacks and maintain remission. Tacrolimus was administered at the dose of 0.1,0.2 mg.day/kg and adjusted in order to achieve levels of 5,10 ng/mL; only mesalazine was continued concomitantly. Steroids and total parenteral nutrition were tapered when appropriate. Results: Median treatment was 27.3 months. Only one patient dropped out due to adverse events. Crohn's disease activity index score significantly decreased after 6 months in 11 patients; for 1 year in nine of them, and 7 years in two of them. The inflammatory bowel disease life-quality questionnaire score significantly increased over the same periods. A marked drop in hospitalizations was recorded. In three out of six patients complete closure of fistulas occurred. Tacrolimus allowed total parenteral nutrition to be withdrawn in three out of five patients. Supplementation with low-dose steroids was required in five patients. Two patients underwent surgery. Conclusions: Tacrolimus therapy appears to be associated with both short- and long-term benefits, and may represent a therapeutic option in Crohn's disease when conventional therapies fail. This study encourages its use in controlled trials. [source] Anti-tumor mechanisms of valproate: A novel role for an old drugMEDICINAL RESEARCH REVIEWS, Issue 5 2002Roman A. Blaheta Abstract Valproic acid (VPA, 2-propylpentanoic acid) is an established drug in the long-term therapy of epilepsy. During the past years, it has become evident that VPA is also associated with anti-cancer activity. VPA not only suppresses tumor growth and metastasis, but also induces tumor differentiation in vitro and in vivo. Several modes of action might be relevant for the biological activity of VPA: (1) VPA increases the DNA binding of activating protein-1 (AP-1) transcription factor, and the expression of genes regulated by the extracellular-regulated kinase (ERK)-AP-1 pathway; (2) VPA downregulates protein kinase C (PKC) activity; (3) VPA inhibits glycogen synthase kinase-3, (GSK-3,), a negative regulator of the Wnt signaling pathway; (4) VPA activates the peroxisome proliferator-activated receptors PPAR, and ,; (5) VPA blocks HDAC (histone deacetylase), causing hyperacetylation. The findings elucidate an important role of VPA for cancer therapy. VPA might also be useful as low toxicity agent given over long time periods for chemoprevention and/or for control of residual minimal disease. © 2002 Wiley Periodicals, Inc. Med Res Rev, 22, No. 5, 492,511, 2002; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/med.10017 [source] Long-term posaconazole treatment and follow-up of rhino-orbital-cerebral mucormycosis in a diabetic girlPEDIATRIC DIABETES, Issue 4 2009Luigi Tarani Abstract:, To demonstrate that the 2-yr clinical follow-up of our patient strongly suggests that long-term therapy with posaconazole (POS) is safe and beneficial in treatment and prevention of relapses of, otherwise fatal, central nervous system mucormycosis. Mucormycosis is a very rare opportunistic mycotic infection of diabetic children. We present the 30-month follow-up of a 12-yr-old girl affected by diabetic ketoacidotic coma, complicated by rhinocerebral mucormycosis and successfully treated with POS at the initial daily dose of 5 mg/kg t.i.d. with fatty food for 3 wk, followed by a daily dose of 10 mg/kg in four doses for 2 months and then 20 mg/kg/d in four doses for 16 months and in two doses for further 5 months. The previous amphotericin B, granulocyte colony-stimulating factor, hyperbaric oxygen and nasal and left maxillary sinus surgical debridement therapy was ineffective in stopping the progression of the infection to the brain. The patient improved within 10 d with reduced ocular swelling and pain, and 6 months after therapy stop, she is in good health and cultures are sterile. This article demonstrates that POS may be a useful drug in mucormycosis in children. We also strongly draw the attention to the main preventive procedure against invasive fungal infection that is the correct management of antidiabetic therapy that prevents the predisposing temporary neutrophils activity deficit, contributing to a better survival rate of diabetic children. [source] The use of etanercept as a non-surgical treatment for temporomandibular joint psoriatric arthritis: a case reportAUSTRALIAN DENTAL JOURNAL, Issue 2 2009L Lamazza Abstract Psoriatic arthritis (PsA) is a chronic inflammatory disease of the skin and joints characterized by extensive intra-articular bone resorption and silver-red scaly plaques most commonly found on extensor surfaces of the skin. When this arthritis affects the temporomandibular joint (TMJ) and does not successfully halt in its early degenerative process, patients may undergo invasive joint reconstruction that irreversibly changes the TMJ physiologic joint dynamics. This study presents a case of TMJ PsA: anterior open bite, limited range of motion, and erythematous desquamative plaques of the upper limb extensors surfaces. The patient previously received non-steroidal anti-inflammatory drugs, immunosuppressors, and corticosteroids over a four-year period while suffering the idiosyncratic drug side effects from long-term therapy without improvement in joint function or rash resolution. The treatment team then chose etanercept, a synthetic fusion protein therapy that binds with tumor necrosis factor (TNF)-alpha, to interrupt reactive inflammatory arthritis. The patient received the TNF-alpha inhibitor monthly for two years. This last treatment led to full remission of both joint symptomatology and skin lesions. Our results should encourage general dental practitioners' involvement in curing patients with psoriatic arthritis when it affects the TMJ. [source] Diagnosis of nail psoriasis: importance of biopsy and histopathologyBRITISH JOURNAL OF DERMATOLOGY, Issue 6 2005C. Grover Summary Background, Involvement of the nail is quite common in psoriasis and at times may be the sole diagnostic clue. However, the histopathology of nail psoriasis has not been adequately evaluated. A confirmation of the diagnosis is required in cases suspected to have nail psoriasis in order to plan long-term therapy. Objectives, To assess the diagnostic significance and safety profile of nail biopsy in cases with nail psoriasis. Methods, Clinical and mycological features were studied in 42 patients with nail psoriasis. Of these, 22 patients gave consent for nail biopsies to be taken and the histopathological changes were assessed. Results, Males were affected more commonly (57%) with a peak incidence in the age group of 10,20 years (29%). Distal onycholysis, discoloration of nail plate, subungual hyperkeratosis and fine nail pitting were the predominant clinical features. In the 22 biopsies done, hyperkeratosis with parakeratosis (91%) was found to be the most common and hypergranulosis was the least common histological finding (36%). Clinicohistological correlation was possible only in 55% cases. Periodic acid-Schiff (PAS) staining was done for all biopsies. Conclusions, Histopathological examination of nails is a valuable diagnostic aid, especially in the absence of skin lesions. Examination of the PAS-stained sections is necessary before making a histological diagnosis of nail psoriasis because onychomycosis and psoriasis may show similar histology. [source] Does topical tacrolimus induce lentigines in children with atopic dermatitis?BRITISH JOURNAL OF DERMATOLOGY, Issue 1 2005A report of three cases Summary Three children with severe atopic dermatitis were noted at routine follow-up to have developed multiple small pigmented macules during long-term therapy with topical tacrolimus 0·1% (Protopic®, Fujisawa). Representative lesions in two of the three cases were confirmed histologically as simple lentigines. The focal distribution of lentigines to sites of tacrolimus use, and the temporal association between use of tacrolimus and development of lesions, suggest that topical tacrolimus is of direct aetiological relevance to their development. Careful long-term follow-up will be required to assess the clinical implications of these findings and whether they represent an increase in risk for melanocytic neoplasia. [source] Manganese increases L-DOPA auto-oxidation in the striatum of the freely moving rat: potential implications to L-DOPA long-term therapy of Parkinson's diseaseBRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2000Pier Andrea Serra We have previously shown that manganese enhances L-dihydroxyphenylanine (L-DOPA) toxicity to PC12 cells in vitro. The supposed mechanism of manganese enhancing effect [an increase in L-DOPA and dopamine (DA) auto-oxidation] was studied using microdialysis in the striatum of freely moving rats. Systemic L-DOPA [25 mg kg,1 intraperitoneally (i.p.) twice in a 12 h interval] significantly increased baseline dialysate concentrations of L-DOPA, dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and uric acid, compared to controls. Conversely, DA and ascorbic acid concentrations were significantly decreased. A L-DOPA oxidation product, presumptively identified as L-DOPA semiquinone, was detected in the dialysate. The L-DOPA semiquinone was detected also following intrastriatal infusion of L-DOPA. In rats given L-DOPA i.p., intrastriatal infusion of N-acetylcysteine (NAC) significantly increased DA and L-DOPA dialysate concentrations and lowered those of L-DOPA semiquinone; in addition, NAC decreased DOPAC+HVA and uric acid dialysate concentrations. In rats given L-DOPA either systemically or intrastriatally, intrastriatal infusion of manganese decreased L-DOPA dialysate concentrations and greatly increased those of L-DOPA semiquinone. These changes were inhibited by NAC infusion. These findings demonstrate that auto-oxidation of exogenous L-DOPA occurs in vivo in the rat striatum. The consequent reactive oxygen species generation may account for the decrease in dialysate DA and ascorbic acid concentrations and increase in enzymatic oxidation of xanthine and DA. L-DOPA auto-oxidation is inhibited by NAC and enhanced by manganese. These results may be of relevance to the L-DOPA long-term therapy of Parkinson's disease. British Journal of Pharmacology (2000) 130, 937,945; doi:10.1038/sj.bjp.0703379 [source] | |||||||||||||||||||||||||