Management of Parkinson Disease

Parkinson disease is a movement disorder caused by progressive dopaminergic neuron degeneration in the substantia nigra and characterized by four cardinal symptoms: resting tremor, bradykinesia, rigidity, and postural instability. Levodopa has been considered the first-choice intervention for Parkinson disease for more than three decades. However, up to 50–90% of levodopa-treated patients develop motor complications within 5–10 years of starting treatment. It is important, therefore, to delay the initiation and/or reduce the dosage requirements of levodopa. The non-ergoline dopamine agonist ropinirole (Requip®) is used as monotherapy or in combination with low-dose levodopa in patients with early disease, and as an adjunct to levodopa in patients with advanced Parkinson disease.As an adjunct to levodopa therapy in patients with more advanced disease, ropinirole is generally more effective than bromocriptine and more effective than placebo. Ropinirole (with or without levodopa) is more effective than placebo and at least as effective as bromocriptine when administered as therapy for early Parkinson disease. It reduces the risk of dyskinesia relative to levodopa and maintains long-term control of the underlying disease symptoms, factors that are associated with improved functional ability. Ropinirole reduced the loss of putamen dopamine storage capacity compared with levodopa in a functional imaging study. However, it was unclear whether this resulted from any neuroprotective activity of ropinirole; further research is required to identify any clinically important neuroprotective activity of dopamine agonists. Ropinirole has a tolerability profile generally similar to that of bromocriptine and levodopa when used as monotherapy. In common with all dopaminergic agents, ropinirole has been linked with sedation and unintended sleep episodes; however, these effects may also result from the underlying disease process in patients with Parkinson disease.Only limited data are available from pharmacoeconomic evaluations of ropinirole. Nevertheless, a cost-minimization analysis indicates that, from a societal viewpoint in Canada, ropinirole is cost saving relative to treatment with levodopa plus a dopa decarboxylase inhibitor in patients with early Parkinson disease. Further economic and quality-of-life assessments of ropinirole are required, particularly comparisons with other dopamine agonists and antiparkinsonian interventions.In conclusion, ropinirole is established as an adjunct to levodopa in advanced Parkinson disease, and as monotherapy or in combination with low-dose levodopa in early disease. It is in the setting of early Parkinson disease that ropinirole may see greatest expansion of its overall role in disease management programs.     

LIM-homeodomain genes as territory markers in the brainstem of adult and developing Xenopus laevis

We investigated expression patterns of the LIM-homeodomain (LIM-hd) genes x-Lhx1, x-Lhx2, x-Lhx5, and x-Lhx9 in the brainstem of Xenopus laevis during larval development and in the adult. The two groups of paralogous genes, x-Lhx1/x-Lhx5 and x-Lhx2/x-Lhx9, showed fundamentally different expression patterns, being expressed in ventral versus dorsal territories of the midbrain and hindbrain, respectively. Indeed, prominent expression of x-Lhx1/5 was found in the mesencephalic tegmentum and the hindbrain reticular formation, whereas conspicuous x-Lhx2/9 expression was observed in the torus semicircularis and isthmic nucleus. A few shared expression domains for the two pairs of paralogs included the optic tectum and the anterodorsal and pedunculopontine nuclei. In each structure, expression of the two paralogs was almost identical, indicating that the regulation of their expression in this part of the brain has evolved slightly since gene duplication occurred. Notable exceptions included the expression of x-Lhx1 but not x-Lhx5 in the Purkinje cells and the expression of x-Lhx9 but not x-Lhx2 in the lateral line nucleus. The analysis of LIM-hd expression patterns throughout development allowed the origin of given structures in early embryos to be traced back. x-Lhx1 and x-Lhx5 were relevant to locate the cerebellar anlage and to follow morphogenesis of the cerebellar plate and cerebellar nuclei. They also highlighted the rhombomeric organization of the hindbrain. On the other hand, x-Lhx2 and x-Lhx9 showed a dynamic spatiotemporal pattern relative to tectal development and layering, and x-Lhx9 was useful to trace back the origin of the isthmus in early development.     

Insulin aspart: a review of its use in the management of type 1 or 2 diabetes mellitus

Insulin aspart (NovoRapid, NovoLog) is a short-acting insulin analogue, which has a faster onset and shorter duration of action than regular human insulin. Insulin aspart administered immediately before meals provided significantly greater improvements in glycosylated haemoglobin and better postprandial glycaemic control than regular human insulin administered 30 minutes before meals, when used in a basal-bolus regimen with neutral protamine Hagedorn (NPH) insulin, in randomised, nonblind studies in patients with type 1 diabetes mellitus. In patients with type 2 diabetes, insulin aspart provided similar glycaemic control to regular human insulin, administered in a basal-bolus regimen with NPH insulin. Small studies suggest that the use of insulin aspart in combination with oral hypoglycaemic agents may be beneficial. Insulin aspart, administered by continuous subcutaneous insulin infusion (CSII) provided better glycaemic control than insulin aspart multiple daily injection regimens in patients with type 1 (but not type 2) diabetes, and had similar efficacy to CSII with insulin lispro or regular human insulin in type 1 diabetes. Limited studies show insulin aspart to be effective in children, adolescents and young adults with type 1 diabetes. Insulin aspart had a tolerability profile similar to that of regular human insulin in clinical trials. The incidence of major or nocturnal hypoglycaemic events reported in patients receiving insulin aspart was lower than that of regular human insulin in several studies.In conclusion, insulin aspart, administered immediately before meals in a basal-bolus regimen with NPH insulin, provided better long-term glycaemic control than regular human insulin administered 30 minutes before meals in patients with type 1 diabetes, and was as effective as regular human insulin in patients with type 2 diabetes. A significantly lower risk of hypoglycaemia was seen in several trials. Insulin aspart CSII provided better glycaemic control than insulin aspart multiple daily subcutaneous injection (MDI) in patients with type 1 (but not type 2) diabetes and had similar efficacy to CSII with insulin lispro or regular human insulin in type 1 diabetes. Insulin aspart is an effective and well tolerated alternative to regular human insulin and insulin lispro for the maintenance of glycaemic control in patients with type 1 or 2 diabetes.     

Epoetin Beta: a review of its clinical use in the treatment of anaemia in patients with cancer

Epoetin beta (NeoRecormon) is a recombinant form of erythropoietin. It increases reticulocyte counts, haemoglobin (Hb) levels and haematocrit. Epoetin beta administered subcutaneously once weekly corrected anaemia and had equivalent efficacy to that of epoetin beta administered three times weekly in patients with haematological malignancies. Subcutaneous epoetin beta reduced transfusion requirements and increased Hb levels versus no treatment in patients with solid tumours and chemotherapy-induced anaemia in nonblind, randomised trials. Anaemia and quality of life were also improved, and blood transfusion requirements were reduced to a significantly greater extent than placebo or no treatment (with supportive blood transfusion) in patients with haematological malignancies. Most patients were receiving chemotherapy. Subcutaneous epoetin beta was well tolerated by patients with cancer; adverse events with the drug occurred with a similar incidence to those with placebo or no treatment (with supportive blood transfusion). Hypertension was relatively uncommon with epoetin beta in clinical trials. Patients with haematological malignancies and a baseline platelet count > or =100 x 10(9)/L, Hb levels of > or =9 g/dL or lower erythropoietin levels have demonstrated better responses to epoetin beta than other patients in clinical trials. However, neither baseline erythropoietin level nor the observed to predicted ratio of erythropoietin levels correlated with the response to epoetin beta in patients with solid tumours and chemotherapy-induced anaemia. A decrease of <1 g/dL or an increase in Hb with epoetin beta during the first chemotherapy cycle indicated a low transfusion need in subsequent cycles in patients with ovarian carcinoma. In general, the efficacy of epoetin beta is not limited by tumour type. Response to the drug occurred irrespective of the nature (platinum- or nonplatinum-based) or presence of chemotherapy treatment in randomised trials. CONCLUSION: Epoetin beta has shown efficacy in the management of cancer-related anaemia in patients with haematological malignancies and of chemotherapy-induced anaemia in patients with solid tumours. Once-weekly administration provides added convenience for patients and may be cost saving, although additional research into the potential pharmacoeconomic benefits of this regimen are required. The drug is well tolerated in patients with cancer and is associated with little injection-site pain when administered subcutaneously. Epoetin beta is an important option in the prevention of chemotherapy-induced anaemia, and a valid and valuable alternative to blood transfusion therapy for the treatment of cancer-related or chemotherapy-induced anaemia.     

Three properties of the hepatitis C virus RNA genome related to antiviral strategies based on RNA-therapeutics: variability, structural conformation and tRNA mimicry

The concept of using RNA molecules as therapeutic agents is receiving increasing attention by basic science and pharmaceutical research. Over the past five years, a number of clinical trials have been initiated to evaluate the efficacy and safety of several RNA agents for the treatment of a range of conditions from cancer to infectious disease. From a molecular biology perspective, two main factors are implicated in RNA therapeutics against pathogenic RNAs: i/ The activity, stability and delivery of the inactivating agent (ribozyme, RNase P, "decoy" RNA, aptamer, small interfering-RNA) and its co-localisation with the target; and ii/ The properties of the RNA substrate, which, in the case of an RNA virus, most likely limit the effectiveness of the inactivating agent. The main reasons are the limited size of the viral genome and the restrictions imposed by the RNA structure and variations at the target. In the first section of this article we review three properties of the HCV RNA genome, from primary sequence to tertiary structure, which imply restrictions and opportunities for RNA-based treatment. In the second section, we briefly describe several of the RNA-based therapeutic strategies against HCV now under development.     

Estimation of the length of nasotracheal tube to be introduced in children

The formula 10.5 + (weight[kg]/2) showed a predictive capacity of 0.8939 to estimate the length (cm) of endotracheal tube to be introduced through the nasal route in 99 children between newborn and 4 years old. In a validation study, the formula maintained a high level of concordance with the true values: 0.9370.     

Tranexamic acid: a review of its use in the management of menorrhagia

Tranexamic acid (Transamin), Cyklokapron, Exacyl, Cyklo-f) is a synthetic lysine derivative that exerts its antifibrinolytic effect by reversibly blocking lysine binding sites on plasminogen and thus preventing fibrin degradation.In a number of small clinical studies in women with idiopathic menorrhagia, tranexamic acid 2-4.5 g/day for 4-7 days reduced menstrual blood loss by 34-59% over 2-3 cycles, significantly more so than placebo, mefenamic acid, flurbiprofen, etamsylate and oral luteal phase norethisterone at clinically relevant dosages. Intrauterine administration of levonorgestrel 20 microg/day, however, produced the greatest reduction (96% after 12 months) in blood loss; 44% of patients treated with levonorgestrel developed amenorrhoea. Tranexamic acid 1.5 g three times daily for 5 days also significantly reduced menstrual blood loss in women with intrauterine contraceptive device-associated menorrhagia compared with diclofenac sodium (150 mg in three divided doses on day 1 followed by 25 mg three times daily on days 2-5) or placebo. Tranexamic acid, mefenamic acid, etamsylate, flurbiprofen or diclofenac sodium had no effect on the duration of menses in the studies that reported such data.In a large noncomparative, nonblind, quality-of-life study, 81% of women were satisfied with tranexamic acid 3-6 g/day for 3-4 days/cycle for three cycles, and 94% judged their menstrual blood loss to be 'decreased' or 'strongly decreased' compared with untreated menstruations. The most commonly reported drug-related adverse events are gastrointestinal in nature. The total incidence of nausea, vomiting, diarrhoea and dyspepsia in a double-blind study was 12% in patients who received tranexamic acid 1g four times daily for 4 days for two cycles (not significantly different to the incidence in placebo recipients). In conclusion, the oral antifibrinolytic drug tranexamic acid is an effective and well tolerated treatment for idiopathic menorrhagia. In clinical trials, tranexamic acid was more effective at reducing menstrual blood loss than mefenamic acid, flurbiprofen, etamsylate and oral luteal phase norethisterone. Although it was not as effective as intrauterine administration of levonorgestrel, the high incidence of amenorrhoea and adverse events such as intermenstrual bleeding resulting from such treatment may be unacceptable to some patients. Comparative studies of tranexamic acid with epsilon - aminocaproic acid, danazol and combined oral contraceptives, as well as long-term tolerability studies, would help to further define the place of the drug in the treatment of menorrhagia. Nevertheless, tranexamic acid may be considered as a first-line treatment for the initial management of idiopathic menorrhagia, especially for patients in whom hormonal treatment is either not recommended or not wanted.     

Population pharmacokinetics of netilmicin in short-term prophylactic treatment

AIMS: To characterize the population pharmacokinetics of netilmicin, an aminoglycoside antibiotic, in adult urology patients and to develop a covariate model for improved dose titration. METHODS: Data from 62 adult patients (55 male, seven female), undergoing urological surgery and treated with netilmicin for short-term prophylaxis, were evaluated retrospectively. The group had (median, range) ages 68, 31-92 years, weights 72, 43-106 kg and heights 167, 148-182 cm. No patient showed renal impairment before netilmicin treatment (serum creatinine 相似文献   

Burden of disease due to cancer in Spain

Background  

Burden of disease is a joint measure of mortality and morbidity which makes it easier to compare health problems in which these two components enjoy different degrees of relative importance. The objective of this study is ascertaining the burden of disease due to cancer in Spain via the calculation of disability-adjusted life years (DALYs).