An evaluation of the cardiovascular safety profile of duloxetine: findings from 42 placebo-controlled studies.

BACKGROUND AND OBJECTIVE: In recent years, new classes of medication, such as the serotonin-noradrenaline reuptake inhibitors (SNRIs), have been developed for use in the treatment of major depressive disorder (MDD). For many years, treatment options were largely limited to the use of monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs). However, there have been published reports of orthostatic hypotension, arrhythmias and corrected QT (QTc) interval changes in patients treated with TCAs. As new medications become available, it is important to understand how their cardiovascular safety profile compares with that of more established agents to aid clinicians and patients in choosing the best treatment options. This study was designed to evaluate the cardiovascular safety profile of the SNRI duloxetine through evaluation of cardiovascular-related parameters and adverse events (AEs). METHODS: The cardiovascular safety of duloxetine was assessed using all placebo-controlled duloxetine clinical trial data as of December 2005. This consisted of data from 42 placebo-controlled clinical trials of 8504 patients who were treated with duloxetine. Additional information from a high-dose clinical pharmacology study and postmarketing safety surveillance are also presented. Of the placebo-controlled trials included in this analysis, clinical indications under investigation included MDD (15 studies), diabetic peripheral neuropathic pain (3 studies), fibromyalgia (2 studies), generalised anxiety disorder (3 studies) and lower urinary tract disorders (19 studies, all related to incontinence). Cardiovascular safety was evaluated based on vital signs, ECGs and the incidence of treatment-emergent AEs potentially related to cardiovascular safety. These safety parameters were analysed across all indications. To identify both serious and non-serious cardiovascular-related AEs, as well as AEs reported as the reason for discontinuation, a comprehensive list of terms derived from the Medical Dictionary for Regulatory Activities (version 8.0) was generated and used to search the duloxetine databases for cardiovascular-related events. RESULTS: Calculation of change from baseline to maximum in ECG parameters showed significant differences between treatment groups for all parameters, with decreases from baseline in RR, QRS and QT intervals for patients receiving duloxetine and increases from baseline for patients treated with placebo. These shifts were related to small heart rate changes, but the mean differences were not considered clinically relevant. Categorical analyses of shifts from normal to abnormal (or abnormal to normal) for heart rate and QT corrected for heart rate using Fridericia's formula (QTcF) values showed that most patients did not shift from their baseline category. Patients with MDD who were treated for up to 1 year with duloxetine had blood pressure changes early in treatment that then stabilised. Even in patients with elevated blood pressure at baseline in these clinical trials, no increased risk of sustained blood pressure elevation with duloxetine treatment was found. CONCLUSION: Overall, the findings presented here support our conclusions that use of duloxetine does not appear to be associated with significant cardiovascular risks in patients with conditions for which the drug has been approved or studied.     

Efficacy and tolerability of a new antipsychotic compound (risperidone): results of a pilot study.

Risperidone is a new benzisoxazole derivative displaying a very potent serotonin antagonism and a potent dopamine antagonism in pharmacological studies. These properties suggest the hypothesis that risperidone may exert antipsychotic effects and be superior to classic neuroleptics in its beneficial effects on negative and affective symptoms and its low extrapyramidal side-effect propensity. In an open pilot study 13 patients suffering from acute schizophrenic psychosis were treated with risperidone within an individually adapted dose range from 1 to 10 mg per day. A good antipsychotic efficacy could be demonstrated in 6 of the 8 patients who completed the trial. Risperidone was very well tolerated. The substance possesses a low EPS-inducing profile. Future research has to test the suggested advantage of risperidone over other neuroleptic drugs and its performance in the treatment of chronic schizophrenic patients.     

A noradrenergic and serotonergic hypothesis of the linkage between epilepsy and affective disorders

Noradrenergic and/or serotonergic deficits, as well as other abnormalities, may contribute to predisposition to some epilepsies and depressions. Evidence for this hypothesis stems from several sources. Epidemiological investigations are intriguing but incomplete. Pharmacological studies show that noradrenergic and/or serotonergic transmission are both anticonvulsant and antidepressant. Therapeutically pertinent investigations show that antidepressant drugs have anticonvulsant properties, whereas antiepileptic drugs are effective in the management of affective disorders. Additional investigations demonstrate that seizures, whether spontaneously occurring or therapeutically induced, protect against depression. Through studies of innate pathophysiology, noradrenergic and serotonergic deficits have been identified in individuals with depression and in animal models of epilepsy, as well as in some humans with epilepsy. Vagal nerve stimulation, a treatment already known to be effective in the epilepsies, is presently under investigation for effectiveness in affective disorder. New evidence suggests that vagal nerve stimulation exerts at least some of its therapeutic effects through its capacity to increase noradrenergic and serotonergic transmission. Finally, emerging evidence supports the concept that some genetic mammalian models of the human epilepsies exhibit analogous manifestations of depression.     

Facework,social politeness and the Alzheimer's patient

A recent paper by (Temple et al., 1999) investigating the politeness abilities of Alzheimer's sufferers has suggested that the sufferers they worked with were capable of employing politeness strategies towards their interlocutor. Given that politeness, according to (Brown and Levinson, 1987) revolves around face and that attending to another person's face requires the ability to take the other's role or perspective, Temple et al.'s findings would seem to contradict the findings of (Hamilton, 1988) who made the claim that Alzheimer's sufferers are unable to take the role of the other. Our proposal is that a more sophisticated view of politeness is required in identifying what the Alzheimer's patient is capable of. A refinement of the notion of politeness would also allow us to reconcile these two views. This refinement may be usefully achieved through employing the subdivision made by (Janney and Arndt, 1992) who propose that social politeness be distinguished from tact. In this approach, it is tact that involves facework while social politeness is more conventionalized or routinized. The distinction between tact and social politeness allows us to recognise certain politeness behaviours as not involving facework. Applying this distinction to our data, we find that our subject does engage in social politeness but, as one would expect from Hamilton's assumptions, she does not appear to be able to attend to the face of her interlocutors with much show of tact. However, in relation to facework, whilst she does not demonstrate much awareness of the need to protect the other's face, she does, in fact, engage with some sophistication in saving her own face. In this paper, we aim to examine not whether Alzheimer's Disease sufferers have the ability to be polite or not but which aspects of politeness remain after other aspects appear to have been lost.     

A Single-Dose Conformal Delivery of Radiotherapy Following Osteoplasty

Multiple myeloma (MM) is a very radiosensitive tumor. Fractionated external beam radiation, which takes approximately 2 weeks of therapy, is typically used to irradiate myelomatous bone lesions with the goal of palliation. However, traditional radiotherapeutic techniques are not only lengthy but they also involve a considerable amount of healthy bone marrow in the treatment ports, which may undermine the total marrow reserve of a patient. Because of the limited survival time of patients with metastatic cancer, novel treatment concepts shortening the overall treatment time is desirable. We present an innovative approach of delivering targeted intra-operative radiotherapy to a solitary osteolytic metastasis in one application, while sparing healthy bone marrow from radiation toxicity and substantially reducing the overall treatment time. A 78-year-old Caucasian male with MM, previously treated with chemotherapy, who was off chemotherapy for 2 years due to bone marrow suppression, presented with a solitary recurrence at the left anterior superior iliac spine of the left iliac wing as diagnosed by PET-CT scan. This lesion was treated with a minimally invasive osteoplasty and intra-operative brachytherapy with to a dose of 8 Gy delivered to the surgical cavity only, followed by injection of the bone cement into the cavity. Three months after the procedure, the area of treatment demonstrated no uptake on a follow-up PET-CT scan. At 1.5 years after this procedure, 100% local control continues to persist in the treated area, as evidenced on nuclear imaging. To our knowledge, this is the first case of using focal intra-operative brachytherapy confined to the area of the pelvis in a patient treated for a solitary metastasis from MM. The purpose of the article is to present a novel approach as a more convenient and focal treatment of bony lesions of MM.     

Stimulation of collagenase 3 expression in synovial fibroblasts of patients with rheumatoid arthritis by contact with a three-dimensional collagen matrix or with normal cartilage when coimplanted in NOD/SCID mice

OBJECTIVE: To study the expression of collagenase 3 (matrix metalloproteinase 13 [MMP-13]) and collagenase 1 (MMP-1) in synovial fibroblasts from patients with rheumatoid arthritis (RA) when cultured within 3-dimensional collagen gels or coimplanted with normal cartilage in immunodeficient NOD/SCID mice. METHODS: Messenger RNA (mRNA) and protein expression of collagenase 3 and collagenase 1 were characterized in synovial and skin fibroblasts by Northern blot and Western blot analysis. The mRNA expression of both collagenases in cell-cartilage implants in NOD/SCID mice was investigated by in situ hybridization in combination with immunohistochemistry of human fibroblasts. RESULTS: Synovial fibroblasts coimplanted with normal cartilage in NOD/SCID mice deeply invaded adjacent cartilage tissue. In this in vivo system of cartilage destruction, collagenase 3 mRNA was induced in synovial fibroblasts at sites of cartilage erosion, while the expression of collagenase 1 mRNA could not be detected. Culture of synovial fibroblasts within 3-dimensional collagen gels was associated with a marked increase in collagenase 3 mRNA expression and proenzyme production. This stimulatory effect was 1 order of magnitude higher in comparison with a 2-4-fold increase upon treatment with interleukin-1beta or tumor necrosis factor a. In contrast, mRNA expression and proenzyme production of collagenase 1 were increased strongly, and to a similar extent, either by contact with 3-dimensional collagen or by proinflammatory cytokines. CONCLUSION: The expression of collagenase 3, in contrast to that of collagenase 1, is preferentially stimulated in synovial fibroblasts by 3-dimensional collagen rather than by proinflammatory cytokines. The induction of collagenase 3 by cell-matrix interactions represents a potential mechanism contributing to the invasive phenotype of synovial fibroblasts at sites of synovial invasion into cartilage in RA.