Tenormin

Mr. Leo Pinczewski MBBS FRACS

• North Sydney Orthopaedic and Sports Medicine Centre
• Sydney, NSW
• Australia

Afer a sample of the original seed stock is obtained hypertension erectile dysfunction generic tenormin 50 mg mastercard, an early-stage pre master bank of just a few vials should be established blood pressure normal low 50mg tenormin otc. This approach has signifcant benefts: it gives great fexibility in the timing of the production process arrhythmia questions and answers discount 100 mg tenormin amex, permits quality control and safety testing to be completed prior to use heart attack 40 best purchase for tenormin, and reduces the overall burden of testing required in the process heart attack 5 days collections purchase genuine tenormin on line. The location arrhythmia recognition quiz purchase tenormin 50mg line, identity and inventory of individual cryovials or ampoules of cells should be thoroughly documented. When cryopreserved cells are transferred to a remote site, it is important to use qualifed shipping containers and to monitor transfers with probes to detect temperature excursions. All containers are treated identically and, once removed from storage, are not usually returned to the stock. The second storage site should operate under an equivalent standard of quality assurance to that at the primary site. However, owing to the limited number of vials remaining, distribution is restricted to use in the production of vaccines and other biologicals. Recommendations for the characterization of cell banks of animal cell substrates B. In some cases, these new cell types provide signifcantly higher yields of product at less cost, while in other cases they provide the only means by which a commercially viable product can be manufactured. Special attention should be given to viruses that commonly contaminate the animal species from which the cell line is derived, and to cell culture reagents of biological origin. Tests capable of detecting such agents should be carried out on cells grown under cell culture conditions that mimic those used during production, and the levels of viral particles should be quantifed. Additional consideration should be given to products derived from cells that contain known viral sequences. Wherever practicable, methods for identity testing should be used that give specifc identifcation of the cell line, in order to confrm that no switching or major cross-contamination of cultures has arisen during cell banking and production. Other tests that may be used but tend to be less specifc include isoenzyme analysis and karyology, which may be particularly useful where there are characteristic marker chromosomes. However, where more specifc genetic markers are available, they should be considered. A small proportion of cell lines – particularly those that are transformed – may show alterations to the expected identity profle. This has been observed 126 Annex 3 in isoenzyme analysis where, in rare cases, a particular cell line may show a consistently diferent profle from that expected for the species of origin; it is also a general issue relating to the efect of genetic instability on molecular identity testing techniques. Such efects in standard technologies are rare but may also arise with the implementation of new techniques. For recombinant protein products, cell-line identity testing should also include tests for vector integrity, expression plasmid copy number, insertions, deletions, number of integration sites, percentage of host cells retaining the expression system, verifcation of protein-coding sequences, and protein-production levels. The probes 10–20 metaphase spreads paint the chromosomes, is insensitive for detecting yielding diferent colours contaminating cells. Spectral karyotyping is able to detect translocations that are not recognizable by traditional banding methods. Isoenzyme analysis Determination of species of Analysis for 4–6 origin within a few hours. It provides the advantage of covering a broad spectrum of organisms and cell lines other than human cells. Periodic testing for viability is not necessary if continuous monitoring records for storage show no deviations out of specifcation, and periodic production runs are successful. If banks are used less than once every 5 years, it may be prudent to generate data to confrm their suitability for manufacturing on a schedule that takes into account the storage condition once every 5 years. For recombinant protein products, emphasis will be on the protein sequence and post-translational modifcations. The copy number of the construct and, if relevant, the sites of chromosomal insertion, should also be determined. The latter is accomplished by sequencing into the cellular fanking regions, but methods such as fuorescent in situ hybridization may provide useful additional information, particularly where concatamers of the gene insert are present at individual chromosomal loci. Additional characterization of the cell biological processes and responses during cultivation (for instance, using global or targeted gene expression, proteomic or metabolic profles and other phenotypic markers) might be useful in further developing a broad understanding of the cell substrate. Appropriate methods should be applied to ensure that cell age is correctly assessed in the event that cell viability falls dramatically at any given step. Losses in viability are refected in increased cultivation times to reach defned levels of growth. The stability of cell function in terms of productivity within the production process also may need to be evaluated. Other stability studies may be performed where bioreactor methods are employed, especially where extended culture periods are involved. Tawed cells should typically have viability levels in excess of 80%, though this is not always achieved and may depend on the cell line. Lower viabilities may still result in suitable growth recovery and in acceptable product qualities. A range of viability tests is available to measure diferent attributes of cell function. Under certain circumstances, such as pre-apoptotic cells excluding trypan blue, viability assays may give misleading results and it is important to be aware of the exact information that a particular viability assay provides. Terefore, it is important to evaluate the growth recovery of cryopreserved cells upon thawing. For certain cell cultures such as hybridomas, where a membrane-integrity test is used, additional cell markers such as indicators of apoptosis should be studied, in order to avoid signifcant overestimation of viability. A suitable viability test should be selected for the cell substrate in question and typical test values established for cultures considered to be acceptable (see sections B. It may also be necessary to select alternative viability assays that are better suited to providing the in-process viability data that are required during production. Accordingly, data on growth characteristics – such as viability, morphology, cell-doubling times, cloning and/or plating efciency – should be 130 Annex 3 developed. For certain cell substrates, it may be appropriate to apply such tests in homogeneity testing (see section B. Experiments to demonstrate homogeneity and growth characteristics may be combined, although the analysis should be carried out separately. In order to ensure this, it is important to recover a proportion of containers from each cell bank and check their characteristics, as indicated in section B. Recovery of a sufcient percentage of vials representative of the beginning, middle and end of the aliquoting process should be demonstrated, in order to give confdence in the production process that is based on the use of that cell bank. Ultimately, stability and integrity of cryopreserved vials are demonstrated when the vials are thawed for production and are shown to produce the intended product at scale. Instead of testing a proportion of containers at diferent stages of the banking process, an alternative strategy to ensure the homogeneity of the banks can be based on the validation of the process method for flling and freezing. Terefore, a model protocol has been developed and is appended to this document (see Appendix 2). The major points included in the model protocol are listed below, along with comments on each item. The tumorigenicity tests that are currently available are in mammalian species, whose body temperatures and other physiological factors are diferent from those of avian and insect species. Terefore, when the test is performed on avian or insect cells, the validity of the data is open to question unless a tumorigenic cell line of the species being tested is included as a positive control. However, as mentioned above, correlations of in vitro tests with in vivo tests are imperfect. If a manufacturer proposes to characterize the cell line as non-tumorigenic, the following tests should be undertaken. The test should involve a comparison between the cell line and a suitable positive reference preparation. This can be accomplished either by the use of rodents that are genetically immunocompromised. Factors (i), (ii), (iii) and (v) usually depend on the number of cells inoculated. Although comparisons of two or more assays have been reported in the literature (68, 73, 74) none take all of these factors into account, nor do they use the same tumorigenic cell lines. Tus, it is not possible to draw defnitive conclusions about the relative sensitivity of the various tumorigenicity assays. Overall experience during the past 30 years, taking into consideration the points mentioned above, has led to the conclusion that the athymic nude mouse is an appropriate test system for determining the tumorigenic potential of cells proposed for use in the production of biologicals. The major advantages of the athymic nude mouse system are that it is easier to establish and standardize and is generally available, while the newborn rat system is more sensitive for assessing the metastatic potential of tumorigenic cells. In some cases, it may be preferable to use newborn athymic nude mice, as these animals are more sensitive than adults for the detection of weakly tumorigenic cells (66). A tumorigenicity testing protocol using athymic nude mice is provided as Appendix 2. The purpose of the positive control is to assure that an individual test is valid, by demonstrating that the animal model has the capacity to develop tumours from inoculated cells. If the positive-control cells fail to develop tumours at the expected frequency, then this could be indicative of problems (such as infections) in the animals or in the testing facility, which can reduce the efciency of tumour development. When the cell substrate has been adapted to growth in serum-free medium, which may contain growth factors and other components that could infuence growth as well as detection of a tumorigenic phenotype, consideration should be given to processing the positive-control cells in the same medium. In designing a tumorigenicity protocol, it is important to recognize that tumours arise spontaneously in nude mice and that the incidence of such tumours increases with the age of the mice. Terefore, databases (both published data and the unpublished records/data of the animal production facility that supplied the test animals) of rates of spontaneous neoplastic diseases in nude mice should be taken into account during the assessment of the results of a tumorigenicity test. In general, negative controls are not recommended because the rates of spontaneous neoplastic disease in nude mice are low, and small numbers of negative-control animals are unlikely to provide meaningful data. For example, if serum-free medium is used to grow the cell substrate, it is conceivable that growth factors may infuence the appearance of spontaneous tumours; consequently, negative-control cells suspended in the same medium may be needed to interpret the test results. In a valid test, progressively growing tumours should be produced in at least 9 out of 10 animals injected with the positive reference cells. If there is no evidence of a progressively growing nodule at the end of the observation period, the cell line may be considered to be non-tumorigenic. Animals bearing nodules that are progressing should be killed before the end of the study if the tumour reaches the limit set by the relevant authorities for the humane treatment of animals. Animals bearing nodules that appear to be regressing should not be killed until the end of the observation period. Cell lines that produce nodules that fail to grow progressively are not considered to be tumorigenic. If what appears to be a metastatic tumour difers histopathologically from the primary tumour, it is necessary to consider the possibility that this tumour either developed spontaneously or was induced by one or more of the components of the cell substrate, such as an oncogenic virus. This may require further testing of the tumour itself, or the tumorigenicity assay may need to be repeated. However, the reported rate of spontaneous neoplastic diseases in the test animals should be taken into account during the assessment of the results. In addition, the histopathology of the tumours must be consistent with the inoculated cells, and a genotypic marker should show that the tumour is not of nude mouse origin. As such, tumours that arise in a tumorigenicity assay contain cells derived from the inoculated cells, while tumours that arise in an oncogenicity assay are derived from the host. To date, three studies have indicated that between 1 and 10 µg of expression plasmids for cellular oncogenes can be oncogenic in mice (34, 43, 44). Recent results suggest that the sensitivity of the assay can be increased by several orders of magnitude, with the use of certain immune-compromised strains of mice that are prone to develop tumours afer inoculation with oncogenes. Each sample should consist of a minimum of 100 cells in metaphase and should be examined for exact counts of chromosomes as well as for breaks and other structural abnormalities. In addition, animal cells contain endogenous agents such as retroviruses that may also be of concern. In general, cell substrates contaminated with microbial agents are not suitable for the production of biologicals. The balance of risk versus beneft must be considered when determining the suitability of a cell substrate for the production of a specifc product. Further, risk-mitigation strategies during production, including purifcation (removal) and inactivation by physical, enzymatic and/or chemical means, should be implemented whenever appropriate and feasible. Even though a cell substrate might be unacceptable for some products, such as a live viral vaccine subjected to neither signifcant purifcation nor inactivation, that same cell substrate may be an acceptable choice for a diferent type of product, such as a highly purifed recombinant protein or monoclonal antibody for which risk mitigation has been achieved by signifcant and validated viral clearance in the production process. It also permits additional time/passages for amplifcation of low-level contaminants or reactivation of viral contaminants that may have been missed in the testing of the upstream bank. Specifc techniques such as molecular and immunological methods and electron microscopy may be required to reveal the presence of such inapparent infections. For new cell substrates, induction of a detectable infection by exposing the cells to special conditions. The strategy developed to test cell substrates for viruses should take into consideration the families of viruses and specifc viruses that may be present in the cell substrate. Consideration should be given to the species and tissue source from which the cell substrate originated, and to the original donor’s medical history in the case of human-derived cell substrates or to the pathogen status of donor animals in the case of animal-derived cell substrates. Tests should be undertaken to detect, and where possible identify, any endogenous or exogenous agents that may be present in the cells. Attention should be given to tests for agents known to cause an inapparent infection in the species from which the cells were derived, thereby making it more difcult to detect. Primary cells are obtained directly from the tissues of healthy animals and are more likely to contain adventitious agents than banked, well-characterized cells. In addition, recent vaccination of source animals should be considered, as the animals may be exposed to live vaccines. The risk with primary cells can be mitigated by rigorous qualifcation of source animals and of the primary cells themselves. When feasible, animals from which primary cultures are established should be from genetically closed focks, herds or colonies that are monitored for freedom from pathogens of specifc concern.

Syndromes

• Severe diarrhea that overwhelms the ability to control passage of stool
• Want to live as a person of the opposite sex
• Before receiving the contrast, tell your health care provider if you take the diabetes medication metformin (Glucophage) because you may need to take extra precautions.
• Free hemoglobin in the serum or urine
• It is appears in a boy (very rare)
• Barium enema
• Bronchoscopy -- camera down the throat to see the airways and lungs
• Zanamivir is taken by inhaler.

Side-effects include digestive intolerance (diarrhoea) blood pressure up cheap tenormin 100mg otc, skin rash prehypertension third trimester cheap generic tenormin uk, aqua genic pruritus blood pressure medication heart rate purchase 50mg tenormin visa, blue-grey or brown lower leg hyperpigmentation (Jallouli blood pressure entry chart order tenormin no prescription, 2013) arrhythmia lying down 100mg tenormin visa, cardiomyopathy hypertension unspecified purchase tenormin cheap online, myopathy and retinopathy. Retinopathy can present with photophobia, blurred distance vision, missing or blacked out areas in the vision field (or while reading) and light flashes. New data about the prevalence of retinopathy has led to a recent update of the American Guidelines of Ophthalmology for toxicity screening (Marmor, 2016). Therefore, a maximum recommended dose of 5 mg/kg of observed (rather than ideal) body weight is proposed. In addition, a baseline fundoscopy and annual screening starting after 5 years, for patients on acceptable doses without major risk factors, is recommended. For patients on higher dosages or patients with risk factors more frequent examinations are recommended. Risk factors include age over 60 years, pre-existing macular degeneration, retinal dystrophy, obesity, liver disease and renal failure (Marmor, 2002; Mosca, 2009) and should be assessed regularly. The rheumatology world has not yet adopted these new recommendations and some critical comments have been published. Bone marrow suppression, increased risk of infections, hepatitis and hypersensitivity reaction are potentially severe but rare adverse events. However, genotyping is not done routinely by many rheumatologists ; a frequent approach is to start and titrate therapy in steps from a low dosage (50mg) up to the desired dose and check tolerability and blood count after every increase, for example every two weeks. A recent cohort study showed its efficacy in refractory to standard of care non-renal manifestations and reduction of corticosteroid use (Tselios, 2016). They mainly consist of gastrointestinal manifestations (diarrhoea, nausea, vomiting), hepatitis and anaemia, the latter mainly observed in patients with renal impairment. Other side effects such as pancreatitis and febrile pancytopenia have been observed rarely. The drug is strictly contraindicated in pregnancy (at least during the first trimester) because of proven teratogenicity, with peculiar involvement of the face (Perez-Aytes, 2008). It is not always well tolerated: transient increase in serum creatinine, hypertension, hypertrichosis, gum hypertrophy, tremor and seizures may occur (Conti, 2000). They can be useful in selected cases with persistent proteinuria despite standard immunosuppression. In the early 1960s, it was found to be dramatically teratogenic (phocomelia) and was withdrawn. Further studies have shown its efficacy in the treatment of leprosy and multiple myeloma. The mechanism of action of the drug is poorly understood, but it appears to display antiangiogenic effects. Thus, polyneuropathy is frequent (at least 20% of patients), can be disabling and is mostly irreversible (Briani, 2004). In some countries, a monthly negative pregnancy test is required before the drug can be prescribed and obtained. Relapses after discontinuation are frequent and may justify the use of a lower maintenance dose such as 50 mg three times weekly. Lenalidomide was recently studied in refractory cases of cutaneous lupus (Cortes-Hernandes, 2012). It is suggested to start with 100 mg daily and then to taper to the minimally efficacious dose in 2-3 months. In the absence of proper controlled trial its use should be limited to selected cases. Treatment cost and lack of evidence-based recommendations clearly limit their use. Basically, only patients with very severe uncontrolled disease and at risk for permanent organ damage or death should be considered for this procedure. The design and choice of outcome measures in trials for a heterogeneous disease such as lupus is a challenge and may have contributed to negative results in the past. Rituximab has an acceptable safety profile, although a concern has been raised based on two cases of progressive multifocal leukoencephalopathy (Molloy, 2012). B-cell depletion usually occurs within 2 weeks after the first infusion and B-cell repopulation after 3 to 40 months. Flares of disease activity have been reported in about 40% of treated patients, mostly concomitant with B-cell reconstitution. However, it is not clear whether patients should be pre-emptively re-treated at the time of reconstitution of B-cells. Of note, 1 case of progressive multifocal leukoencephalopathy has been reported in a belimumab-treated patient (Fredericks, 2014). Several molecules were currently developed to block this pathway (Lauwerys, 2013a). Two dosages (300mg and 1000mg) were tested against placebo in moderate to severe lupus in addition to standard therapy. Herpes zoster and influenza infections were reported more frequently in the anifrolumab groups. It was shown to display tolerogenic and immunomodulatory effects in preclinical lupus models, i. Two randomized controlled trials, performed in patients with inactive or stable disease without a history of thrombosis, suggest that the use of combined oral contraceptives, containing 30-35 mcg of ethynyl oestradiol, does not increase the incidence of flares, nor the rate of thrombotic events (Petri, 2005; Sanchez-Guerrero, 2005). In patients with the antiphospholipid syndrome (excluded in the study by Petri et al. Severe flares were not more frequent in the treated group but there were significantly more mild and moderate flares (relative risk: 1. Moreover, as in the general population, thromboembolic events were more common, although the difference was not statistically significant (Buyon, 2005). Refractory lupus needs special attention and is likely best managed in expert centres. The following paragraphs specifically deal with certain organ involvements and summarize our best knowledge They should not be applied “à la lettre” but should serve as a guide for optimal care. The current paradigm is to induce a response with an intensive approach using potentially toxic drugs for a short period of time and to maintain the response with a less aggressive immunosuppressant for the long-term. This said, complete renal response rates after 6 months of induction therapy remain low with current therapies (in most studies below 30%), which means that there is room for improvement. Similarly, relapses occur in more than 20-40% of patients (according to length of follow-up) despite maintenance therapy, indicating that further research is needed. Prognostic factors include non-white race, poor socioeconomic status, uncontrolled hypertension, high activity and chronicity on biopsy, renal impairment at baseline and poor initial response to therapy (Austin, 1995). The Euro-Lupus Trial showed similar efficacy between option i and ii, although the patients were mostly of Caucasian descent and with moderate nephritis (Houssiau, 2002). Results after 10 years’ follow-up have been published and are comparable (Houssiau, 2010). The design of these two trials are different and their results should therefore not be compared head-to-head. Their stringent antiproteinuric effect, through their effect on podocytes is of interest, as well as the possibility to use them during pregnancy. Nevertheless, their toxicity profile (hypertension, renal impairment, effects on lipid profile, tremor, hirsutism, gum hyperplasia, etc. An understudied topic is when to stop immunosuppression, as very few studies have addressed this pivotal question (Moroni, 2006). In the latter cases, most physicians consider that the presence of proliferative lesions guides therapy. Based on the nephrology experience, for patients with mild proteinuria a “watchful waiting” approach with optimal blockade of the angiotensin renin aldosterone system is usually appropriate. Subcutaneous heparin is used in the prevention of thrombosis in patients with nephrotic syndrome and low serum albumin (< 2 g/dL). In some very refractory cases, it may be wiser to step down immunosuppression, when the battle is lost anyway, in order to avoid further toxicity. More studies are needed to clarify the potential confounding effect of lupus disease activity on the observed associations. Other demyelinating diseases, such as multiple sclerosis, need to be ruled out (Magro Checa, 2013). The second dilemma deals with the mechanism involved: is it inflammation or thrombosis mediated by anti phospholipid antibodies? While this question might look trivial in theory, the answer is always difficult at the bedside. Improvement was observed in 61% of the patients, stabilisation in 29% and deterioration in 10% (Neuwelt, 1995). The differential diagnosis is broad: some more common conditions, such as rosacea, need to be ruled out. In patients with cutaneous involvement, photo protection is very important and strict sunscreen adherence and adequate clothing must be emphasised and/or application of a sun protection factor ≥ 50 spf about 20 minutes before sun exposure (Kuhn, 2011a). Anifrolumab showed significant improvement of disease activity including skin lesions, suggesting efficacy in cutaneous lupus (Furie, 2015). While the classical acute polyarthritis is usually promptly responsive to therapy, few interventions (including rehabilitation procedures) are helpful in Jaccoud’s arthropathy. These data show that this comorbidity cannot be neglected and risk factors should be actively assessed and if possible treated, for example by vitamin D3 and calcium supplementation, exercise and smoking cessation. Mild thrombocytopenia, as for example often seen in the presence of antiphospholipid antibodies, does not require specific therapy. This diagnosis should always be excluded in a lupus patient with pancytopenia, mainly acute thrombocytopenia, haemolysis, an excess of schistocytes on blood smears, renal failure and other micro thrombotic manifestations. Bone marrow aspiration shows the typical picture of macrophages phagocytosing haematopoietic cells. Pleuro pericardiocentesis may be required in case of large effusions or to rule out other diagnoses in difficult cases. Antimalarials contribute to a more favourable lipid (Rahman, 1999) and glucose (Petri, 1994) profile and display some antithrombotic activity (Ruiz-Irastorza, 2006), by reducing the binding of antiphospholipid anti-beta2-glycoprotein I complexes to phospholipid bilayers (Rand, 2008). In vitro and in vivo studies suggest that statins have direct anti-inflammatory, antithrombotic and plaque-stabilizing effects via a number of mechanisms, besides their well-known lipid-lowering effect. Not only opportunistic infections but also common pathogens, such as Streptococcus pneumoniae and Haemophilus influenzae, contribute to mortality. Some patients take their medications only for a few days before the visit the clinic, a common phenomenon in chronic diseases known as ”white coat compliance”. Thus, a hypertensive patient who wants to please his physician will take a few blood pressure lowering pills for a short period of time preceding the visit and will be declared compliant since his/her blood pressure levels measured the day of the visit will be deemed satisfactory. In a retrospective analysis, more lupus flares were observed in patients who were less compliant (Costedoat-Chalumeau, 2007). Non-adherence can be addressed in clinical practice by repeated explanations given to lupus patients and their relatives on the reasons why each drug is prescribed, and by sketching the global treatment plan as soon as the treatment is started, so that patients understand that many of the drugs will be progressively withdrawn or their dose tapered, even if some will be prescribed for several years. In this respect, the help of a nurse practitioner in our busy lupus clinics can be most valuable. They are also believed to have antithrombotic properties and may reduce cardiovascular risk. Azathioprine and mycophenolate mofetil can both be used for long-term maintenance treatment. Yet, further improvement is eagerly awaited since complete renal remission rate is only 30% after induction therapy and since up to 40% of patients suffer from renal relapse. Other biologic therapies are currently being tested, with promising results for the type-1 interferon inhibitor anifrolumab. Several trials are currently ongoing under the umbrella of the Lupus Nephritis Trials Network ( Recurrence of lupus nephritis after renal transplantation is rare and graft survival is by and large comparable to a control population. Traditional risk factors should therefore be monitored and controlled by lifestyle modification. Immunization against influenza and Streptococcus pneumoniae is strongly recommended. 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Efficacy of ziprasidone in dysphoric mania: pooled analysis of two double-blind studies blood pressure emergency level order tenormin with amex. Extreme attributions predict transition from depression to mania or hypomania in bipolar disorder arteria networks corporation cheap tenormin generic. A double-blind arrhythmia overview discount 100 mg tenormin free shipping, placebo-controlled study with quetiapine as adjunct therapy with lithium or divalproex in bipolar I patients with coexisting alcohol dependence blood pressure of 150/90 purchase 50 mg tenormin with mastercard. Suicide risk in placebo-controlled trials of treatment for acute manic episode and prevention of manic-depressive episode arterial bleeding buy discount tenormin 50mg line. Rapid versus non-rapid cycling as a predictor of response to olanzapine and divalproex sodium for bipolar mania and maintenance of remission: post hoc analyses of 47-week data hypertension 12080 tenormin 50mg low cost. 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Efficacy and safety of once versus twice-daily carbamazepine extended-release capsules for the treatment of manic symptoms in patients with bipolar I disorder. A multicenter, randomized, double-blind, placebo-controlled trial of extended-release carbamazepine capsules as monotherapy for bipolar disorder patients with manic or mixed episodes. Extended-release carbamazepine capsules as monotherapy for acute mania in bipolar disorder: a multicenter, randomized, double-blind, placebo-controlled trial. Predictors of response to treatment of acute bipolar manic episodes with divalproex sodium or placebo in 2 randomized, controlled, parallel-group trials. Early nonresponse in the antipsychotic treatment of acute mania: A criterion for reconsidering treatment? Risk of postpartum episodes in women with bipolar disorder after lamotrigine or lithium use during pregnancy: A population-based cohort study. Further neuroimaging evidence for the deficit subtype of schizophrenia: a cortical connectomics analysis. Long-term effects of cognitive-behavioural therapy and lithium therapy on depression in the elderly. Association between lithium serum level, mood state, and patient-reported adverse drug reactions during long-term lithium treatment: a naturalistic follow-up study. Rash in adult patients receiving lamotrigine to treat bipolar I disorder in Korea: a multicenter, prospective, naturalistic, open-label trial. A diagnosis of bipolar spectrum disorder predicts diagnostic conversion from unipolar depression to bipolar disorder: a 5-year retrospective study. A naturalistic retrospective review of weight gain in bipolar patients treated with second generation antipsychotics. Comparative risk of seizure with use of first And Second-Generation antipsychotics in patients with Schizophrenia and mood disorders. Who will benefit from antidepressants in the acute treatment of bipolar depression? Rapid and sustained antidepressant response with sleep deprivation and chronotherapy in bipolar disorder. Treatment-emergent mania in unipolar and bipolar depression: focus on repetitive transcranial magnetic stimulation. A clinical review of aripiprazole in bipolar depression and maintenance therapy of bipolar disorder. Bipolar depression: criteria for treatment selection, definition of refractoriness, and treatment options. Efficacy of aripiprazole versus placebo as adjuncts to lithium or valproate in relapse prevention of manic or mixed episodes in bipolar I patients stratified by index manic or mixed episode. Third generation anticonvulsants in bipolar disorder: a review of efficacy and summary of clinical recommendations. Agomelatine or placebo as adjunctive therapy to a mood stabiliser in bipolar I depression: randomised double-blind placebo-controlled trial. Effectiveness of cognitive behavioral therapy in treating bipolar disorder: An updated meta-analysis with randomized controlled trials. Managing the aftermath of mania Newcastle, 2 September 2005: Consensus Meeting Statement. Tiagabine in the treatment of acute affective episodes in bipolar disorder: efficacy and acceptability. Double-blind comparison of addition of a second mood stabilizer versus an antidepressant to an initial mood stabilizer for treatment of patients with bipolar depression. Efficacy of a protein kinase C inhibitor (tamoxifen) in the treatment of acute mania: a pilot study. Temperament and prodromal symptoms prior to first manic/hypomanic episodes: results from a pilot study. Role of atypical antipsychotics in rapid cycling bipolar disorder: a review of the literature. J C: Placebo dysphoric mania Psychiatry 156 (5), 702-709)14 and Tohen, 2000 (Arch. Industry 22540407 Young, 20092 High Moderate dropout rate (28%); Randomization and blinding procedures not disclosed. Industry 19118324 Sachs, 20065 High High withdrawal rate (47%), randomization and blinding procedures not disclosed Industry 16401666 Vieta, 20056 Moderate Blinding not described, moderate dropout level (34%), not balanced between the groups. Industry 20096936 McIntyre, 20099 High Randomization and blinding procedures not described. Strength of evidence assessment: asenapine versus active comparator for acute mania # Studies/ Finding or Overall Study Comparison Outcome Design Summary Consistency Directness Precision Grade/ Limitations (n analyzed) Statistic Conclusion Response 3 wk Remission 3 wk Asenapine vs. Lack of disclosure of methods to allocate Industry and protect the blind also increases the risk. Sachs, 201513 Moderate A moderately high dropout rate combined with a lack of disclosure for the methods of Industry allocation and concealment create strong conditions where bias may be present. Pools results for blinded and unblinded without Industry establishing similarity of groups 15572276 Sachs, 200217 High Lacks randomization and blinding procedures. Period three efficacy scores are likely to be biased 22503488 by the large non-completer rate. Industry 20096936 Shafti, 201033 Moderate Randomization and blinding procedures not described. Patients discharged from hospital at Industry differing times and doesn’t account for this as a possible confounder. Industry 19014751 Perlis, 200634 High Randomization and blinding procedure not described. Study notes consistency in traits between dropouts and those who 12716270 complete, which may be an indication that outcomes may be less biased. Industry 14662554 Shi, 200227 High Randomization procedure not described, although does note “randomization codes”.

Progress Board blood pressure 9460 tenormin 50 mg on line, a blue-ribbon panel made up of business-people and academics appointed by the British Columbia government to offer advice on economic and social issues arrhythmia lidocaine purchase tenormin with visa, has proposed that drugs either be decriminalized or that the War on Drugs be stepped up so as to completely eliminate the drug trade in this province heart attack 32 proven 50mg tenormin. The status quo is “clearly unacceptable if we seek truly to reduce the rates of crime and victimization in the province blood pressure visual chart order generic tenormin line,” the Progress Board stated blood pressure monitor chart printable buy tenormin with amex. The so-called other “option blood pressure medication karvea order cheap tenormin on-line,” the elimination of drug trafficking and use, is no option at all—only a chimera that even the most Draconian measures have failed to conjure into reality anywhere in the world. Unless we are willing to see our society metamorphose into a brutal police state, no coercive policy will come close to even limiting drug use, let alone eliminating it. Once we understand that the current assault on addicts creates greater insecurity for everyone and severe hardship for users, once we understand that stressing people chronically and mercilessly can in no way promote their capacity for healthy transformation, it becomes a straightforward matter to envision approaches that rely not on moralizing but on science and humane values. The indispensable foundation of a rational stance toward drug addiction would be the decriminalization of all substance dependence and the provision of such substances to confirmed users under safely controlled conditions. Legalization would make manufacturing and selling drugs legal, acceptable commercial activities. Decriminalization refers only to removing from the penal code the possession of drugs for personal use. It would create the possibility of medically supervised dispensing when necessary. The fear that easier access to drugs would fuel addiction is unfounded: drugs, we have seen, are not the cause of addiction. Despite the fact that cannabis is openly available in Holland, for instance, Dutch per-capita use of marijuana is half that in the United States. Decriminalization also does not mean that addicts will be able to walk into any pharmacy to get a prescription of cocaine. Their drugs of dependence should be dispensed under public authority and under medical supervision, in pure form, not adulterated by unscrupulous dealers. Addicts also ought to be offered the information, the facilities and the instruments they need to use drugs as safely as possible. The health benefits of such an approach are self-evident: greatly reduced risk of infection and disease transmission, much less risk of overdose and, very importantly, comfortable and regular access to medical care. Not having to spend exorbitant amounts on drugs that, in themselves, are inexpensive to prepare, addicts would not be forced into crime, violence, prostitution or poverty to pay for their habits. They would not have to decide between eating or drug use, or to scrounge for food in garbage cans or pick cigarette butts out of sidewalk puddles. I admit I am ambivalent about the decriminalization of certain drugs, particularly crystal meth, and I understand why some people would resist even discussing the possibility. But if it seems bizarre to suggest that such a potentially brain-toxic drug be legally administered to addicts, consider that the street products currently available are full of impurities, mixed with noxious chemicals that magnify the damage from the stimulant itself. By bringing the crystal meth addict into a therapeutic interaction with the health care system, we would be fostering the possibility of use and gradual detoxification and withdrawal under relatively safe circumstances—relatively, because there is no safe way to use crystal meth. Above all, such an approach would create a basis for gently shepherding the addict toward rehabilitation. It would provide an opportunity to create a healing relationship with users who are currently relegated to streets and back alleys. Further, if many users no longer had to turn to illicit drug labs and dealers for their substance, the underground economy of crystal meth would be deprived of much of its profit and allure. As we discussed in Chapter 3, some young street people who use crystal meth see it as a way of survival. If the necessary physical, psychological and social supports were provided, I believe it would not take long to diminish the appeal of methamphetamine and to wean the vast majority of stimulant addicts away from this harmful chemical. Many people fear that decriminalization and the controlled dispensing of drugs will lead to widespread substance use among people who are now deterred from becoming addicts only by existing legal prohibitions. Like other tenets of the War on Drugs, this view entirely lacks supporting evidence. For example, for many decades in the United Kingdom, heroin has been dispensed, under legal supervision, to addicts. The same type of program has been offered on a limited basis in other countries as well, and nowhere has it been found that this measure served in any way to entice unaddicted people into addiction. That is not surprising, given that addiction is a response to life experience, not simply to a drug. People who do not suffer the searing emotional pain that drives hardcore drug addiction will rarely fall into dependency on chemicals, even if these were more readily available—and, once more, public access to habit-forming substances is not being proposed. The call for the decriminalization of drugs for personal use does not imply legal acceptance of drug dealing. Criminalization and prevention are not identical—if anything, the first undermines the other. Paradoxical though it may seem, current drug laws against possession make drugs more readily available to potential new users than decriminalization would. Only the War on Drugs creates the raison d’être of the international trafficking industry, most of whose wealth is based on satisfying the cravings of established drug addicts. Without the exorbitant profits yielded by supplying to addicted users desperate for their substances, the illegal market would shrink to a fragment of its present size. Further, much of the street-level front-line sales force of the illicit drug trade consists of users raising money to support their habit. With the decriminalization of possession for personal use and the medically supervised distribution of drugs, the incentive to sell to new “customers,” including young kids, would largely evaporate. Policing resources could then be concentrated on the remaining large-scale traffickers—if any. Addicts should not be coerced into treatment, since in the long term coercion creates more problems than it solves. On the other hand, for those addicts who opt for treatment, there must be a system of publicly funded recovery facilities with clean rooms, nutritious food and access to outdoors and nature. Well-trained professional staff need to provide medical care, counselling, skills training and emotional support. Our current nonsystem is utterly inadequate, with its patchwork of recovery homes run on private contracts and, here and there, a few upscale addiction treatment spas for the wealthy. No matter how committed their staff and how helpful their services may be, they are a drop in comparison to the ocean of vast need. In the absence of a coordinated rehabilitation system, the efforts of individual recovery homes are limited and occur in a vacuum, with no follow-up. It may be thought that the cost of such a drug rehabilitation and treatment system would be exorbitant. No doubt the financial expenses would be great—but surely less than the funds now freely squandered on the War on Drugs, to say nothing of the savings from the cessation of drug-related criminal activity and the diminished burden on the health care system. To expect an addict to give up her drug is like asking the average person to imagine living without all her social skills, support networks, emotional stability and sense of physical and psychological comfort. Those are the qualities that, in their illusory and evanescent way, drugs give the addict. People like Serena and Celia and the others whose portraits have appeared in this book perceive their drugs as their “rock and salvation. We have to demonstrate that esteem, acceptance, love and humane interaction are realities in this world, contrary to what she, the addict, has learned all her life. It is impossible to create that island for people unless they can feel secure that their substance dependency will be satisfied as long as they need it. One of the greatest difficulties we human beings seem to have is to relinquish long-held ideas. One fixed image we cling to , as iconic in today’s culture as the devil was in previous ages, is that of the addict as an unsavoury and shadowy character, given to criminal activity. There is nothing more intrinsically criminal in the average drug user than in the average cigarette smoker or alcohol addict. The drugs they inject or inhale do not themselves induce criminal activity by their pharmacological effect, except perhaps in the way that alcohol can also fuel a person’s pent-up aggression and remove the mental inhibitions that thwart violence. Stimulant drugs may have that effect on some users, but narcotics like heroin do not; on the contrary, they tend to calm people down. It is withdrawal from opiates that makes people physically ill, irritable and more likely to act violently—mostly out of desperation to replenish their supply. The criminality associated with addiction follows directly from the need to raise money to purchase drugs at prices that are artificially inflated owing to their illegality. The addict shoplifts, steals and robs because it’s the only way she can obtain the funds to pay the dealer. History has demonstrated many times over that people will transgress laws and resist coercion when it comes to struggling for their basic needs—or what they perceive as such. Sam Sullivan, Vancouver’s quadriplegic mayor, told a conference on drug addiction once that if wheelchairs were illegal, he would do anything to get one, no matter what laws he had to break. It was an apt comparison: the hardcore addict feels equally handicapped without his substances. As we have seen, many addicts who deal in drugs do so exclusively to finance their habit. As this book is being completed, the disturbing details of the serial murder case against pig farmer Robert Pickton are emerging in a British Columbia courtroom. If convicted, Pickton will be counted among the most prolific and most sadistic killers of women in North American history. I believe that as a society we are unwitting accomplices in the deaths of the Downtown Eastside women who allegedly became Pickton’s victims because our criminalization of drug use drove those women into prostitution and into the underground street life that led to their deaths. If an evidence based policy had been in operation in this country, these dozens of women—and their many counterparts elsewhere—might still be alive. On the immediate practical level, we would feel safer in our homes and on our streets and much less concerned about the danger of our cars being burgled. In cities like Vancouver such crimes are often committed for the sake of obtaining drug money. More significantly perhaps, by exorcising this menacing devil of our own creation, we would automatically give up a lot of unnecessary fear. Many addicts could work at productive jobs if the imperative of seeking illegal drugs did not keep them constantly on the street. It’s interesting to learn that before the War on Drugs mentality took hold in the early twentieth century, a prominent individual such as Dr. William Stewart Halsted, a pioneer of modern surgical practice, was an opiate addict for over forty years. During those decades he did stellar and innovative work at Johns Hopkins University, where he was one of the four founding physicians. He was the first, for example, to insist that members of his surgical team wear rubber gloves—a major advance in eradicating post-operative infections. Throughout his career, however, he never got by with less than 180 milligrams of morphine a day. Here was a man with almost unlimited resources— moral, physical, financial, medical—who tried everything he could think of and he was hooked until the day he died. But surely, if their substance needs were met, they would have much greater opportunity to realize their potential to be creative and contributing members of society. Decriminalization of drug use would establish the possibility of integrating addicts into the larger community, an essential step if they are to be rehabilitated in any large numbers. In Chapter 1 I introduced Stan, a Native Canadian man, an addict and street dweller just out of jail. On chilly nights Stan should not be sleeping on stone steps under an archway in the Downtown Eastside. Without having to steal to support his drug habit, he would not have lived in prison the past eighteen months but in a recovery home or, if still needing to use, in a decent housing facility. He ought to be receiving remedial training for his learning disabilities and counselling to help him overcome the emotional defensiveness and impulsive reactivity that has so often landed him in trouble. Seeking insight into my First Nations patients, I spoke with psychiatrist Lewis Mehl-Madrona, author of Coyote Medicine: Lessons from Native American Healing and Associate Professor of Family Medicine and Psychiatry at the University of Saskatchewan. Unless people have another community, an alternative community that provides them with more belonging, being wanted, and purpose, the so-called treatment always fails. What seems to work here for aboriginal people is to switch their allegiance to an alternative community, modern but honouring traditional values. As long as they can maintain their position in that non-using community, they are not using substances. They need to be invited into communities that can offer them acceptance, belonging and value. At least transitionally, such communities have to be founded and maintained with public support until, step by step, former users are fully able to join society at large. Those unable to give up their habits ought not to be ostracized, nor should their voices be excluded from social discourse. If we understood the sources of their dysfunction, we would want to reduce their suffering, whether or not they continue to use. We need to wake to the reality that our present system actively generates misery for users and nonusers alike and places intolerable burdens on society. At the same time, 14 per cent is spent on treatment, 7 per cent on research, and 3 per cent each for addiction prevention and harm reduction. She came late, panting into my office with a high fever and a strangulating cough. Her pneumonia had begun several days before that, when she woke up after one of Vancouver’s heavy windstorms to find that the windows of her hotel room had been shattered during the night and the water in her sink was frozen solid. In a commentary published in the Globe’s web edition I summarized Serena’s history and explained that she deals drugs only to support her own cocaine habit. The piece ignited a lively set of exchanges at the newspaper’s website, indicating how deeply felt are the views of many people on the issue of drug addiction.

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