Also of interest are studies of interferon-a, used for the treatment of hepatitis or cancer, which results in depressive-like symptoms in a large number of patients. Here we discuss a few of the most interesting targets for treatment of depression; for a more thorough review see ref 167. TNFα and depression One of the most consistently altered proinflammatory cytokines in depressed subjects is TNFα. An inverse correlation between levels of TNFα and treatment response has been reported.168,169 TNFα immunotherapy also causes depression, indicating Inhibitors,research,lifescience,medical that this cytokine may contribute to the etiology of mood disorders and is not simply a marker for

depression (for reviews see refs 168,170). Moreover, a recent large clinical trial using an antibody neutralization approach demonstrated significant antidepressant effects of TNFα reduction.171 This finding is supported by preclinical studies demonstrating that TNFα infusions produce a prodepressive effect,172 and that TNFα receptor null mutant mice have an antidepressant phenotype in the forced swim Inhibitors,research,lifescience,medical and sucrose Inhibitors,research,lifescience,medical consumption tests.173

Taken together, the preclinical and clinical studies provide strong support for TNFα receptors, particularly TNFR2, as targets for the treatment of mood disorders. IL-1β, stress, and depression There is also strong evidence that the proinflammatory cytokine IL-1β plays a key role in the pathophysiology of stress and depression, and that the IL-1β signaling is a relevant target for drug development.174,175 These findings

include: i) clinical studies reporting an increase in serum levels IL-1β in MDD176-180;ii) reports that IL-ip produces Inhibitors,research,lifescience,medical stress like effects, including activation of the IIPA axis, regulation of monoamines, and behavioral responses in rodent models181; iii) evidence that IL-1β contributes to conditioned Inhibitors,research,lifescience,medical fear and depressive like behavior,182 and produces anhedonia and disrupts incentive motivation in rodent models183; iv) preclinical reports that IL-1β decreases hippocampal neurogenesis and underlies the decrease observed in response to stress184; v) our report that CUS-induced anhedonia and decreased neurogenesis produced by is blocked by pharmacological inhibition or null mutation of IL-1β receptors.184 Studies are currently underway to determine if blockade of peripheral, as well as central IL-1β signaling is sufficient to block the effects of stress and produce almost antidepressant actions. Interferon and IDO Recent studies demonstrate that one of the key factors contributing to the depressive actions of inflammation and activation of the innate immune system is the induction of a tryptophan degradative enzyme, indoleamine 2,3-dioxygenase (IDO). Chronic inflammation and infection can lead to sustained induction of interferon, which is then responsible for the Verteporfin supplier increased levels of IDO.

Briefly, a solution of drug and polymer (10–20% polymer concentration) in dichloromethane was injected into an aqueous continuous phase at a ratio between 250 and 350 parts of polymer phase:aqueous phase, under stirring with a Silverson

L4R mixer (Silverson machines, MA, USA) at 5000rpm. Subsequently, #Camptothecin in vivo randurls[1|1|,|CHEM1|]# the solvents were removed by stirring after which the microspheres were recovered by filtration, suspended in a suitable vehicle, filled into vials, and freeze-dried. The microspheres were characterized as described Inhibitors,research,lifescience,medical in Section 2.3. 2.3. Characterization of Microspheres 2.3.1. Particle Size Particle size distribution of the microspheres prior to vialing was determined using a laser Inhibitors,research,lifescience,medical diffraction technique (Malvern 2600c Particle Sizer, Malvern, UK). The particles were suspended in 0.05% Tween 80 and counted using a laser sensor [41]. The average particle size was expressed as volume mean diameter in microns (μm). 2.3.2. Surface Morphology The surface morphology was examined by scanning electron microscopy (SEM) (Hitachi S800, Japan) at an appropriate magnification, after Inhibitors,research,lifescience,medical palladium/gold coating of the microsphere sample on an aluminum stub. 2.3.3. Bulk Density Bulk density of the microspheres was determined by transferring a weighed amount of microspheres to a graduated cylinder. The cylinder was subsequently tapped 50 times from

a vertical distance of approximately Inhibitors,research,lifescience,medical 0.5 inches and the occupied volume recorded. The tapping process was repeated until the volume occupied by particles remained unchanged. The final volume was recorded as bulk volume,

Vb, and the tapped bulk density (g/cc) was calculated as M/Vb, where “M” was the weight of microspheres employed. 2.3.4. Drug Content Risperidone content in the microspheres was analyzed by a reverse phase HPLC method using a Nucleosil C-18 column (Phenomenex, Torrance, CA) at a flow rate of 1 mL/min. The mobile phase consisted of 30% v/v acetonitrile and 0.1% (v/v) trifluoroacetic acid in water. Drug content (%) was expressed as the “weight of drug in microspheres/weight of microspheres × 100.” 2.3.5. In Vivo Studies In accordance Inhibitors,research,lifescience,medical with Institutional Guidelines and an in-house Methisazone developed and an approved protocol, four groups of male Sprague-Dawley rats (Harlan Inc., Indianapolis, IN) weighing approximately 300gm were used in the in vivo study. Group 1 received Formulation A, Group 2 received Formulation B, Group 3 received Formulation C, and Group 4 received Formulation D. Briefly, vials containing freeze dried microspheres along with diluent were reconstituted with WFI (water for injection) and injected subcutaneously at the base of the rat neck at a dose of 20 or 40mg/kg Risperidone (Table 1). Blood was sampled from the rat tail vein at predetermined intervals, after which the samples were centrifuged in Microtainer tubes (Becton Dickinson & Co., Franklin Lakes, NJ) and serum was collected.

Clinical consequences: TDM useful to control whether plasma concentrations are plausible for a given dose; optimizing of clinical response In nonresponders who display low concentrations Is possible. 4. Probably useful Suggested therapeutic ranges from steady-state pharmacokinetic studies

at therapeutically effective doses. Level of evidence: Valid clinical data so far lacking or Inconsistent results. Clinical consequences: Inhibitors,research,lifescience,medical TDM useful to control whether plasma concentrations are plausible for a given dose. 5. Not recommended Unique pharmacology of the drug, eg, irreversible blockade of an enzyme or flexible dosing according to clinical symptoms. Level of evidence: Textbook knowledge, basic pharmacology. Clinical consequences: TDM should not be used. Drug-specific TDM recommendations The knowledge of plasma concentrations ranges observed

after treatment of subjects at well-defined doses of the antidepressant Inhibitors,research,lifescience,medical (Table III) may efficiently help the clinician In some of the situations listed in Table II: suspicion of noncompliance, drug Interactions, problems occurring after switching from an original preparation to a generic form (and vice versa), or presence of a pharmacogenetic PM or UM status. The information available in Table III is also helpful In situations where the levels of recommendations 3 and 4 apply (le, TDM useful or probably useful). Table Inhibitors,research,lifescience,medical III. Dose-related steady-state plasma concentrations of antidepressants.11 Generally, arithmetic means ± standarad deviations are given; numbers in parentheses

indicate ranges. md# Inhibitors,research,lifescience,medical median value; gm, geometric mean; m, males; f, females. *Extensive … However, the data presented In Table III are Insufficient to allow levels of recommendations Inhibitors,research,lifescience,medical 1 or 2, as It does not Include studies on the plasma concentration–clinical effectiveness relationship. Therefore, the literature had to be reexamined to define which antidepressants may get a level 3 or 4 of recommendation for their monitoring. By consensus, a therapeutic range was then also defined for their “main” (= depression) indication (Table IV), as data for other indications (eg, anxiety disorders) are most often lacking, and some studies suggest that optimal ranges may differ, depending on the pathology154 Antidepressants differ widely in their chemical structure and their pharmacological activity, even though most are serotonergic isothipendyl and/or noradrenergic. “Therapeutic windows” have been defined for most tricyclic antidepressants, and TDM is recommended to avoid intoxications, which may be lethal (Table IV), As regards more check details recently introduced antidepressants, a clearcut plasma level–clinical effectiveness relationship was not demonstrated for tetracyclic antidepressants (maprotiline, mianserin, or mirtazapine), trazodone, reboxetine, the monoamine oxidase inhibitors mocloberoide and tranylcypromine,133 and SSRls.

More severe forms of the disorder require progressive sleep phase delay in 3-hour steps round the clock until a satisfactory timing is achieved which then has to be fixed. Additional measures to maintain

the improved sleep schedule include early-morning exposure to bright light and firm agreement with the adolescent to maintain a new pattern of social activities and sleep. Melatonin in the evening might also help. Difficulties achieving and maintaining an improved sleep-wake schedule by these means are compounded Inhibitors,research,lifescience,medical if there is a vested interest in maintaining the abnormal sleep pattern, for example, to avoid school (“motivated sleep phase delay”). Psychological problems, including depression, may well also make successful treatment less likely. Inhibitors,research,lifescience,medical The teenager’s reluctance to go to bed earlier and to get up at the required time is often misinterpreted as “typical difficult adolescent behavior” causing trouble in the MM-102 chemical structure family. Otherwise the condition might be mistakenly viewed as the usual form of school non attendance, primary depression, or substance misuse. Differential diagnosis of childhood parasomnias Parasomnias are repetitive unusual behaviors or strange experiences

that occur just before, during, or arising Inhibitors,research,lifescience,medical out of sleep, or on waking. The many parasomnias (some primary sleep disorders, others secondary to medical or psychiatric conditions) now officially recognized (over 30 in ICSD-2)

indicate how commonly and in many ways (some subtle, others dramatic) sleep can be disturbed by episodic events. Confusion between the different parasomnias seems to be common. For Inhibitors,research,lifescience,medical example, in pediatric textbook accounts, sleep terrors and nightmares (two very different types of parasomnia) are mistaken for each other. Indeed, sometimes there is a tendency to call any dramatic parasomnia a nightmare. Correct diagnosis is important Inhibitors,research,lifescience,medical because different parasomnias each have their own significance and call for contrasting types of advice and treatment. The following brief account is concerned with the main features to be recognized in reaching the correct diagnosis. Fiiiphasis is placed on just some those of the more dramatic parasomnias (namely arousal disorders, nightmares, and sleep-related epileptic seizures) as these often cause most confusion and concern. Detailed accounts of these parasomnias and others are provided elsewhere.24 Often an accurate diagnosis can be made by means of a detailed account of the subjective and objective sequence of events from the onset of the episode to its resolution, and of the circumstances in which the episode occurred, including its duration and timing. Audiovisual recording (including by means of home recording by parents) can be very informative and often adds details that are missed in descriptions given in the clinic.

” The dominant strategy for repairing a broken, injured, or damaged brain was to replace the lost neurotransmitters (for example, providing L-dopa for Parkinson’s disease [PD], which works pretty well for a while) or, more experimentally, to replace the missing or dead neurons (as in neural

transplantation for treating Inhibitors,research,lifescience,medical PD, Huntington’s disease [HD], Alzheimer’s disease, amyotrophic lateral sclerosis, or spinal cord injury). The replacement of dead cells by transplantation of externally derived cells continues both experimentally and clinically and, with the new hope provided by the Wortmannin order availability (albeit limited) of the pluripotent human embryonic stem cells, Inhibitors,research,lifescience,medical optimism for transplantation therapy has been renewed. The previously accepted dogma of adult neural stability is now being called into question. Pioneering studies by Raisman,3

Bjorklund;’ and Aguayo5 and their colleagues in the 1960s and 1970s revealed that damaged axons could grow under some extraordinary circumstances. These studies have led to a recent stampede of very promising work that could lead to the regeneration of cut or damaged axons due to spinal cord injury.6 A deeper blow to the dogma of adult neural stability has been the recent acceptance of the ability Inhibitors,research,lifescience,medical of certain areas of the adult brain to generate new neurons throughout life, known as adult Inhibitors,research,lifescience,medical neurogenesis. Early evidence of this ability was generated by Altman and colleagues in the 1960s and 1970s,7 and was beautifully extended to birds by Goldman and Nottebohm in the 1980s,8 and later to nonhuman primates and humans in the 1990s.9 During this same period, it was discovered that adult neurogenesis itself was not stable and

predictable, but was, in fact, highly regulated by experience, with stress and aging decreasing neurogenesis and environmental enrichment and Inhibitors,research,lifescience,medical exercise increasing neurogenesis. Stem cells in the adult brain The surprising observation that neurogenesis continues in the adult nervous system has led to the discovery that there are stem cells in the adult brain that generate the new neurons. A stem cell is an uncommitted cell that, when it divides, can give rise to itself (self-renewal) and can also Oxalosuccinic acid give rise to any or all of the three main cell lineages of the brain: neurons, astrocytes, and oligodendrocytes. Using a variety of methods, it is now possible to isolate these stem cells from the adult brain and use specific growth factors, like fibroblast growth factor (FGF) and epidermal growth factor (EGF), to induce them to divide indefinitely in culture dishes in the laboratory. .Most of the studies that have determined that the cells from the brain are stem cells have done so by studying the cells in vitro; the demonstration of “sternness” in vivo in the adult brain is difficult.

For all drugs and dosages, the most popular choice was increasing the dosage, followed by augmenting with lithium or another antidepressant, or changing to a different drug. Conclusion The question of nonresponse is clearly important and has to be considered within the recent evolution of psychiatric classification and treatment. First, traditional classifications are being increasingly criticized for failing to define homogeneous patient groups, who might respond in a predictable

way to a specific treatment. The fact that psychiatric classification is in a state of flux is exemplified by the ongoing revision process of Inhibitors,research,lifescience,medical DSM. Research in neuroscience is expected to play a major part in the preparation of DSM-V.35 The necessity for a classification that could better guide treatment choice is manifest. Second, psychopharmacology is changing. Inhibitors,research,lifescience,medical There is an evolution from drugs directed at symptoms toward drugs directed at syndromes and the http://www.selleckchem.com/products/dinaciclib-sch727965.html pathophysiology Inhibitors,research,lifescience,medical of psychiatric disorders. New drugs

are being evaluated for their overall efficacy, eg, for their efficacy on syndromes and cognition, rather than on a single symptom. More is required today from treatment methods. Patients and clinicians are no longer satisfied with a mere reduction in symptoms. Etiological treatment is an ideal; in some cases, this ideal might become reality. The notion

of nonresponse is best understood in its historical dimension. Our opinion is still influenced by traditional thought patterns. Inhibitors,research,lifescience,medical However, nonresponse is likely to be envisaged quite differently in the near future. A few tasks will remain crucial, such as the definition of criteria for treatment response, and the delineation of factors that exert a negative influence on drug efficacy. The problem of nonresponse Inhibitors,research,lifescience,medical exists in all domains of medicine. It is crucial for patients and their families to understand that the physicians did ail they could and offered the best available treatments to patients who remained nonresponders.
One of the elusive goals of pharmacotherapy is the ability to identify the relevant characteristics of a. patient with a particular disorder in such a way as to permit, selection of the best pharmacological DNA ligase agent: the medication with the greatest, likelihood of effectiveness and the least, likelihood of adverse or undesirable effects. Despite the considerable number of treatments in our psychotherapeutic armamentarium, any individual treatment applied to a group of persons with a given disorder will leave an un acceptably high percentage nonresponsive, again consequent, to lack of efficacy or inability to tolerate the treatment. To increase the odds of therapeutic success, it.

79,80 Yet, as we have seen, while neuron loss and LB formation are widespread in PD, they are also highly select in targeting only particular cell groups and generally sparing all but a few circumscribed regions of cortex.74,81 This serves to distinguish idiopathic PD from Lewy body dementia (LBD), a much rarer condition in which the neurodegenerative changes are qualitatively indistinguishable from those of PD yet differ sharply in quantitative terms.82-84 In LBD, unlike Inhibitors,research,lifescience,medical PD, there is diffuse and severe cortical involvement, which appears to explain the prominent

cognitive decline that appears early in LBD, but is seldom a feature of PD. Autonomic nervous system Autonomic disturbances in PD are frequent, and varied, due to cell loss and LB pathology involving both preganglionic and postganglionic components of both the sympathetic and parasympathetic nervous systems.85-87 The earliest, pathological changes in PD are in fact, extranigral,

beginning with formation of LBs and loss of cholinergic neurons within the dorsal glossopharyngcus-vagus Inhibitors,research,lifescience,medical complex.37,45 Progressive loss of these preganglionic parasympathetic neurons is Inhibitors,research,lifescience,medical one of the factors contributing to the dysphagia and esophageal dysmotility that occur frequently in PD patients.88,89 Postganglionic parasympathetic cell loss and LB pathology within upper portions of the myenteric plexus account for the esophageal and gastric dysmotility syndromes that, are common accompaniments of PD87; esophageal involvement, when severe, can Inhibitors,research,lifescience,medical be indistinguishable from achalasia.90 Involvement of the colonie myenteric plexus in PD is associated with constipation and more severe forms of colonic inertia,

depending on the magnitude of cell loss.86 One of the most common disturbances in PD is orthostatic hypotension, Inhibitors,research,lifescience,medical presumably resulting from the characteristic loss of preganglionic sympathetic neurons in the intermcdiolateral nucleus of the thoracic spinal cord.91 Destruction of postganglionic neurons within the sympathetic chain results in sympathetic denervation of the heart, as indicated by diminished Silmitasertib cardiac uptake of a tracer that, uses the same neuronal transport mechanism as NA.92 While the clinical effects of cardiac sympathetic denervation are unknown, the diagnostic significance may be considerable.93 Evidence heptaminol of cardiac sympathetic denervation occurs early and often in PD, but not in other forms of parkinsonism, such as multiple system atrophy.94 Etiopathogenesis Although the etiology and pathogenesis of sporadic PD have yet to be established, several predisposing factors and pathogenic pathways have been implicated. Among the latter are oxidative stress associated with mitochondrial dysfunction,95-98 proteolytic stress due to dysfunction of the ubiquitin-proteasome system (UPS),99,100 and local inflammation.

2006; van Kuijk et al. 2009). Patients older than 80 years of age or patients with diabetes were excluded by study design in many clinical trials (Ali et al. 2007; Hausenloy et al. 2007; Hoole et al. 2009b; Venugopal et al. 2009, 2010; Rahman et al. 2010; Thielmann et al. 2010; Choi et al. 2011). A subgroup analysis in the study by Pedersen et al. (2012) suggests that age stratification might have an important role in the selection of patients who should undergo RIPC procedures (Pedersen et al. 2012; Tweddell 2012), and this potential confounder should be seriously taken into account Inhibitors,research,lifescience,medical when interpreting the available trial data. In all trials, no

severe local adverse events were observed, except in the study by Walsh et al. Inhibitors,research,lifescience,medical (2009) with iliac cross-clamping, in which three patients died (asystole, myocardial infarction, and cardiac arrest) and four patients developed lower limb ischemia requiring intervention. Minor local adverse events

occurred in the study by Cai et al., with slight skin erythema developing in two patients and a temporally constriction feeling in one patient after RIPC (Li et al. 2013). In addition, a phase Ib study of 33 patients by Koch et al. (2011) confirmed that RIPC with limb ischemia is feasible, safe, and well tolerated in alert patients with subarachnoid hemorrhage. Therefore, we may hypothesize that RIPC Inhibitors,research,lifescience,medical protocols with limb ischemia are potentially safe and hence can be tested with safety in larger scale randomized clinical trials. Most of the trials focused on postoperative cardiac and/or renal function after RIPC with conflicting results (Tables ​(Tables4).4). Preconditioned patients undergoing abdominal Inhibitors,research,lifescience,medical aneurysm artery repair were found to have lower rates of renal injury when compared with controls in a metanalysis by Alreja et al. (2012). In the same metanalysis, RIPC was related

to lower levels of postoperative myocardial injury, although the results from the trials that Inhibitors,research,lifescience,medical were analyzed were highly heterogeneous (Alreja et al. 2012). In another metanalysis of randomized clinical trials, Pilcher et al. (2012) found that 12 h after open cardiac surgery, RIPC subgroups had significantly lower troponin levels compared with controls. However, Nature Immunology there is see more uncertainty regarding the correctness of the aforementioned result due to the statistical heterogeneity between the studies, as the effect of RIPC on postoperative troponin concentration was significantly milder in fully blinded studies, compared with partially blinded (Pilcher et al. 2012). Similarly, in a metanalysis by Brevoord et al. (2012), troponin release and the incidence of periprocedural myocardial infarction were both significantly decreased in preconditioned patients undergoing cardiac surgery, PCI, or vascular surgery. However, no difference in mortality rates or major adverse cardiovascular events has been found between RIPC subgroup and controls (Brevoord et al. 2012).

The use of miRNAs as a peripheral biomarker in MDD is gaining momentum. Belzeaux et al examined miRNA expression profiles in peripheral blood mononuclear cells (PBMCs) collected from

16 severe MDD patients and 13 matched controls at baseline, and 2 and 8 weeks after AC220 mw treatment (Table I). 179 A comparison of miRNA expression between MDD patients and controls at baseline and at 8 weeks showed a similar Inhibitors,research,lifescience,medical number of dysregulated miRNAs (14 miRNAs, with 9 miRNAs upregulated and 5 downregulated). miRNAs that showed changes between MDD and controls at base line included: has-miR-107, miR-133a, miR-148a, miR-200c, miR-381, miR-425-3p, miR-494, miR-517b, miR-579, miR-589, miR-636, miR-652, miR-941, and miR-1 243. Only two miRNAs showed stable overexpression in MDD patients during the 8-week follow-up compared with controls (miR-941 and miR-589). They also identified miRNAs exhibiting significant variations of expression among patients Inhibitors,research,lifescience,medical with clinical improvement (7 upregulated and

1 downregulated). Fourteen dysregulated miRNAs had putative mRNA targets Inhibitors,research,lifescience,medical that were differentially expressed in MDD, suggesting that a common RNA regulatory network functions in MDD. These results suggest the potential utility of miRNA signatures as markers of major depressive episode evolution. Bocchio-Chiavetto et al conducted a whole-miRNA ome quantitative analysis in the blood of 10 MDD subjects after 12 weeks of treatment with escitalopram (Table I).180 They Inhibitors,research,lifescience,medical found that 30 miRNAs were differentially expressed after the escitalopram treatment: 28 miRNAs were upregulated, and two miRNAs were downregulated. Thirteen (let-7d, let-7e, miR-26a, miR-26b, miR-34c-5p, miR-103, miR-128, miR-132, miR-183, miR-192, miR-335, Inhibitors,research,lifescience,medical miR-494, and miR-22) play a role in neural plasticity and stress response and in the pathogenetic mechanisms of several neuropsychiatric

diseases. miR-132 exerts critical functions in the biological circuits implicated in neurogenesis and synaptic plasticity, stimulating axonal and dendritic outgrowth in different brain areas.181 This miRNA, together with miR-26a, miR-26b, and miR-183, widely contributes to PDK4 the action of the neurotrophin BDNF in the brain.103,134,182,183 miR-132, miR-26a, miR-26b, miR-183, let-7d, let-7e, miR-26b, miR-103, miR-128, miR-494, and miR-22 have been reported to play a role in the pathogenesis of psychiatric disorders and in the mechanism of action of antipsychotic drugs and mood stabilizers. Moreover, postmortem studies on the brains of bipolar disorder patients showed increased levels of miR-22* in the prefrontal cortex.184 On the other hand, miR-494 and miR-335 are downregulated in the prefrontal cortex of MDD patients.

These observational studies have now sparked the conduct of large-scale randomized controlled trials currently ongoing in cancer. We show in this paper that the spectacular effects on new indications or new outcomes reported in many observational studies in chronic obstructive pulmonary disease (COPD), HRT, and cancer are the result of time-related biases, such as immortal time bias, that tend to seriously exaggerate the benefits of a drug and that eventually disappear with the proper statistical analysis. In all, while observational studies are central to assess the effects of drugs, their proper Inhibitors,research,lifescience,medical design and analysis are essential to avoid bias. The scientific

evidence on the potential beneficial effects in new indications Inhibitors,research,lifescience,medical of existing drugs will need to

be more carefully assessed before embarking on long and expensive unsubstantiated trials. Keywords: Cohort studies, drug effectiveness, drug indications, observational studies, randomized controlled trials, scientific evidence INTRODUCTION The randomized controlled trial is the fundamental paradigm to evaluate the effectiveness of medications in the clinical setting. It is the essential study Inhibitors,research,lifescience,medical design required by regulatory agencies to approve the marketing of a drug or a new indication for an existing drug. Despite extensive pre-approval trials, medications can have important Selleck Adriamycin unintended side-effects even if used properly. The epidemiological approach of observational studies has been recognized as an essential tool to address post-marketing drug safety issues and study the actual effects of medications as used in the population, a different Inhibitors,research,lifescience,medical situation from the experimental setting in which the drugs were developed and approved. This approach is particularly important for less frequent but severe adverse events or long-term adverse effects that cannot and could not be detected by the randomized trials required for

initial drug approval. Moreover, the use of existing computerized databases arising from the routine collection of data in the usual care of patients has become essential for the rapid conduct Inhibitors,research,lifescience,medical of these observational studies in this field called pharmacoepidemiology. For example, health care databases worldwide have been used to rapidly assess the risks and benefits of several drugs such as NSAIDs, beta-agonists, anti-depressants, anti-hypertensives, statins, gastric-acid suppressants, corticosteroids, and many others, on major disease Immunity – Cell outcomes.1–9 Another less common situation where observational studies have been used is to uncover new indications for drugs that are already on the market or to assess the effectiveness of such available drugs in the same indication but on new outcomes not studied in pre-approval trials. An example of the effectiveness of a drug on new outcomes is that of hormone replacement therapy (HRT), an effective treatment for menopausal symptoms.