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Platelet-Active Drugs: The Relationships Among Dose, Effectiveness, and Side Effects. part 42
Both abciximab therapy and stenting were studied in the Controlled Abciximab (ReoPro) and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) trial of patients with MI. In this group of patients, who appeared to be at a relatively low risk (Table 8), abciximab had a beneficial effect in the PTCA group but did not affect death or reinfarction in the stent group.
Abciximab was compared to tirofiban as treatment for PCI in the TARGET study (Table 8). Abciximab treatment was found to be associated with a statistically significant lower rate of ischemic complications after 30 days, but at 6 months the differences were less appar
Five completed trials have examined the efficacy and safety of tirofiban, lamifiban (a nonpeptide GPIIb/IIIa blocker the development of which has been discontinued), and eptifibatide in approximately 25,000 patients with acute coronary syndromes without persistent ST-segment elevation who were randomized to receive a GPIIb/IIIa antagonist or placebo, in addition to conventional antithrombotic therapy (Table 9).i2,2 These studies demonstrated a 0 to 27% reduction in the RR of MI or death at 30 days. Both eptifibatide and tirofiban have received approval from the FDA for the treatment of acute coronary syndromes, including patients who are to be managed medically and those undergoing PCI. However, in the GUSTO IV-ACS trial, abciximab therapy (0.25 mg/kg bolus followed by a 0.125 g/kg/min infusion) for 24 or 48 h was not beneficial as a first-line medical treatment in patients with acute coronary syndromes. A meta-analysis of all major randomized clinical trials of GPIIb/IIIa antagonists in patients with acute coronary syndromes who were not routinely scheduled to undergo early coronary revascularization suggested a 9% reduction in the odds of death or MI at 30 days. However, the true size of the additional benefit resulting from short-term, high-grade blockade of GPIIb/IIIa combined with standard antithrombotic therapy is somewhat uncertain, since the 95% CI ranged from 2 to 16%. Moreover, the 1% absolute difference in death or MI was balanced by an absolute excess of 1% in major bleeding complications associated with GPIIb/IIIa antagonists vs control. The Platelet IIb/IIIa Antagonist for the Reduction of Acute coronary syndrome events in a Global Organization Network (PARAGON)-B Investigators have reported that dose-titrated lamifiban had no significant effects on clinical outcomes in patients with non-ST-segment elevation acute coronary syndromes and yet caused excess bleeding, thus reinforcing the uncertainty noted above. Of note, a subgroup analysis of these studies identified a consistent and significant mortality advantage for patients with diabetes, even in the GUSTO IV-ACS study, raising the possibility that platelets may play a more important role in the pathogenesis of the ischemic damage in diabetic patients.
Platelet-Active Drugs: The Relationships Among Dose, Effectiveness, and Side Effects. part 41
Eptifibatide received approval from the FDA for use in
Table 8 —GPIIb/IIIa Antagonists in PCI
| Trial | Patients, No. | Compound | Placebo, % | GPIIb/IIIa Antagonist, % | RRR, % |
| EPIC | 2,099 | Abciximab | 10.3 | 6.9 | 30.0 |
| EPILOG | 2,792 | Abciximab | 9.1 | 3.8t | 58.2 |
| CAPTURE | 1,265 | Abciximab | 9.0 | 4.8 | 46.7 |
| EPISTENT | 1,603 | Abciximab | 10.2 | 4.8J | 52.9 |
| IMPACT-II | 4,010 | Eptifibatide | 8.4 | 6.9 | 17.9 |
| RESTORE | 2,139 | Tirofiban | 6.4 | 5.0 | 21.9 |
| ESPRIT | 1,023 | Eptifibatide | 9.2 | 5.5 | 40.0 |
| TARGET | 2,398 | Tirofiban | 7.2 | ||
| 2,411 | Abciximab | 5.7 | 21.8 | ||
| CADILLAC§ | |||||
| PTCA | 1,046 | Abciximab | 3.3 | 1.9 | 42.4 |
| Stent | 1,036 | Abciximab | 3.2 | 3.5 | -9.4 |
Rates of death or myocardial infarction at 30 days are shown. RRR = RR reduction; EPILOG = Evaluation in PTCA to Improve Long-term Outcome With Abciximab GPIIb/IIIa Blockade; CAPTURE = c7E3 Antiplatelet Therapy in Unstable Refractory Angina; EPISTENT = Evaluation of Platelet IIb/IIIa Inhibitor for Stenting Trial; TARGET = Tirofiban (Aggrastat) and ReoPro Give Similar Efficacy Outcomes Trial; CADILLAC = Controlled Abciximab (ReoPro) and Device Investigation to Lower Late Angioplasty Complications. tAbciximab plus low-dose heparin. jAbciximab plus stenting vs placebo plus stenting.
Death and reinfarction were recorded separately, not as a composite.
PCI in 1998 based on data from the IMPACT-II and PURSUIT trials, and the dosing was modified based on the efficacy demonstrated in the ESPRIT trial. The c7E3 Antiplatelet Therapy in Unstable Refractory Angina (CAPTURE) trial demonstrated the efficacy of treatment with abciximab for 18 to 24 h prior to PCI in patients with unstable angina who were refractory to conventional antithrombotic and antianginal therapy. The Evaluation in PTCA to Improve Long-Term Outcome With Abciximab GP IIb/IIIa Blockade (EPILOG) trial demonstrated the efficacy of abciximab therapy in a broad population of patients undergoing PCI, not just in high-risk patients, as in the EPIC and CAPTURE trials. The Evaluation of Platelet IIb/IIIa Inhibitor for Stenting (EPISTENT) trial demonstrated that abciximab therapy decreased the frequency of ischemic complications of PCI associated with stent insertion during the first 30 days, and that there also were fewer ischemic complications during this time period in patients who were treated with PCI and abcix-imab alone without stent insertion compared to those treated with stenting alone. Furthermore, the 1-year mortality rate difference was statistically significant between stenting alone (2.4%) and stenting plus abciximab therapy (1%), and this mortality rate difference was sustained for longer periods of time.
Challenges to Probiotic-Based Therapies
However, recently Lactobacillus salivarius and L fermentum strains were shown to enhance both natural and acquired immune responses, as evidenced by activation of NK cells and the expansion of Tregs, whereas Bifidobacterium infantis can induce Foxp3+ T cells that protect mice against Salmonella typhimurium infection. Therefore, it is likely both branches of the immune system contribute to LAB-induced protection against respiratory and Viagra online pathogens. In addition, a number of LAB can produce antibacterial compounds, including Lactobacillus plantarum, which can inhibit the induction of virulence factors and thus the pathogenicity of P aerogenosa, suggesting that intrinsic antibacterial effects of LAB could contribute to protection against respiratory pathogens if administered directly to the site of infection. 
Challenges to Probiotic-Based Therapies
It is likely that the antiinflammatory efficacy of a probiotic results from a combination of signaling pathways activated as a result of a specific pattern of microbe-derived ligands interacting with the corresponding receptors on host cells (Fig 2). Little is known, however, concerning the nature of the probiotic-host cell interactions, or how these interactions could be manipulated to obtain stronger regulatory responses. Factors to be considered include localization of particular bacteria in the GI tract and strain-specific cell wall components and metabolic products.
Although animal studies have provided clear evidence that certain LAB can have profound immu-noregulatory effects and regulate immune responses beyond the GI tract, the fact remains that the results of clinical trials have been highly variable. With particular regard to asthma there have been no beneficial effects reported. It is clear that candidate probiotic strains display a range of immune effects and therapeutic efficacies in specific disease states or model systems. However, strain differences are unlikely to explain all of the observed variability, as in clinical tests the same strains have produced conflicting results.
Active Drugs: Effectiveness and Side Effects
High-level inhibition of ADP-induced aggregation could be achieved soon after the bolus dose, but there was an early loss of inhibition of platelet aggregation before a steady state was achieved. Regimens employing a second bolus dose 30 min after the first were then studied (180 g/kg/2.0 g/kg/min plus a second bolus of 90 g/kg; 250 g/kg/2.0 g/kg/min plus a second bolus of 125 g/kg). From these studies, the dose used in the ESPRIT trial (ie, bolus dose of 180 g/kg, second bolus dose of 180 g/kg at 10 min followed by 2 g/kg/min infusion) was selected.
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Studies of patients with unstable angina undergoing PCI have demonstrated that a bolus dose of 180 g/kg followed by an infusion of 2.0 g/kg/min produced more complete and sustained inhibition of platelet function than did standard-dose therapy with abciximab (ie, 0.25 mg/kg bolus plus 0.125 g/kg/min infusion). In another, similar study, however, platelet inhibition produced 5 min after the bolus dose of abciximab was administered was greater than that produced by eptifibatide. In the Au-Assessing Ultegra (GOLD) study, patients with lower levels of inhibition of platelet function had the greatest risk of developing major adverse cardiac events.
A modest increase in hemorrhagic complications has been reported in patients treated with eptifibatide in the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial and the ESPRIT trial. Eptifibatide treatment with Canadian Cialis has been associated with a small increase in profound thrombocytopenia. An immunologic mechanism has been identified in some patients. Thus, patients receiving eptifibatide should be monitored soon after the initiation of therapy for the development of thrombocytopenia. An algorithm for the detection and management of thrombocytopenia after GPIIb/IIIa blockade has been proposed. No data are available concerning the safety of reinfusing eptifibatide, but high levels of antibodies that bind to platelets in the presence of eptifi-batide have been found in patients who develop thrombocytopenia after reexposure to eptifibatide.
5.4 Efficacy and safety of IV GPIIb/IIIa antagonists
The efficacy and safety of GPIIb/IIIa antagonists were evaluated initially in patients undergoing PCI. Over
20,000 patients have been enrolled in nine studies of abciximab, eptifibatide, and tirofiban (Table 8). The first of these phase III trials, the EPIC trial, resulted in approval in many countries for the use of abciximab (ReoPro; Lilly; Indianapolis, IN) in 1994 for PCI patients who are at high risk of developing ischemic complications. Eptifibatide has been studied in the IMPACT-II and ESPRIT trials, and tirofiban has been studied in the RESTORE trial. Although neither the IMPACT-II nor RESTORE trials achieved their predefined efficacy end points, there was a positive trend in each case (Table 8).
Probiotics and Lung Infection
Significantly, the maintenance of a clinically unresponsive state following aeroallergen exposure in atopic individuals has been associated with increased IDO activity and IL-10 production. Overall it appears that the ability of certain microbes to promote IDO activity, in addition to IL-10 expression by DCs, may be important in the generation of a regulatory immune response and the establishment of tolerance.
Probiotics and Lung Infection in Canadian Pharmacy
The increase in antibiotic resistance and need for new and improved strategies to tackle infectious disease have led to an examination of the therapeutic potential of commensal induced modulation of the mucosal immune response. Consequently, it has been discovered that certain LAB do have protective effects against bacterial and viral infections in the GI and respiratory systems. Administration of probiotics has been associated with lower incidence of ventilator-associated pneumonia, reduced respiratory infections in healthy and hospitalized children and reduced duration of common cold infection. It should be noted that in addition to causing morbidity and mortality directly there is good evidence that respiratory infections, particularly viral infections, are a contributing factor not only to the exacerbation of asthma, but also to development of the disease Indeed, it has been suggested that the focus of potential beneficial effects of probiotics in asthma should be directed at identifying organisms capable of reducing viral infections in early life.
In mouse studies, intranasal administration of LAB protects against respiratory pathogens. However, direct exposure of the probiotic organism to the airway mucosa is not required, and LAB can protect host animals from airway infection through an interaction with GALT, such as Peyer patch cells, and indirect enhancement of respiratory immunity (Fig 1). The protective effects of both intranasal and oral probiotics are generally associated with upregulation of natural killer (NK) cell and/or macrophage activity in the airway mucosa.
NK cells are the main components of host-nonspecific cell-mediated immunity
NK cells are the main components of host-nonspecific cell-mediated immunity, recognizing and helping to control a wide range of pathogens, including viruses, bacteria, and intercellular parasites. NK cells are activated by IL-12 that is produced by antigen-presenting cells, such as macrophages, DCs, and Langerhans cells. Here again, data suggest that the dialog between DCs and bacteria is key to controlling the immune effects of LAB beyond the GI tract. Koizumi demonstrated that feeding mice with Lactobacillus pentosus significantly enhances NK activity of spleen cells and induced NK1.1-positive NK and NK T cells to produce interferon (IFN)-g. Viagra online canadian pharmacy at
The increase in IFN-g production did not occur through direct action of L pentosus on NK cells but was dependent on IL-12 produced by CD11c+ DCs following a toll-like receptor (TLR) 2- and/or TLR4-dependent interaction between the DC and LAB. Strains of LAB differ greatly in their ability to induce high levels of IL-12 in human DCs and consequently DC-dependent IFN-g production by NK cells. 
Alveolar macrophages provide the first line of defense against organisms that reach the lower airways. In addition to their phagocytic function, alveolar macrophages can synthesize and release various protein and lipid mediators on contact with pathogens or pathogenic substances. LAB have been well characterized in terms of an ability to induce cytokine production following contact with mononuclear phagocytes.
The ability of orally administered L casei to dose-dependently enhance the phagocytic activity of alveolar macrophages likely contributes to the accelerated recovery of the innate immune response and improved outcomes following Streptococcus pneumoniae respiratory infection in malnourished mice and in young mice infected with Pseudomonas aeruginosa. Here again, the suggestion is that stimulation of the GALT leads to a general enhancement or priming of the innate immune response in the airway.
Physical Sources of ED
This is a medical term referring to your basic constitution — how you’re made up. Scientists have long suspected a genetic link to certain forms of ED but the research is inconclusive. While erectile dysfunction itself may not be carried in a man’s genetic makeup, it is possible for a medical condition to be passed down in 
a hereditary gene that carries ED as one of its characteristics. ED is associated with cardiovascular disorders such as hypertension or coronary heart disease. Hence a genetic predisposition to these diseases may hint at a likelihood of Genetic ED healthcare medications online. In a Finnish study of twins and siblings a link was established.
Assess whether your father or other close male relatives have suffered from ED at some point in their lives. This information may be hard to obtain and hard to distinguish from Acquired ED, brought on by the likes of excessive alcohol intake or smoking. If you suffer from Lifelong ED i.e. ever since your first sex experience, there is likelihood it is genetic.
While a genetic cause may sound fatally insoluble, the good news is that there’s a lot that can be done to overcome Genetic ED. And the results are very encouraging. From my experience, I have had good results from the application of my program’s therapy, especially with prescription drugs, where the identified potential source is Genetic ED. Note I have stressed ‘potential’ as it’s practically impossible to isolate an ED source as 100% genetic.
Methods of assisted conception
Should methods of natural family planning fail then there are currently a number of methods of assisted conception that can be used. The choice of which technique to use (for any couple) is dependent on a range of factors and includes the:
- quality generic viagra online canada (and quantity) of the sperm available (freshly ejaculated or cryopreserved)
- physiology of the female partner
- choice of the patients
- funding available to the patient.
With regard to the latter point, it is a sad reflection that in circumstances where public money is unavailable to fund treatment and the couple needs to fund their own, then the choice of treatment may be sometimes dictated by the cost rather than its clinical effectiveness. However, little has been published on this topic and so it remains anecdotal as to whether the avail-ability of funding is a major factor in influencing the outcome of fertility treatment in this group of patients.
As such, there are very different treatment prednisone online pharmacy options available for a man who has some recovery of spermatogenesis following a medical treatment compared with a man who might be azoospermic after treatment and only have the limited resource of his frozen samples in storage.
For example, for a man who, at the time of entering an assisted conception programme with his partner, is ejaculating moderate number of motile spermatozoa and from whose ejaculates at least five million motile sperm per millilitre can be prepared, a relatively simple procedure such as IUI using freshly ejaculated sperm would seem most appropriate. Whereas in a man whose ejaculates have been consistently azoospermic but who has frozen samples from which at least 10 or 20 motile sperm can be identified, then ICSI would certainly be required. However, in reality this is a some-what simple way of looking at the decision as in each case account needs to be taken of the biology of the man’s partner and there are many circumstances where the aggressiveness of the assisted conception treatment has to be increased because of pathological factors on the female side. For example, previous disease or damage to the Fallopian tubes will almost certainly require the couple to use IVF even if the quality of sperm available would be sufficient for IUI in another woman.
An interesting question is the decision that is made surrounding the use of fresh or frozen sperm in cases where the quality of the two (in terms of the concentration of motile sperm) is very similar post-treatment. Anecdotally, opinion is divided as to which is the better option, the anxiety being that following any medical treatments involving cytotoxic drugs there is a known increase in sperm chromosomal abnormalities that theoretically could lead to an increase in spontaneous abortions, stillbirths or birth defects in children.
ED Findings From the Canada area Community Health Survey
Conceptual and methodological issues need to be addressed. First, the definition and measurement of Erectile Dysfunction varies from study to study. All definitions of ED, however, are based on patients’ self-report, which is typically assessed by single-item scales or questionnaire measures.
Some differences are evident among these scales, although studies show overall concordance in the prevalence rates and association with well- known comorbidities and risk factors. Early landmark studies, such as MMAS and National Health and Social Life Survey (NHSLS) used single-item scales, which assessed erection difficulties over several months or in the past year.
Subsequent studies used 5- or 15-item versions of the IIEF, a multidimensional, self-report scale that assesses male sexual function over a 4-week period.
Single-item instruments have the advantage of high completion rates and low patient burden. On the other hand, multidimensional scales provide broader and more complete assessment of disease severity. Despite such differences, largely similar results have been obtained across studies using these different measures.
A second, and potentially more challenging issue, concerns the complex and often bidirectional interactions between variables. For example, depression may be a cause or a consequence of ED in many studies.
These studies support a direct association between ED and mood. In other studies, the causal relationships among the major risk factors for ED are less evident. Biomedical, psychosocial, and lifestyle factors may interact in complex ways. Separating the effects of one risk factor or comorbidity from another and determining the direction of causality among these factors, can be difficult if not impossible to ascertain in cross-sectional studies alone.
More research is needed to elucidate these associations. The increased evidence of a link between ED and CVD with the potential for ED to serve as a sentinel marker of subclinical vascular disease has led to an increased awareness of Erectile Dysfunction as a “barometer” of vascular health and the early opportunity for primary prevention in at-risk men. The 2nd Princeton Consensus Conference has called for the routine assessment of cardiovascular risk in all ED patients and subsequent classification of ED patients into low, moderate, or high risk of CVD and recommendation for aggressive lifestyle modification in patients with ED and CV risk factors.
However, further understanding is needed of the link between endothelial dysfunction and Erectile Dysfunction and the specific role of endothelial dysfunction in the progression and remission of ED to:
- Refine our understanding of pathophysiologicalprocesses of ED in human subjects;
- Improve the identification of ED patients at higher risk of CVD who would benefit most from preventive interventions, such as statin therapy, perioperative beta blocker therapy, etc.;
- Establish the primacy of endothelial dysfunction in ED incidence and progression and relationship to other predictors.
Sex : The Truth and Nothing but the Truth
Fact: What Is Good for Your Body Is Good for Your Sex Life
What Is Good for Your Sex Life Is Good for Your Body
The interrelationship between your physical body and sexual function is crucial to sexual health. Good lifestyle habits and choices—such as proper sleep, regular exercise for physical conditioning, healthy diet, moderation in your use of alcohol—provide the foundation for easy sexual function. Taking good care of your physical body is a prerequisite for satisfying sex. Positive, realistic expectations and cooperation with your partner are good for your sexual function. This interrelationship makes sense in the context of physiological sexual response and the importance of relaxation and comfort with your partner.
Fact: Satisfying Sex Is Important to Your General Health Viagra in Canada
When men feel sexually healthy and satisfied, men walk tall. Our sexual feelings, emotional well-being, confidence in the world, and even our physical health are essentially intertwined. On the other hand, a man who is troubled with his sexuality is at risk for low self-esteem, irritability, anxiety, and even physical illness. This interrelationship is an important reason that sexual dysfunction is considered both a psychological and a medical concern. The mind–body connection is valid.
Fact: Satisfying Sex Involves Lovemaking Skills
Good sex is more than performing as a “stud.” Healthy physical conditioning, realistic psychological thinking, emotional health, and interpersonal cooperation for mutual pleasure are all part of good psychosexual (love-making) skills. While procreation may be biologically natural, satisfying lovemaking skills are not automatic but are developed through healthy attitudes, behaviors, and emotional intimacy. You can develop comfort and confidence with psychosexual skills and strengthen your desire, arousal, and orgasm response.
Fact: Knowledge Is Power Canadian health care mall
Accurate and realistic knowledge about men’s bodies and male sexuality is crucial. Sexual health for men involves understanding physical, psychological, and relationship factors. Being realistic and thinking accurately about your body and your sexual function is a crucial component of sexual health.
This is essential because the public presentation of sex has nearly no relationship to the truth. The media, marketing, and public discourse is about getting your attention more than teaching you the truth about sex in real people’s lives. This is a major problem and one of the most important motivations for our writing this book.
You also need a good understanding of your emotional life. It is important to understand the differences between your sex drive (“feeling horny”) and positive and negative emotions like anxiety, loneliness, enjoyment, or pride in a job success. All energy in the body is not sexual energy, although there is a tendency for men to interpret a variety of emotions as sexual and try to manage their emotions by sexualizing them. For example, most men have masturbated to relieve anxiety or stress.
You also need to understand what healthy sexual behaviors are. Men care about sexual performance. Sexual function (performance) for men is fundamental, and to dismiss this important component of male sexuality is self-defeating. We’ll coach you how to put sexual function into perspective; otherwise, it becomes a huge barrier to sexual pleasure, sexual acceptance, and relationship intimacy.