Risk Of Cardiovascular Side Effects Research Articles

Selection of NSAIDs for rational pharmacotherapy of chronic musculoskeletal pain: a clinical pharmacologist's perspective

Chronic musculoskeletal pain (CMSP) is one of the most common pathological conditions that limits patients' physical activity and reduces their quality of life. The analgesic and anti-inflammatory effects of non-steroidal anti-inflammatory drugs (NSAIDs) make them the basis of pharmacotherapy for patients with chronic conditions affecting various parts of the musculoskeletal system. The main target of NSAIDs, cyclooxygenase (COX), exists in the form of two main isoforms, COX-1 and COX-2, the inhibition of each of which leads to a cascade of reactions at the cellular and tissue level that can cause both targeted pharmacological effects and side effects. The diversity of the chemical structures of NSAIDs leads to differences in their pharmacodynamic and pharmacokinetic parameters and correspondingly to differences in their efficacy and safety profile. Selective COX-2 inhibitors, coxibs, have shown an increased risk of cardiovascular side effects, which has led to significant restrictions on their use. Cardiotoxicity is not as pronounced with the non-selective COX inhibitors, but the range of their side effects is extremely wide. These side effects are dose-dependent and are characteristic, first of all, of systemic NSAIDs.The combination of systemic and topical NSAIDs makes it possible to reduce the dose of the former and improve the safety profile of anti-inflammatory therapy. Among the non-selective COX inhibitors with a satisfactory safety profile and high anti-inflammatory activity, the group of oxicams and especially tenoxicam should be emphasised, which are characterised by a maximum duration of action, which is an advantage in the treatment of patients with CMSP. This review addresses the issues of rational selection of NSAIDs based on comparative data on pharmacodynamics, pharmacokinetics and clinical trial results.

Cardiovascular risk following cannabinoid treatment for patients with chronic pain

Abstract Background Treatment with medical cannabis for chronic pain is in popular demand, and a rising number of countries allow physicians to prescribe medical cannabis for pain management. However, data on drug-safety is scarce. Studies have showed a risk of cardiovascular side effects following use of recreational cannabis warranting further investigations into the safety of prescribing medical cannabis. Purpose We investigated risk of new-onset arrhythmias (tachy- or bradyarrhythmia and conduction disorders), acute coronary syndrome (ACS) and heart failure (HF) following use of prescribed medical cannabis compared with no use in a nationwide cohort of patients with chronic pain. Methods Using nationwide Danish registers, a cohort of patients with chronic pain and without prior history of arrhythmias, ACS, HF or prescribed medical cannabis (cannabinoid, cannabidiol or dronabinol) use were followed from 2018–2021. Any patient from the cohort initiating first-time treatment with medical cannabis was identified and matched 1:10 to corresponding controls within the cohort using incidence density sampling. Matching parameters were age group, sex, and chronic pain diagnosis. Follow-up was initiated at the date of the first claimed prescription of medical cannabis or the corresponding date among controls. We reported 180-day standardized absolute risks (AR) with 95% confidence intervals (CI) and risk ratios (RR) from fitted multivariable logistic regression models comparing patients exposed to medical cannabis with patients not exposed. Separate analyses for each chronic pain group were conducted as well. Results Among 1.6 million patients with chronic pain, 4,562 patients claimed at least one prescription of medical cannabis (exposed) and were each matched to 10 controls (non-exposed). Exposed and non-exposed patients were identical in relation to matching parameters; however, exposed patients were slightly more comorbid, and a larger proportion was concomitantly treated with other pain medication (Table). The risk of new-onset arrhythmia was elevated among exposed patients with 180-day AR of 0.71% (95% CI 0.47%–0.94%) compared with 0.43% (95% CI 0.37%–0.49%) yielding a RR of 1.64 (95% CI 1.04–2.23). The risk of new-onset ACS and HF was not increased comparing exposed to non-exposed with corresponding 180-day ARs of 0.13% (95% CI 0.03%-0.23%) vs 0.11% (95% CI 0.08%–0.14% and 0.13% (95% CI 0.03%–0.24%) vs 0.14% (95% CI 0.11%–0.17% (corresponding RRs of 1.2 [95% CI 0.3–2.1] and 0.9 [95% CI 0.2–1.7]) (Figure). Subgroup analyses of each chronic pain group yielded similar results. Conclusion In a nationwide cohort of patients with chronic pain, use of medical cannabis was associated with a 64% risk increase of arrhythmias compared with no use. This poses a potential health concern and is vital knowledge for any physician prescribing medical cannabis. Use of medical cannabis was not associated with an elevated risk of ACS or HF. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Ib Mogens Kristiansens Almene FondHelsefonden

Comparative analysis of the use of non-steroidal anti-inflammatory drugs in Montenegro, Finland and Croatia in the period 2010-2019.

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used drugs. However, numerous studies have shown that non-selective cyclooxygenase (COX) inhibitors can also significantly increase the risk of cardiovascular side effects. Diclofenac has the highest risk, while naproxen has the lowest risk of developing these complications. The aim of the study was to analyze the structure and amount of NSAIDs consumed in Montenegro, Finland and Croatia in the last 10 years. In our study, we used 90% drug use (DU90) and ATC/DDD methodology. Drug consumption is shown in DDD/1000 inhabitants/day, and drug prices per DDD in Euros (€). Pearson's correlation test was used to examine the correlation between the number of drugs consumed and their price. Diclofenac consumption is 3 to 4 times higher in Montenegro compared to Croatia, and 9 to 10 times higher than in Finland. The average price of diclofenac in Montenegro was around € 0.07 per DDD, in Finland around € 0.26 per DDD and in Croatia € 0.19 per DDD. In Montenegro, the Pearson correlation test did not show a statistically significant association between high diclofenac consumption and its DDD price but showed a positive strong correlation between DDD price growth and naproxen consumption growth. The situation in Montenegro regarding the consumption of diclofenac is unfavorable and it is necessary to change the attitude and awareness of doctors and patients about the use of diclofenac. It is also necessary to replace diclofenac with naproxen, which is a slightly more expensive but safer drug.

Reduced arterial elasticity after anabolic–androgenic steroid use in young adult males and mice

High-doses of anabolic–androgenic steroids (AAS) is efficient for building muscle mass, but pose a risk of cardiovascular side effects. Little is known of the effect of AAS on vasculature, but previous findings suggest unfavorable alterations in vessel walls and vasoreactivity. Here, long-term effect of AAS on vascular function and morphology were examined in male weightlifters, and in a mimicking animal model. Arterial elasticity and morphology were tested with ultrasound, pulse wave velocity (PWV) and carotid intima media thickness (cIMT) in 56 current male AAS users, and 67 non-exposed weightlifting controls (WLC). Female mice were treated with testosterone for 14 days and echocardiography were applied to evaluate vascular function and morphology. Male AAS users had higher PWV (p = 0.044), reduced carotid artery compliance (p = 0.0005), and increased cIMT (p = 0.041) compared to WLC. Similar functional changes were found in the ascending aorta of mice after 7- (p = 0.043) and 14 days (p = 0.001) of testosterone treatment. This animal model can be used to map molecular mechanisms responsible for complications related to AAS misuse. Considering the age-independent stiffening of major arteries and the predictive power of an increase in PWV and cIMT, the long-term users of AAS are at increased risk of severe cardiovascular events.

MO528: Identifying Drivers of Patients’ and Physicians’ Preferences for Treatments of Anemia of Chronic Kidney Disease: A Qualitative Study

Abstract BACKGROUND AND AIMS Anemia is an important and common complication of chronic kidney disease (CKD). As the treatment landscape evolves, improving our limited understanding of patient and physician preferences for the management of anemia of CKD may help to better address patients’ treatment needs. Qualitative interviews were conducted to identify key treatment aspects that affect patients’ and physicians’ treatment preferences. METHOD A targeted literature informed the design and content of semi-structured qualitative interviews. All interviews were conducted (by telephone, in local language) with CKD patients (non-dialysis dependent and peritoneal dialysis dependent) and physicians from the USA, Germany and Japan. Interviews comprised of three parts. Part 1 discussed patients’ symptoms and quality of life, while physicians were asked about their clinical experience. Part 2 covered treatment experience and concerns, and included semi-structured discussions about benefits, adverse events and convenience. In part 3, patients and physicians were presented with a hypothetical treatment choice that required benefit–risk trade-offs. All data were analyzed using mixed deductive and inductive analysis, and results were visualized using a conceptual map. Subsequently, an attribute selection workshop was held with nephrologists from the USA and Germany, in which findings from the literature review and qualitative interviews were reviewed at length to identify drivers for patient and physician preferences for anemia treatments. RESULTS A total of 18 patients (n = 6 from each country) and 12 physicians (n = 4 from each country) participated in the qualitative interviews. Patients were at least in CKD stage 3 with 50% in stage 5. Most patients (72%) were receiving treatment with a recombinant human erythropoietin. Most frequently reported comorbidities were hypertension (78%), type 2 diabetes (46%) and hyperlipidemia (22%). All physicians had been in clinical practice for 40–50 years and 75% were in private practice. Figure 1 depicts the attribute conceptual map. Control of hemoglobin within target range was important to both patients and physicians. Physicians linked hemoglobin control to fewer symptoms and better quality of life. Nine out of 12 physicians (75%) spontaneously stated that they were concerned about the cardiovascular (CV) risk associated with use of erythropoiesis-stimulating agents. Patients reported experiencing several symptoms associated with anemia of CKD, with fatigue/tiredness (lack of energy) and dizziness being the most common. Physicians also highlighted these as important, and patients linked improvements in lack of energy to treatment success. Patients raised concerns about the convenience of intravenous (time commitment) and subcutaneous (storage requirements, self-injection) administration, but considered oral pills to be convenient and familiar. Once-daily administration of oral pills was considered easier to remember than thrice weekly. CONCLUSION This study demonstrated that patient and physician treatment preferences are multi-factorial, driven by clinically important attributes such as keeping within hemoglobin target ranges, reducing fatigue and weakness and the risk of CV side effects. Drug regimen attributes such as dosing frequency and dosing requirements affected perceived convenience. While all aspects contribute jointly to perceived value, they appear to have different relative importance. These findings are suitable for designing a subsequent preference elicitation survey that will aim to elicit trade-offs between the relevant treatment aspects and better understand patient and physician preferences. Sponsorship: GlaxoSmithKline (Study number: 213 496).

Oral Progestins in Hormonal Contraception: Importance and Future Perspectives of a New Progestin Only-Pill Containing 4 mg Drospirenone.

Hormonal contraceptives are an effective and safe method for preventing pregnancy. Progestins used in contraception are either components of combined hormonal contraceptives (tablets, patches or vaginal rings) or are used as a single active ingredient in progestin mono-preparations (the progestin-only pill (POP), implants, intrauterine systems or depot preparations). Progestins are highly effective in long-term contraception when used properly, and have a very good safety profile with very few contraindications. A new oestrogen-free ovulation inhibitor (POP) has recently been authorised in the USA and the EU. This progestin mono-preparation contains 4 mg of drospirenone (DRSP), which has anti-gonadotropic, anti-mineralocorticoidic and anti-androgenic properties. The hormone administration regimen of 24 days followed by a 4-day hormone-free period was chosen to improve bleeding control and to maintain oestradiol concentrations at early follicular-phase levels, preventing oestrogen deficiency. Clinical trials have demonstrated a high contraceptive effectiveness, a very low risk of cardiovascular side effects and a favourable menstrual bleeding pattern. Due to the long half-life of DRSP (30 – 34 hours), the effectiveness of the preparation is maintained even if a woman forgets to take a pill on a single occasion. Studies involving deliberate 24-hour delays in taking a pill have demonstrated that ovulation inhibition is maintained if a single pill is missed. Following a summary of the current status of oestrogen-free contraception, this review article will describe the clinical development programme of the 4 mg DRSP mono-preparation and the resulting data on the effectiveness and safety of this new oestrogen-free oral hormonal contraceptive.

Effect of Magnesium Sulfate on Epinephrine-Mediated Adverse Effects during Liposuction Procedures: A prospective Randomized controlled Study

Background: During liposuction procedures, injection of wetting solution containing epinephrine is performed. This may increase the risk of cardiovascular side effects in large volume cases. Magnesium sulfate has cardioprotective effects, and can prevent complications related to epinephrine. The aim of the work: To assess the effect of adding intravenous magnesium sulfate, during the administration of epinephrine containing wetting solution, on the incidence of epinephrine-mediated cardiovascular side effects during liposuction surgery. Patients and Methods: This was a prospective randomized study comprised a total of 94 cases into two equal groups. The epinephrine group included 47 cases that had epinephrine in their wetting solution, and epinephrine-Mg group included the remaining cases that had adrenaline in the wetting solution along with intra venous. administration of MgSO4. Heart rate, blood pressure, arrhythmia incidence, isoflurane, and morphine consumption were recorded. Results: No significant difference was noticed as regard basal and induction heart rate and mean arterial pressure [MAP]. However, the epinephrine-Mg group showed significantly lower readings on subsequent assessment. There was no significant difference among both groups regarding the incidence of arrhythmia; the epinephrine group had more cases with arrhythmia. Isoflurane consumption decreased significantly in the epinephrine-Mg group in comparison with the epinephrine group, while morphine consumption did not significantly differ between them. Conclusion: Based on our findings, intravenous administration of magnesium sulfate decreases heart rate, blood pressure, and inhalational anesthesia consumption during liposuction. However, it has no significant impact neither on the incidence of arrhythmia, nor morphine consumption.

High risk of cardiovascular side effects after treatment of Hodgkin's lymphoma - is there a need for intervention in long-term survivors?

BackgroundHodgkin lymphoma (HL) patients have a good prognosis after adequate treatment. Previous treatment with mantle field irradiation has been accompanied by an increased long-term risk of cardiovascular disease (CVD). This study identified co-morbidity factors for the development of cardiovascular side effects and initiated an intervention study aimed to decrease morbidity and mortality of CVD in HL survivors.DesignHodgkin lymphoma patients aged ≤45 years diagnosed between 1965 and 1995 were invited to participate. In total, 453 patients completed a questionnaire that addressed co-morbidity factors and clinical symptoms. Of these, 319 accepted to participate in a structured clinical visit. The statistical analyses compared individuals with CVD with those with no CVD.ResultsCardiovascular disease was reported by 27.9%. Radiotherapy (odds ratio [OR]: 3.27), hypertension and hypercholesterolemia were shown to be independent risk factors for the development of CVD. The OR for CVD and valve disease in patients who received radiotherapy towards mediastinum was 4.48 and 6.07, respectively. At clinical visits, 42% of the patients were referred for further investigation and 24% of these had a cardiac ultrasound performed due to previously unknown heart murmurs.ConclusionRadiotherapy towards mediastinum was an independent risk factor for CVD as well as hypercholesterolemia and hypertension. A reasonable approach as intervention for this cohort of patients is regular monitoring of hypertension and hypercholesterolemia and referral to adequate investigation when cardiac symptoms appear. Broad knowledge about the side effects from radiotherapy in the medical community and well-structured information regarding late side effects to the patients are all reasonable approaches as late effects can occur even 40 years after cancer treatment.

Comparative Review of Drugs Used in Diabetes Mellitus—New and Old

Background: Diabetes mellitus (DM) is a syndrome of chronically elevated glucose level in the blood either due to insulin resistance, insulin deficiency or both. In addition, it may occur due to defective metabolism of carbohydrates, fats and proteins. There are 3 main types of DM: Type 2 DM is more prevalent in adults and is typically due to relative insulin deficiency, deficiency of insulin in children leads to DM type 1; and lastly, gestational diabetes occurs during pregnancy resulting from an imbalance of placental hormones. Introduction: Insulin, Biguanides and Sulfonylureas are some of the drug classes used to treat DM. However, their use is complicated by numerous side effects, such as; hypoglycemia & weight gain from insulin and sulfonylureas; lactic acidosis, vitamin B12 deficiency and gastrointestinal upset with metformin. Route of administration and cost are also important factors to consider when prescribing. It is for this reason the quest for newer, safer and easier to administer drugs is ongoing. Methodology: Used all the articles available on anti Diabetic drugs on web especially in British Medical Journal, Elsevier, Pubmed, Google scholar and Wikipedia etc. Got a final review article to compare the older and newer anti Diabetic drugs. Results and Conclusion: Insulin is good for controlling acute hyperglycemic states in DM but it causes acute hypoglycemia and lipodystrophy. Metformin is good hypoglycemic and easily available but causes hypoglycemia, metallic taste, Lactic acidosis and B12 deficiency. Sulfonylureas are good hypoglycemic but causes severe hypoglycemia acutely and weight gain so contraindicated for obese or hypertensive patients. While newer antidiabetics such as GLP 1 agonists increases insulin secretions has very low risk of hypoglycemia, causes weight loss as compared to insulin and decreases risk of cardiovascular side effects but still can’t be used in renally impaired patients, causes pancreatitis and can not be given in gastroparesis patients, similarly a newer drug of this class known as LY2189265 has long halflife of 90 hours, better efficacy, but causes pancreatitis and increase diastolic BP in high doses, pancreatitis is not associated with lixisenatide (GLP 1 agonist), while DPP4 inhibitors which increases GLP 1 in body has less risk of hypoglycemia, GI side effects, are weight neutral can be used in CKD but causes headaches and Nasopharyngitis. Bromocriptine or pegvisomant are used in patients of growth hormones adenoma induced DM as a medical therapy but are associated with psychosis and hallucinations. Meglitinides increases insulin secretion and has minuscule risk of hypoglycemia but can not be used in CKD patients. Otelixizumab and Teplizumab decrease T cell functions and save beta cells from immune reactions used in DM 1 but cause immune suppression and is an orphan drug. Recombinant GAD used in vaccines decreased antibody mediated beta cell damage but is still under studies.

The Effects of Cannabidiol, a Non-Intoxicating Compound of Cannabis, on the Cardiovascular System in Health and Disease.

Cannabidiol (CBD) is a non-intoxicating and generally well-tolerated constituent of cannabis which exhibits potential beneficial properties in a wide range of diseases, including cardiovascular disorders. Due to its complex mechanism of action, CBD may affect the cardiovascular system in different ways. Thus, we reviewed the influence of CBD on this system in health and disease to determine the potential risk of cardiovascular side effects during CBD use for medical and wellness purposes and to elucidate its therapeutic potential in cardiovascular diseases. Administration of CBD to healthy volunteers or animals usually does not markedly affect hemodynamic parameters. Although CBD has been found to exhibit vasodilatory and antioxidant properties in hypertension, it has not affected blood pressure in hypertensive animals. Hypotensive action of CBD has been mainly revealed under stress conditions. Many positive effects of CBD have been observed in experimental models of heart diseases (myocardial infarction, cardiomyopathy, myocarditis), stroke, neonatal hypoxic ischemic encephalopathy, sepsis-related encephalitis, cardiovascular complications of diabetes, and ischemia/reperfusion injures of liver and kidneys. In these pathological conditions CBD decreased organ damage and dysfunction, oxidative and nitrative stress, inflammatory processes and apoptosis, among others. Nevertheless, further clinical research is needed to recommend the use of CBD in the treatment of cardiovascular diseases.

Synthesis, Characterization, and Biodistribution of Quantum Dot-Celecoxib Conjugate in Mouse Paw Edema Model.

Increased risk of cardiovascular side effects has been reported with many of the drugs in the market, including nonsteroidal anti-inflammatory drugs (NSAIDs). Hence, it is critical to thoroughly evaluate the biodistribution and pharmacokinetic properties of the drugs. Presently nanotechnology in combination with noninvasive imaging techniques such as magnetic resonance imaging (MRI), computed axial tomography (CAT), and positron emission tomography (PET) provides a better estimate of the spatio-temporal distribution of therapeutic molecules. Optical imaging using quantum dot- (QD-) tagged biological macromolecules is emerging as a fast, economical, sensitive, and safer alternative for theranostic purposes. In the present study, we report the nanoconjugates of mercaptopropionic acid- (MPA-) capped CdTe quantum dots (QDs) and Celecoxib for bio-imaging in carrageenan-induced mouse paw edema model of inflammation. QD-Celecoxib conjugates were characterized by fluorescence, FT-IR, NMR, and zeta-potential studies. In vivo imaging of QD-Celecoxib conjugates showed clear localization in the inflamed tissue of mouse paw within 3 h, with a gradual increase reaching a maximum and a later decline. This decrease of fluorescence in the paw region is followed by an increase in urinary bladder region, suggesting the possible excretion of QD-drug conjugates from mice within 24 h.

Inhibition of microsomal PGE synthase-1 reduces human vascular tone by increasing PGI2 : a safer alternative to COX-2 inhibition.

The side effects of cyclooxygenase-2 (COX-2) inhibitors on the cardiovascular system could be associated with reduced prostaglandin (PG)I2 synthesis. Microsomal PGE synthase-1 (mPGES-1) catalyses the formation of PGE2 from COX-derived PGH2 . This enzyme is induced under inflammatory conditions and constitutes an attractive target for novel anti-inflammatory drugs. However, it is not known whether mPGES-1 inhibitors could be devoid of cardiovascular side effects. The aim of this study was to compare, in vitro, the effects of mPGES-1 and COX-2 inhibitors on vascular tone in human blood vessels. The vascular tone and prostanoid release from internal mammary artery (IMA) and saphenous vein (SV) incubated for 30min with inhibitors of mPGES-1 or COX-2 were investigated under normal and inflammatory conditions. In inflammatory conditions, mPGES-1 and COX-2 proteins were more expressed, and increased levels of PGE2 and PGI2 were released. COX-2 and NOS inhibitors increased noradrenaline induced vascular contractions in IMA under inflammatory conditions while no effect was observed in SV. Interestingly, the mPGES-1 inhibitor significantly reduced (30-40%) noradrenaline-induced contractions in both vessels. This effect was reversed by an IP (PGI2 receptor) antagonist but not modified by NOS inhibition. Moreover, PGI2 release was increased with the mPGES-1 inhibitor and decreased with the COX-2 inhibitor, while both inhibitors reduced PGE2 release. In contrast to COX-2 inhibition, inhibition of mPGES-1 reduced vasoconstriction by increasing PGI2 synthesis. Targeting mPGES-1 could provide a lower risk of cardiovascular side effects, compared with those of the COX-2 inhibitors. This article is part of a themed section on Targeting Inflammation to Reduce Cardiovascular Disease Risk. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.22/issuetoc and http://onlinelibrary.wiley.com/doi/10.1111/bcp.v82.4/issuetoc.

Pharmacological assessment of ibuprofen arginate on platelet aggregation and colon cancer cell killing

Nonsteroidal anti-inflammatory drugs (NSAIDs), including ibuprofen, are amongst the most commonly used medications and produce their anti-inflammatory and analgesic benefits by blocking cyclooxygenase (COX)-2. These drugs also have the potential to prevent and treat cancer and some members of the class including ibuprofen can produce anti-platelet effects. Despite their utility, all NSAIDs are associated with increased risk of cardiovascular side effects which our recent work suggests could be mediated by increased levels of the endogenous NO synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA) leading to reduced endothelial NOS activity and associated endothelial cell dysfunction. ADMA is a cardiotoxic hormone and biomarker of cardiovascular risk whose effects can be prevented by l-arginine. The ibuprofen salt, ibuprofen arginate (Spididol®) was created to increase drug solubility but we have previously established that it not only effectively blocks COX-2 but also provides an arginine source able to reverse the effects of ADMA in vitro and in vivo. Here we have gone on to explore whether the formulation of ibuprofen with arginine influences the potency and efficacy of the parent molecule using a range of simple in vitro assays designed to test the effects of NSAIDs on (i) platelet aggregation and (iii) colon cancer cell killing. Our findings demonstrate that ibuprofen arginate retains these key functional effects of NSAIDs with similar or increased potency compared to ibuprofen sodium, further illustrating the potential of ibuprofen arginate as an efficacious drug with the possibility of improved cardiovascular safety.

Combining NSAIDs with misoprostol may reduce risk of cardiovascular side effects

Combining NSAIDs with misoprostol may reduce risk of cardiovascular side effects

The mathematical formula of the intravaginal ejaculation latency time (IELT) distribution of lifelong premature ejaculation differs from the IELT distribution formula of men in the general male population.

PurposeTo find the most accurate mathematical description of the intravaginal ejaculation latency time (IELT) distribution in the general male population.Materials and MethodsWe compared the fitness of various well-known mathematical distributions with the IELT distribution of two previously published stopwatch studies of the Caucasian general male population and a stopwatch study of Dutch Caucasian men with lifelong premature ejaculation (PE). The accuracy of fitness is expressed by the Goodness of Fit (GOF). The smaller the GOF, the more accurate is the fitness.ResultsThe 3 IELT distributions are gamma distributions, but the IELT distribution of lifelong PE is another gamma distribution than the IELT distribution of men in the general male population. The Lognormal distribution of the gamma distributions most accurately fits the IELT distribution of 965 men in the general population, with a GOF of 0.057. The Gumbel Max distribution most accurately fits the IELT distribution of 110 men with lifelong PE with a GOF of 0.179. There are more men with lifelong PE ejaculating within 30 and 60 seconds than can be extrapolated from the probability density curve of the Lognormal IELT distribution of men in the general population.ConclusionsMen with lifelong PE have a distinct IELT distribution, e.g., a Gumbel Max IELT distribution, that can only be retrieved from the general male population Lognormal IELT distribution when thousands of men would participate in a IELT stopwatch study. The mathematical formula of the Lognormal IELT distribution is useful for epidemiological research of the IELT.

Evaluation of the Efficacy and Safety of the Ophthalmic Insert Mydriasert in Patients Undergoing Retinal Angiography

To verify the efficacy to obtain mydriasis and cardiovascular safety of Mydriasert (ophthalmic insert containing tropicamide and phenylephrine) in diabetic and nondiabetic patients undergoing retinal angiography by comparing it with usually administered eyedrops (tropicamide 1% and phenylephrine 10%). This was a prospective randomized study. A total of 154 eyes of 77 patients were randomly divided into 2 groups: group 1 consisted of 78 eyes, group 2 consisted of 76 eyes, and the patients were monitored for pupillary dilation, blood pressure, heart rate, and possible adverse effects at 0, 20, 40, 60, and 90 minutes. No severe adverse effects were observed in either group. In the entire sample studied, the mean pupillary diameter was greater in the eyedrops group after 20 and 40 minutes, while mydriasis was similar in the 2 groups after 60 minutes. The diabetic patients treated with Mydriasert had less mydriasis than those treated with eyedrops after 20 and 40 minutes, and diabetic patients showed less mydriasis than the nondiabetic patients after 60 and 90 minutes. There was no significant between-group difference in mean heart rate or systolic and diastolic blood pressure at any of the time points. Mydriasert assures an adequate degree of mydriasis for retinal angiography in both diabetic and nondiabetic patients. There are no differences in efficacy or safety between the insert and the usually administered eyedrops, but the low total drug dose administered with the insert reduces the risk of cardiovascular side effects.

Cancer drugs and the heart: importance and management

Progress in the detection and treatment of cancer has led to an impressive reduction in both mortality and morbidity. Due to their mechanism of action, however, conventional chemotherapeutics and some of the newer anti-cancer signaling inhibitors carry a substantial risk of cardiovascular side effects that include cardiac dysfunction and heart failure, arterial hypertension, vasospastic and thromboembolic ischaemia, dysrhythmia, and QT prolongation. While some of these side effects are irreversible and cause progressive cardiovascular disease, others induce only temporary dysfunction with no apparent long-term sequelae for the patient. The challenge for the cardiovascular specialist is to balance the need for life-saving cancer treatment with the assessment of risk from cancer drug-associated cardiovascular side effects to prevent long-term damage. This review discusses concepts for timely diagnosis, intervention, and surveillance of cancer patients undergoing treatment, and provides approaches to clinical uncertainties.

Nonsteroidal Anti-Inflammatory Drugs and Their Effects in the Elderly

Management of chronic pain can often be a challenging task, especially in the elderly. Patients over the age of 65 years have altered metabolism and pharmacodynamics that increase their susceptibility to adverse side effects. Nonsteroidal anti-inflammatory drugs (NSAIDs) are a common component of pain management in this population. Nonselective NSAIDs as well as selective Cox-2 inhibitors have been associated with side effects, including renal dysfunction, heart failure, gastrointestinal toxicity and increased risk of cardiovascular side effects. These adverse effects are particularly important in the elderly, and thus use of NSAIDs in this population must be scrutinized carefully. If NSAIDs are utilized, they should be tailored to the individual patient and administered in the lowest dose and for the shortest duration possible. It is hoped that future studies will provide further insight into the safety of these agents in elderly patients.

Chapter 11. Barbiturates

Chapter 11. Barbiturates

Dosimetry, toxicity, and response in a phase IIa trial of no-carrier added iobenguane I-131 (nca-MIBG): A New Approach to Neuroblastoma Therapy (NANT) study.

9512 Background: 131I-MIBG is specifically taken up in neuroblastoma, with a response rate >30% in relapsed disease. The presence of non-radioactive “carrier” MIBG molecules increases risk of cardiovascular side effects and can inhibit tumor uptake of 131I-MIBG, reducing tumor radiation. Our primary aim was to establish the maximum tolerated dose (MTD) of no-carrier-added MIBG with autologous hematopoietic stem cell (AHSC) support. Methods: Eligible patients were age 1-30 years with resistant neuroblastoma, MIBG avid tumors, and cryopreserved AHSC. The nca-MIBG therapeutic dose was escalated in 3 mCi/kg increments from 12-21 mCi/kg using a 3+3 design. The administered dose was limited by gamma image-derived pretreatment organ dosimetry and normal tissue tolerance estimates of Emami (1991). AHSC were infused 14 days post therapy. Response and toxicity were evaluated day 60. Dose limiting toxicity (DLT) was failure to engraft or grade 3 or 4 non-hematologic toxicity except grade 3 pre-defined exclusions. Results: Fifteen eligible patients were treated with 8.8 to 18.6 mCi/kg, including 3 patients each entered and evaluable at levels 12, 15, 18 mCi/kg (444-666 GBq/kg) without required dose adjustment or DLT. Of six additional patients entered, one was inevaluable for DLT due to early disease progression, and the other five assigned to 21 mCi/kg required dose reductions of 13 to 45% to meet organ dose limits. Median whole body radiation dose received was 3.3 Gy (2.0-4.0); median liver dose, 11.6 Gy (9.1-25.8); lung 11.5 Gy (5.9-15.3); kidney 15.5 Gy (8.3-23.4); adrenal 3.3 (2.0-3.9); thyroid 35.7 (2.1-108). In 7 patients there were 12 target lesions (mass 1.8-175 g) with received doses of 26-378 Gy. There was no related grade 3 or 4 non-hematologic toxicity; all patients engrafted promptly. No patients at 15 or 18 mCi/kg had ANC<500. The overall response rate (complete + partial) was 27%; by dose received responses were 0/6 at 12 mCi/kg, 1/3 at 15 mCi/kg, and 3/6 at 18 mCi/kg. Conclusions: No-carrier added iobenguane-131 with AHSC support is feasible at 18 mCi/kg with an apparent dose/response. The promising responses support a pivotal phase IIb study of 18 mCi/kg.