Safety cardiovascular

The Central Role of Cardiovascular Safety in Drug Development and Therapeutic Use 

It is an unfortunate but immutable fact that no biologically active drug is free from the possibility of causing adverse reactions in certain individuals who are genetically and/or environmentally susceptible. 

Although marketed medical products are required by federal law to be safe for their intended use, safety does not mean zero risk. A safe product is one that has acceptable risks, given the magnitude of benefit expected in a specific population and within the context of alternatives available. 

A similar decision process occurs at the level of the individual patient once a relevant drug is approved the physician and the patient must decide together that a particular course of pharmacotherapy has a favorable benefit-risk balance for the drug to be prescribed. 

The process of benefit-risk estimation can be represented as follows (Turner 2010)  

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With the availability of NSAIDs with COX-2 selectivity, clinicians postulated that these agents would avoid the need to add an additional prophylactic agent to therapy in patients with PUD risk factors. However, selective COX-2 inhibitors have not been shown to be any more effective than the combination of a PPI and a non-selective NSAID in reducing the incidence of ulcers, and questions remain regarding their long-term cardiovascular safety. 

As a consequence, more selective inhibitors of the COX-2 enzyme may offer enhanced gastrointestinal safety but compromised cardiovascular safety. As shown in Fig. 55-4, when the... 

Cyclooxygenase-2 (COX-2)-selective inhibitors produce results comparable with those of traditional NSAIDs. However, cardiovascular safety concerns and the high cost of COX-2 inhibitors argue against their use for this disorder. 

Hanson, L.A., Bass, A.S., Gintant, G., Mittelstadt, S., Rampe, D. and Thomas, K. (2006) ILSI-HESI cardiovascular safety subcommittee initiative evaluation of three non-clinical models of QT prolongation. Journal of Pharmacological and Toxicological Methods, 54, 116—129. 

However, when compound 15 was tested for h E RG K+ channel inhibition, a basic cardiovascular safety indicator related to the QT prolongation syndrome [32], and linked to ventricular fibrillation and sudden death [33], we were unpleasantly surprised. Although the lead compound 1 exhibited very weak binding to the hERG K+ channel (IC50 > 5000 nM), the optimized compound 15 was afairly potent hERG blocker with an inhibition concentration IC50 of 300 nM (in patch-clamp assay). 

Regulatory guidance for non-clinical cardiovascular safety pharmacology testing is given in the ICH S7A and B.25,42 The effects of an NCE on blood pressure, heart rate, and the ECG should be evaluated. Furthermore, in vivo, in vitro, and ex vivo evaluations, including methods for (assessing) repolarization and conductance abnormalities, should... 

Chiang, A.Y., Smith, W.C., Main, B.W., and Sarazan, R.D., Statistical power analysis for hemodynamic cardiovascular safety pharmacology studies in beagle dogs, /. Pharmacol. 

Issues of cardiovascular safety have brought safety pharmacology to the forefront, especially with issues like prolongation of the QTc interval. In the United States, IND s must routinely include the core battery of cardiovascular, CNS, and pulmonary function studies. The reader is referred to Chapter 13 for a thorough discussion of this important topic. 

Pratt CM, Mason J, Russell T et al. Cardiovascular safety of fexofenadine. Ami Cardiol 1999 83 1451-4. 

Gastrointestinal safety of COX selective inhibitors compared with non-selective NSAIDs the principle areas of concern are upper gastrointestinal and cardiovascular safety. 

Cardiovascular safety. Both drug types promote salt retention, can exacerbate heart failure and tend to raise blood pressure. COX-2 selective drugs also appear to raise the risks of thrombotic events, notably stroke and myocardial infarction, and recent evidence suggests that non-selective NSAIDs also raise these risks, though it is unclear whether to the same degree. For both drug types, dose and duration of treatment appear to affect risk. 

Forane) agent, largely owing to cardiovascular safety... 

Salpeter SR. Cardiovascular safety of beta 2-adrenoceptor agonist use in patients with obstructive airway disease a systematic review. Drugs Aging 2004 2i 405-4i4. 

Cardiovascular safety of COX-2 inhibitors. Med Lett Drugs Ther 2001 43 99-100. 

Stealth liposomes (HSPC Drug delivery system for Examined in cardiovascular safety No adverse findings seen... 

U.S. Food and Drug Administration. Avandia (Rosiglitazone) Ongoing Review of Cardiovascular Safety. http //www.fda.gov/Safety/MedWatch/SafetyInformation/ Safety AlertsforHumanMedicalProducts/ucm201446.htm (accessed July 2012). 

Kloner RA, Jackson G, Hutter AM, et al. Cardiovascular safety update of tadalafil retrospective analysis of data from placebo-controlled and open-label clinical trials of tadalafil with as needed, three times-per-week or once-a-day dosing, Am J Cardiol 2006 97 1778-1784. 

Cardiovascular Safety Effects on vascular tone have received the most attention, as a result of toxicities that were identified very early in the development of the first systemically administered PS ODNs. We showed that there was correlation between complement activation and the reported alterations in blood pressure and heart rate in monkeys treated with high doses of PS ODN [40-42], The observation appears to be unique or at least more prominent in monkeys, and that has actually driven the need to characterize the toxicity of oligonucleotide therapeutics in monkeys as the nonrodent species. (Note that complement activation has not proved to be a significant issue in the clinic, although in clinical studies we strive to avoid plasma levels that might be associated anaphylactoid responses in monkeys.)... 

Because the monkey is the most sensitive species for the effects on complement, we have opted to perform cardiovascular safety studies as part of subchronic study protocols using implanted telemetry units in selected monkeys (two/sex in at least two different treatment groups, including the high dose) to measure ECG, mean arterial pressure, heart rate, and body temperature. These parameters are then recorded at frequent intervals for a 24-hour period prior to treatment to establish circadian fluctuations and normal response to various stimuli encountered during the day. This technique enables us to assess both acute alterations related to complement activation after single doses and chronic safety after repeated administration. 

Other cardiovascular safety in dogs, in vitro blood compatibility, derivatives of gamma calicheamicin on murine bone marrow hematopoietic colony formation in vitro in vitro stability of hP67.6 conjugate in human, monkey, and rat plasma... 

Other local intra-arterial tolerance in the rabbit, local paravenous tolerance in the rats in vitro hemolytic potential and blood compatibility testing Special toxicology studies renal safety in dogs, cardiovascular safety in cynomolgus monkeys, cardiovascular and respiratory safety in rabbits Single dose guinea pigs, mice... 

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