Class effect

The ACC/AHA recommends that P-blockers be initiated in all patients with NYHA FC I to IV or ACC/AHA stages B through D heart failure if clinically stable.1 To date, only three p-blockers have been shown to reduce mortality in systolic HF, including the selective prantagonists bisoprolol and metoprolol succinate, and the non-selective pr, p2-, and arantagonist carvedilol.29 33 The positive findings should not be extrapolated to be indicative of a class effect, as bucindolol did not exhibit a beneficial effect on mortality when studied for HF, and there is limited information with propranolol and atenolol. 

Known class effects have previously been seen in primates. 

Model-independent techniques compare data pairs observed at corresponding time values, where time is only a class effect, as in a paired -test or in an ANOVA. A data-poor set of only two or three observations, originating from routine quality control of an immediate-release dosage form, cannot be treated other than model independent. 

If the data are recorded at corresponding time values, an alternative is to treat them in a way similar to paired differences as in a paired f-test or in an ANOVA, where time is not considered as continuous independent variable but only as a class effect. The result is a model-independent index, which... 

Poor tolerabihty at effective concentrations Unsatisfactory pharmacokinetics or metabohsm Low potency Low or absent efficacy If due to specific compound, need back-up If a class effect, stop programme May be possible to design a better molecule May be possible to design a more potent molecule If principle disproved, stop programme... 

Class effects of drugs may be statistically associated both with the off-target activities and the desired therapeutic activities. 

Generally, the impression so far is that HDACi display a somewhat lower toxicity profile compared to conventional cytotoxics. The most common toxicity seen is nausea/vomiting and fatigue, mild myelosuppression and diarrhea and these feature as adverse effects in many chnical trials. The toxicities observed may be due to the individual drug or the consequence of inhibiting HDAC itself (class effect). It is postulated that interference with additional cellular pathways, not just histone acetylation, may be responsible for the differential toxicity seen clinically, especially if these different compounds are used at higher doses. 

As a class effect NRTIs are associated with lactic acidosis and hepatic steatosis, conditions which may occur more frequently in pregnant women. The individual NRTIs have their own adverse reactions. Pancreatitis is seen with lamivudine, stavudine, di-danosine and rarely with zalcitabine while the latter three agents can also induce peripheral neuropathy. 

Ball P. (2000). Quinolone-induced QT interval prolongation A not-so unexpected class effect. Journal of Antimicrobial Chemotherapy 45 557-559. 

By reducing preload and afterload in asymptomatic patients, ACE inhibitors (eg, enalapril) slow the progress of ventricular dilation and thus slow the downward spiral of heart failure. Thus, ACE inhibitors are beneficial in all subsets of patients—from those who are asymptomatic to those in severe chronic failure. This benefit appears to be a class effect that is, all ACE inhibitors appear to be effective. 

Wascher TC. Sulfonylureas and cardiovascular mortality in diabetes a class effect Circulation 1998 97(14) 1427-8. 

Fluid retention with thiazolidinediones may be dose-dependent and a class effect (99). There is little or no evidence to suggest a direct negative effect on cardiac performance. Because the symptoms may be due to increased permeability of the microcirculation, they may respond more quickly to drug withdrawal than to diuretic therapy. 

There are no differences in outcome between these two patterns of hepatotoxicity, rapid risers, in whom hver failure takes only a few days to develop, and slower risers. The estimated death rate is one in 100 000, but the estimate of the FDA advisory committee was one in 15 154 at 8 months of treatment. It is unclear whether hepatotoxicity is a class effect of thiazohdinediones or whether the lipophilic alpha-tocopherol moiety of troghtazone is responsible for this effect. The basic quinone structure of alpha-tocopherol is common to other drugs that can form hepatotoxic free radicals by CYP2E1-mediated oxidation. 

Tolman KG. Thiazolidinedione hepatotoxicity a class effect Int J Clin Pract Suppl 2000 (113) 29-34. 

Harats D, Yodfat O, Doolman R, Gavendo S, Marko D, Shaish A, Sela BA. Homocysteine elevation with fibrates is it a class effect Isr Med Assoc J 2001 3(4) 243-6. 

In a comparison of atorvastatin with pravastatin, of 224 patients taking atorvastatin, two had clinically significant increases in alanine transaminase activity (32). They recovered during the next 4 months, one after withdrawal of atorvastatin and the other after a dosage reduction. Withdrawals due to adverse effects were similar in the two groups. One patient developed hepatitis while taking atorvastatin, but was able to tolerate simvastatin (33). The authors concluded that this adverse effect was not a class effect. Eosinophils in a liver-biopsy specimen pointed to an immunological mechanism. 

The authors suggested that pancreatitis may be a class effect of the statins. 

Erectile dysfunction has been reported in 12% of 339 men treated with fibrate derivatives or statins, compared with 5.6% of similar patients not taking these drugs (62). The mechanism is unknown and should be confirmed in randomized studies. A class effect has been suggested by the case of a 57-year-old man who had impotence after taking lovastatin for 2 weeks and also when he later tried pravastatin (63). 

Singh S, Nautiyal A, Dolan JG. Recurrent acute pancreatitis possibly induced by atorvastatin and rosuvastatin. Is statin induced pancreatitis a class effect JOP 2004 5(6) 502 1. 

It appears that all ACE inhibitors tested to date have beneficial effects in patients with chronic heart failure. Recent studies have documented these beneficial effects with enalapril, captopril, lisinopril, quinapril, and ramipril. Thus, this benefit appears to be a class effect. 

FIGURE 5.2 Schematized presentation of the mixed-model approach for assemblage-level extrapolation. Note A similar approach is followed for species-level mixed-model extrapolation. The system can be simplified by assuming response addition for all extrapolations except the baseline toxicity assessment (approach of Hamers et al. [1996], yielding combi-PAF). The system can also be more complex when predictions for compound class effects are made for different species groups. 

Typically these studies cost from 1.5 to 3 million to conduct. Based on the perceived probability of a significant QT interval effect (based on preclini-cal studies, class effects, and ECG data from phase 1 studies) a decision must be made whether to conduct the definitive QT study prior to proceeding with a proof-of-concept study in patients, or whether to delay this study until the proof of concept (POC) has been demonstrated. Of note, for many biophar-maceutical products it would not be possible nor ethical to dose to steady state in healthy volunteers, to dose at two to four times anticipated therapeutic exposures, or to use a crossover design with reasonable washout periods. Thus a QT study performed with a biopharmaceutical may need to vary from the usual design and the E14 guidance, and may present great challenges for subject or patient recruitment. 

Hybridization-Independent Toxicides Many, if not most, of the toxicities that have been observed with PS ODN and other oligonucleotide classes are related to the hybridization-independent effects. These class effects are related to the chemistry, and many are known to be related to the interaction of oligonucleotides with proteins (reviewed in [17,30,31] [1]). Toxicities such as the prolongation of aPTT, the activation of complement, and immunostimulation are all examples of oligonucleotide protein interactions that are independent of hybridization. Thus reducing protein binding also reduces the likelihood of some of these toxicities, but that comes at a cost. Reduced protein binding... 

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