Significant Adverse Effect

Several steroidal and non-steroidal glucocorticoid receptor selective dissociated agonists are in development by many pharmaceutical companies and some are now in clinical development. This suggests that the development of dissociated glucocorticoids with a greater margin of safety is possible and may even lead to the development of oral compounds that do not have significant adverse effects. 

Ticlopidine inhibits the P2Yj2 platelet ADP receptor, thus inhibiting ADP-dependent activation of the GP Ilb/IIIa receptor. It has a slow onset of action and takes 3-7 days to reach its maximal antiplatelet effect. It is inactive in vitro and must undergo activation by the hepatic cytochrome p450 enzyme system. Secondary prevention trials have found that ticlopidine-treated patients have an estimated RRR of 33% for the composite endpoint of stroke, myocardial infarction, or vascular death after ischemic stroke. Significant adverse effects include bone marrow depression, rash, diarrhea, and thrombotic thrombocytopenic purpura. No clinical trials have studied ticlopidine for the treatment of stroke in the acute phase. 

Corticosteroids, while effective for rapidly inducing remission, are not effective for maintenance therapy and are associated with significant adverse effects with long-term use. Therefore, systemic or topical corticosteroids should not be used for maintaining remission in patients with IBD. Unfortunately up to 50% of patients treated acutely with corticosteroids become dependent on them to prevent symptoms.2... 

At present, pegylated interferon plus ribavirin is the regimen of choice for the treatment of hepatitis C.41 Interferon, pegylated interferon, and ribavirin have significant adverse effects, as discussed below. 

Methysergide is an ergotamine derivative that impacts central serotonin balance.51 It is reserved for use in migraineurs refractory to other agents, due to its significant adverse-effect profile. As an ergot compound, it is a vasoconstrictor that may worsen vascular dilatory reserves and precipitate cardiovascular events or ischemic stroke in those with... 

Children treated with GH replacement therapy rarely experience significant adverse effects, whereas adults are more susceptible to dose-related adverse effects. Treatment with GH may mask underlying hypothyroidism. GH-induced symptoms, such as edema, arthralgia, myalgia, and carpal tunnel syndrome, are common and necessitate dose reductions in up to 40% of adults. Benign increases in intracranial pressure may occur with GH therapy and generally are reversible with discontinuation of treatment. Often, GH therapy can be restarted with smaller doses without symptom recurrence. 

Because prostheses are the most invasive treatment available, they are only considered in patients who do not respond to medications or external devices, or those who have significant adverse effects from other therapies. Patient satisfaction rates can be as high as 80% to 90% with partner satisfaction rates just slightly lower.9 The primary risks of insertion of prostheses are infection and device failure, although these only happen in 2% to 3% and 2% to 14% of patients, respectively. Higher infection rates have been reported in uncontrolled diabetic patients, paraplegics, and patients undergoing reimplantation or penile reconstruction.14,15 Most prostheses can be expected to last from 7 to 10 years.16... 

Successful therapy for ED results in an increase in erections suitable for intercourse, and most importantly in an improvement in the patient s quality of life. Ideally, the therapy chosen is free of significant adverse effects, discomfort, and inconvenience. Laboratory evaluation and a physical exam are not necessary for evaluation of effectiveness, but may be necessary to determine if adverse events are occurring. 

The systemic carbonic anhydrase inhibitors are associated with significant adverse effects which include paresthesias of the hands and feet, nausea, vomiting, and weight loss. Patients... 

It is important to remember that adverse effects of topical corticosteroids may be systemic in nature and hypothalamic-pituitary-adrenal axis suppression can occur, especially when high-potency corticosteroids are used. Infants and small children may be more susceptible due to their increased skin sur-face body mass ratio.18 Topical corticosteroids may also cause striae, skin atrophy, acne, telangiectasias, and rosacea.2,10,18 Atrophy can result in thin, fragile, easily lacerated skin. Striae are caused by tearing of dermal connective tissue and are irreversible.18 Due to their significant adverse-effect profile, it has been recommended that no topical corticosteroid be used regularly for more than 4 weeks without review and reassessment.2... 

Absorption, Distribution, Metabolism, and Excretion. There are no data available on the absorption, distribution, metabolism, or excretion of diisopropyl methylphosphonate in humans. Limited animal data suggest that diisopropyl methylphosphonate is absorbed following oral and dermal exposure. Fat tissues do not appear to concentrate diisopropyl methylphosphonate or its metabolites to any significant extent. Nearly complete metabolism of diisopropyl methylphosphonate can be inferred based on the identification and quantification of its urinary metabolites however, at high doses the metabolism of diisopropyl methylphosphonate appears to be saturated. Animal studies have indicated that the urine is the principal excretory route for removal of diisopropyl methylphosphonate after oral and dermal administration. Because in most of the animal toxicity studies administration of diisopropyl methylphosphonate is in food, a pharmacokinetic study with the compound in food would be especially useful. It could help determine if the metabolism of diisopropyl methylphosphonate becomes saturated when given in the diet and if the levels of saturation are similar to those that result in significant adverse effects. 

Reproductive Effects. There is sufficient qualitative evidence to support the conclusion that at high occupational exposure levels lead has significant adverse effects on human reproduction, including increased incidences of spontaneous abortion, miscarriages, and stillbirths. The mechanisms responsible for these effects are unknown at this time, but many factors may contribute to these results. These factors include indirect effects of lead on maternal nutrition or hormonal status before and during pregnancy to... 

Many drugs when given to a pregnant woman produce significant adverse effects on the fetus. For each of the drugs below, match the most likely adverse effect. 

In utero exposure to mercury did not produce significant adverse effects on adult performance, although gender differences may interact with methylmercury on certain behaviors... 

Significant adverse effects of zinc on growth, survival, and reproduction occur in representative sensitive species of aquatic plants, protozoans, sponges, molluscs, crustaceans, echinoderms, fishes, and amphibians at nominal water concentrations between 10 and 25 pg Zn/L (Table 9.6). Latent effects of zinc intoxication after brief exposures are poorly documented. One study showed that sensitive species of freshwater crustaceans exposed to zinc concentrations as low as 150 pg/L for as little as 30 minutes had delayed effects that included increasing immobility for up to 172 hours after exposure (Brent and Herricks 1998). 

Proposed criteria for protection of aquatic life include mean zinc concentrations of <47 to <59 pg/L in freshwater, and <58 to <86 pg Zn/L in seawater. Results of recent studies, however, show significant adverse effects to a growing number of freshwater organisms in the range of 5 to 51 pg Zn/L, and to saltwater biota between 9 and 50 pg Zn/L, suggesting that some downward modification in the proposed criteria is necessary. 

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