Incidence Of Serious Adverse Effects Research Articles

Epoetin (recombinant human erythropoietin). A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in anaemia and the stimulation of erythropoiesis.

Epoetin (recombinant human erythropoietin) is a sialoglycoprotein hormone that appears to be immunologically and biologically equivalent to the endogenous compound, enhancing erythropoiesis dose-proportionally. The therapeutic efficacy of epoetin in the treatment of anaemia associated with chronic renal failure has been established, with almost all patients responding with increases in haematocrit and haemoglobin levels, and improvements in quality of life. Some patients demonstrate relative epoetin resistance and require a higher dosage to achieve target haemoglobin and haematocrit levels. Maintenance of an adequate iron supply is essential and iron supplementation is recommended if serum ferritin is below 100 to 150 micrograms/L or transferrin saturation is less than 20%. The incidence of serious adverse effects may be reduced by maintaining a moderate rate of increase in the haematocrit with close monitoring of blood pressure and dialysis efficacy. Individual titration of epoetin dosage is recommended, with increases made in small increments to achieve haematocrit and haemoglobin levels of 30 to 33% and 10 to 12 g/dl, respectively, although the optimal haematocrit for each patient should be individually determined. Some patients will also require a modest increase in heparin dosage because of a possible increase in clotting tendency. Hypertension is the most common adverse effect in patients with chronic renal failure, occurring partially as a result of increasing blood viscosity and peripheral vascular resistance with the correction of anaemia. Maintenance epoetin therapy has been given for more than 2 years without a decrease in responsiveness and does not appear to adversely affect the outcome of renal transplantation. Thus, epoetin represents a significant therapeutic advance in the treatment of anaemia associated with chronic renal failure and should be considered a first option for these patients. Its potential value in the treatment of anaemia associated with other disorders and in facilitating autologous blood donation remains to be fully determined.

Hydroxyurea in the management of therapy resistant psoriasis.

Eighty-five patients with extensive chronic plaque psoriasis, unresponsive to conventional topical therapy, were treated with long-term hydroxyurea in a dose of 0.5-1.5 g daily. Fifty-two (61%) had a satisfactory remission during treatment without significant adverse effects. Treatment was discontinued in 33 patients (39%), due to an inadequate response or significant relapse during treatment and because of adverse reactions (19%). Four (4.7%) patients on hydroxyurea developed actinic psoriasis. Significant haematological abnormalities occurred in 30 patients (35%), but these became normal following a reduction in the dose of hydroxyurea or temporarily stopping the drug. In only six was it considered necessary to discontinue treatment because of bone marrow suppression. Our experience suggests that hydroxyurea is an effective long-term treatment for psoriasis that is refractory to conventional topical therapy and that the incidence of serious adverse effects compares favourably with other cytotoxic drugs.

Aerosolized pentamidine in HIV. Promising new treatment for Pneumocystis carinii pneumonia.

Pneumocystis carinii pneumonia is the most common life-threatening disease diagnosed in patients infected with the human immunodeficiency virus (HIV). Patients treated for their initial episode are at risk for recurrence of the disease. HIV-positive patients with low T4 lymphocyte counts are also at risk. Conventional treatment regimens with parenteral pentamidine isethionate (Pentam 300) or trimethoprim-sulfamethoxazole have a 50% to 60% incidence of serious adverse effects and a 20% to 40% rate of failure. Aerosolized pentamidine represents a promising new therapy for HIV-infected patients. Major adverse reactions have not been reported with its use. The Food and Drug Administration's (FDA's) recent approval of aerosolized pentamidine may also have a positive effect on healthcare costs by preventing episodes of P carinii pneumonia. In addition, FDA approval may result in reimbursement of patients for this new therapy by more insurance companies.

The place of ACE inhibitors in the current treatment of chronic heart failure

In assessing the place of any therapy for chronic heart failure (CHF) there are two main considerations does the treatment make patients feel better and does it make them live longer? It is then important to see whether this treatment offers any advantages over other treatments; here the side effect profile may be a crucial determinant. There is now sufficient evidence to compare angiotensin converting enzyme (ACE) inhibitors to diuretics and other vasodilators in these respects (but not enough to make any comparison with digoxin). With regard to symptomatology, several well designed large scale, placebo-controlled trials have shown that ACE inhibitors improve symptoms and exercise tolerance in advanced CHF when added to diuretics (and other treatments). 1-3 In less severe CHF the evidence is different. Richardson et al. have shown that an ACE inhibitor alone may be an insufficient treatment in patients with mild heart failure compared to a diuretic alone, especially if there is a previous history of acute pulmonary oedema.4 It has also been suggested that increasing the dose of diuretic may improve symptoms and exercise tolerance more than adding an ACE inhibitor in patients with mild to moderate CHF.5 The combination of an ACE inhibitor, it should be stressed, does cause some clinical improvement and considerations other than symptomatic benefit may be important in deciding whether to add an ACE inhibitor or more diuretic (see below).6'7 In contrast to the case with diuretics, there is good evidence to suggest that ACE inhibitors are superior to other vasodilators in terms of symptomatic benefit and also in terms of side effects, tachyphylaxis and neuroendocrine suppression.8 10 Turning to mortality, there is no evidence to show that diuretics improve prognosis in CHF and some suspicion that they may contribute to progression of the syndrome (see below). Certain vasodilators, on the other hand, may reduce mortality. The VHeFT-1 trial compared a high dose hydralazine isosorbide dinitrate (ISDN) combination (300mg/160mg daily respectively), prazosin (20mg daily) and placebo as adjunctive therapy in patients with mild to moderate heart failure.1' Prazosin was not superior to placebo but the hydralazine ISDN combination reduced mortality from 19.5% to 12.1% after 1 year. The patients in this study were, however, atypical there was a high incidence of alcohol-related disease (40%), a somewhat low incidence of coronary artery disease (44%) and all patients were male and relatively young (mean 58 years). Even more importantly approximately one-third of patients had to have a reduction in dosage, or the discontinuation of either or both drugs, during this study because of adverse effects. More recently the Consensus trial study group have reported that the addition of enalapril (mean daily dose 18.4mg) to maximal conventional treatment in patients with severe CHF resulted in a reduction in 1 year mortality from 52% to 31%.12 The patients in this study were much more typical of British hospital practice 73% had coronary artery disease, they were of both sexes and had a mean age of 70 years. Also in contrast to the VHeFT-1 trial, there was a much lower incidence of serious adverse effects (17% withdrawn on enalapril compared with 14% on placebo). Crucially, 44% of the enalapril-treated patients were already receiving other vasodilators (mainly ISDN) and yet still showed a reduction in mortality. All this information suggests that ACE inhibitors do indeed make patients with CHF feel better and live longer. They seem to be more effective than other vasodilators in these respects and certainly have fewer adverse effects.9 ACE inhibitors must, however, remain complementary to diuretics. The latter offer initially superior symptom control but do not improve prognosis. There are also other reasons to believe that ACE inhibitors and diuretics

Clinical consequences of age-related impairments in vascular compliance

Advancing age is associated with progressive reductions in the vascular distensibility of major vessels. Two clinically relevant consequences of physiologically impaired arterial compliance of aging, increased systolic blood pressure and decreased carotid arterial baroreflex sensitivity, are discussed. While arterial thickening and stiffening with age are associated with increased systolic blood pressure, diastolic blood pressure is generally stable or even decreases slightly with advancing age. Thus, the prevalence of isolated systolic hypertension increases dramatically with age. This long-neglected abnormality has recently attracted attention, and the view that systolic hypertension is harmless and its treatment fraught with a high incidence of serious adverse effects has now been shown to be myth. Several studies indicate substantial risk associated with isolated systolic hypertension, especially with regard to increasing prevalence of stroke. A recent multicenter trial has shown that systolic blood pressure can be safely lowered with low doses of thiazide diuretics. Currently, a National Institutes of Health sponsored multicenter trial aims to determine whether treatment of isolated systolic hypertension is associated with reduced risk. Age-related impairments in baroreflex sensitivity reduce the capacity of normal elderly persons to increase the heart rate in response to hypotensive stress and contribute to the increased prevalence with advancing age of orthostatic hypotension. This must be taken into account in the design of pharmacologic treatment regimens in older persons.

Rationale for calcium entry-blocking drugs in systemic hypertension complicated by coronary artery disease

There is considerable rationale for the use of the calcium entry-blocking drugs for the treatment of hypertension and prevention of recurrent episodes of angina pectoris in patients with systemic hypertension and significant coronary artery disease—the 2 entities commonly occurring together. Calcium entry-blocking drugs improve myocardial blood flow while decreasing myocardial oxygen demand. These agents can be given to most patients with ischemic heart disease and its complications, and are associated with a relatively low incidence of serious adverse effects and toxicity during long-term therapy. They reduce the frequency of anginal attacks, prolong exercise time to ST-segment depression or angina and improve exercise capacity. With long-term therapy, tolerance does not develop as it does in many patients with the “long-acting” nitrates. Calcium entry-blocking drugs reduce systolic blood pressure in patients with hypertension by a decrease in peripheral vascular resistance and a uniform improvement in blood flow affecting the myocardium, kidney and brain. There are no central nervous system adverse effects and hypokalemia does not occur. Unlike therapy with the β-blocking drugs, chronic treatment with the calcium entry blockers does not reduce the serum level of high-density lipoprotein cholesterol nor increase serum triglyceride concentration. The calcium blockers decrease the arterial blood pressure without increasing intravascular plasma volume and are associated with only a slight increase in reflex-mediated sympathetic activity and heart rate, the latter occurring predominantly with nifedipine. Calcium entry-blocking drugs provide alternative or preferred therapy to β-blocking agents in patients with a combination of hypertension and angina pectoris. They are likely to be more effective in elderly patients and in blacks and can be prescribed for patients with bronchospastic disease and symptomatic peripheral vascular disease. For many reasons, of the 3 currently available calcium blockers, dilatizem is likely to be the most effective calcium entry blocker for monotherapy In patients with hypertension and ischemic heart disease, although most worldwide experience for this indication has been with nifedipine.

Calcium-entry blocking agents in the treatment of systemic hypertension

Calcium-entry blocking agents resemble established dilators such as diazoxide, minoxidil and hydralazine in that they act predominantly on the arterial resistance vessels and have little or no effect upon the veins. They have therefore been evaluated in the treatment of hypertension. Controlled studies have shown that verapamil and nifedipine are effective in decreasing blood pressure when given as sole agents. The antihypertensive effect of nifedipine is additive with that of a β blocker, and nifedipine is also effective when given as a “third step” agent in combination with a p blocker (or α methyldopa) and a diuretic. In contrast to other directly acting dilators, nifedipine causes, at most, only moderate stimulation of renin secretion and verapamil does not increase renin release at all; neither drug induces sodium retention. Both verapamil and nifedipine produce a moderate incidence of unwanted effects; these are mostly subjective in nature, but verapamil may cause constipation that is occasionally severe and nifedipine sometimes causes ankle swelling. Calcium-entry blockers should be considered as initial therapy when some contraindication exists to the use of other standard drugs. Nifedipine appears preferable to hydralazine for use in combination with a β blocker and a diuretic: it is at least as effective as hydralazine and has a lower incidence of serious adverse effects.