Volume 2, Number 9: September 1999

Increased proinflammatory cytokines in patients with chronic stable angina and their reduction by aspirin.

Effect of cilostazol on the neuropathies of streptozotocin-induced diabetic rats.

Drug prescriptions and costs in diabetic polyneuropathy

Fish oils in coronary atherosclerosis

Increased proinflammatory cytokines in patients with chronic stable angina and their reduction by aspirin.

Reference: Circulation 1999 Aug 24;100(8):793-8

Background:Proinflammatory cytokines released by injured endothelium facilitate interaction of endothelial cells with circulating leukocytes and thus may contribute to development and progression of atherosclerosis. We investigated whether cytokines and C-reactive protein (CRP) are indicative of myocardial ischemia or of diseased vessels and whether they are influenced by aspirin treatment in patients with chronic stable angina.

Methods and Results:Plasma macrophage colony stimulating factor (MCSF), IL-1b, IL-6, and CRP were measured in 60 stable patients after 48-hour Holter monitoring and in 24 matched controls. All patients had angiographic documentation of disease and positive exercise ECGs. Patients with ischemia on Holter monitoring (n=40) received aspirin or placebo in a 6-week, randomized, double blind, crossover trial. Blood sampling was repeated at the end of each treatment phase (3 weeks). Compared to controls, patients had more than twice median MCSF (800 versus 372 pg/mL), IL-6 (3.9 versus 1.7 pg/mL), and CRP (1.25 versus 0.23 mg/L) levels (P<0.01 for all comparisons). MCSF was related to ischemia on Holter monitoring (P<0.01), to low ischemic threshold during exercise (P<0.01), and together with IL-1b to number of diseased vessels (P<0.05). MCSF, IL-6, and CRP were all reduced after 6 weeks of aspirin treatment (P<0.05).

Conclusions-These findings suggest that cytokines are associated with both ischemia and anatomic extent of disease in patients with stable angina. Reduced cytokine and CRP levels by aspirin may explain part of aspirin's therapeutic action.

 Effect of cilostazol on the neuropathies of streptozotocin-induced diabetic rats.

Reference: Korean J Intern Med 1999;14(2):34-40

OBJECTIVES: This study examined the effect of cilostazol, a potent phosphodiesterase inhibitor, on the progression of neuropathies associated with streptozotocin-induced diabetes mellitus in Sprague-Dawley rats.

METHODS: Eight weeks after streptozotocin treatment, a pelleted diet containing 0.03% cilostazol (15 mg/kg body weight) was given for four weeks. Body weight, blood glucose level, motor nerve conduction velocity (MNCV), myelinated fiber density and size distribution of sciatic nerves were compared between age-matched normal rats (Group 1), control diabetic rats (Group 2) and cilostazol-treated diabetic rats (Group 3).

RESULTS: Body weight was significantly reduced and blood glucose level was significantly increased in diabetic rats (Group 2 and 3) compared to normal rats. MNCV and cAMP content of sciatic nerves were significantly reduced in diabetic rats 12 weeks after streptozotocin treatment. Myelinated fiber size and density were also significantly reduced, and thickening of the capillary walls and duplication of the basement membranes of the endoneural vessels were observed in the diabetic rats. Whereas both body weight and blood glucose level of Group 3 did not differ significantly from those of Group 2, cilostazol treatment significantly increased MNCV and cAMP content of sciatic nerves in Group 3 but not to the levels observed in Group 1. MNCV positively correlated with cAMP content of sciatic nerves (r = 0.86; p < 0.001). Cilostazol treatment not only restored myelinated fiber density and size distribution but reversed some of the vascular abnormalities.

CONCLUSION: These findings suggest that a reduced cAMP content in motor nerves may be involved in
the development of diabetic neuropathy, and that cilostazol may prevent the progression of diabetic neuropathy by restoring functional impairment and morphological changes of peripheral nerves

Drug prescriptions and costs in diabetic polyneuropathy

Reference: Dtsch Med Wochenschr 1999;124(22):681-6.

BACKGROUND AND OBJECTIVE: Numerous medications are used in the treatment of diabetic polyneuropathy (PNP) without evidence of their efficacy. This study was undertaken to obtain the costs of drugs prescribed to patients with PNP throughout the Federal Republic of Germany in primary-care practices.

PATIENTS AND METHODS: Data (stored in the Medi-Plus data bank of the Institute for Medical Statistics, Frankfurt) from 400 primary-care practices were analysed for the year 1996 with regard to diagnoses and prescriptions for 40,112 diabetics over the age of > or = 20 years. A polyneuropathy (PNP) had been diagnosed in 3548 patients (8.8%) (age: 68 +/- 12 years, 56% women). The cost of medications listed for the treatment of PNP was identified and extrapolated to the total prescription cost for treated diabetic PNP in the whole of Germany. In addition the proportion of costs for drugs with unproven efficacy was calculated.

RESULTS: Antidepressives were prescribed for 13%, carbamazepine for 4%, and lipoic (thioctic) acid for 41% of diabetics with PNP. Annual costs per patient (mean value) were DM 203 for lipoic acid, DM 53 for vasoactive drugs and DM 42 for analgesics. Projection for the estimated total number of diabetic patients with PNP treated in primary care practices (n = 361,400) gave a total cost of DM 116 million (95% confidence limit: DM 109-123), of which DM 41 million (35%) was for medications of unproven efficacy.

CONCLUSION: In Germany one third of drug costs for diabetic patients with PNP in primary care is for medications of unproven efficacy. Cost-effective guidelines for the treatment of diabetic PNP are urgently required.

The Effect of Dietary Omega-3 Fatty Acids on Coronary Atherosclerosis. A Randomized, Double-Blind, Placebo-Controlled Trial

Reference: Ann Intern Med 1999; 130: 554-562

SUMMARY: Many epidemiological studies have suggested that a high intake of oily fish decreases the incidence of ischemic heart disease. This is thought to be due to the omega-3 fatty acid content of fish oils. Animal models have suggested that these fish oils can reverse atherosclerotic changes. This randomized, double-blind, placebo-controlled trial from Munich, Germany, examines whether a dietary intake of omega-3 fatty acids has antiatherosclerotic potential in humans with preexisting atherosclerosis.

PATIENTS AND METHODS: Subjects undergoing diagnostic coronary angiography were recruited if they had a stenosis greater than 20% in at least one vessel and revascularization (PTCA or CABG) planned or performed in the previous six months in no more than one vessel. Patients were randomized to receive treatment with either fish oil or matched placebo capsules. Each capsule contained one gram of fatty mixture. The fish oil capsules contained a fish oil concentrate. The placebo capsules contained no marine omega-3 fatty acids but other fatty acids similar in composition to those found in a normal European diet. For the first three months the subjects took six capsules (6 g) daily, and for the next 21 months they took 3 capsules (3 g) daily. After 24 months the coronary angiography was repeated. All pairs of baseline and end-of-study angiograms were reviewed by an expert panel of three invasive cardiologists unaware of treatment allocation. Lesions detected on one film were compared with the other film and graded as to whether they had progressed or regressed. A record was kept of all cardiovascular events occurring throughout the trial. 223 subjects were recruited over a 2-year period; 112 were assigned to fish oil treatment and 111 to placebo. Mean age was 58 years. 80% were male. Half had a history of a previous myocardial infarction; in one-third this was within the previous six months. On the baseline angiograph, just under half had a greater than 70% stenosis in one coronary vessel and a further 35% had this in two or more vessels.

RESULTS: At the end of the study, paired baseline and final angiograms were available in 162 subjects: 82 in the fish oil group and 80 in the placebo group. In the placebo group, there were changes in atheroma in 48 matched coronary segments: 36 showed mild progression, 5 showed moderate progression, and 7 showed mild regression. In the fish oil group, there were changes in 55 segments: 35 showed mild progression, 4 moderate progression, 14 mild regression, and 2 moderate regression. The differences between the groups reaches statistical significance at the 5% level. 7 patients in the placebo group experienced a myocardial infarction (4) or stroke (3), compared with 2 in the placebo group (1 MI, 1 stroke). This difference was not statistically significant.

CONCLUSION: Overall, therefore, the patients in the fish oil group showed a slightly greater probability of atherosclerotic regression and less progression than those treated with placebo. Of course, the "placebo" used was itself a fatty acid mixture, which may have had deleterious effects on patients' atheroma. Although the study did not show a significant reduction in clinical outcomes, the primary endpoint measure, namely, change in atheromatous stenosis, should be a good surrogate marker for these over a period of time. A study of greater duration would be of interest.