Low cholesterol and cancer.

PURPOSE: The relation between plasma cholesterol (CH) concentration and mortality is complex. The plasma CH concentration correlates positively with mortality from coronary heart disease, but some studies have shown a negative relation with death from cancer. If these two relations reflect causal mechanisms that are reversible by changing the plasma CH concentration, the benefits of lipid reduction for heart disease might be offset by an increased mortality from cancer. Different aspects between lipid metabolism and cancer, as well as new insights into this interesting field, are discussed. METHODS: The literature was searched using MedLine through 1966 and January 1996. RESULTS: There is no evidence from the data available at present that the association between low CH and a higher risk of cancer is causal. CONCLUSION: This issue should not affect the advice on health matters offered by doctors, especially to patients with other risk factors for cardiovascular disease. The possibility that hypercholesterolemia (HC) drugs can induce a reduction of tumor-cell growth makes them potentially useful as an adjuvant to chemotherapy and ultimately increases the probabilities in the prevention and treatment of cancer.

Long-term continuous intravenous insulin therapy with a portable insulin dosage-regulating apparatus.

A portable insulin dosage-regulating apparatus (PIDRA) was used with five volunteer diabetic subjects for periods ranging from 1 wk to more than 3 months to explore the possibilities of achieving near normoglycemic control over long time periods with such an apparatus. PIDRA consists of a matchbox size pump with insulin reservoir and a pocket size electronic control box. It can infuse a preprogrammed basal rate of insulin plus externally manipulated supplementary doses in rectangular profiles. The quality of blood glucose control was monitored with the Miles Biostator and through self-testing by the patient in the outpatient phases. Under inpatient conditions, the relatively simple PIDRA insulin administration profile was almost as effective in achieving normoglycemia as the Biostator, and good control could be maintained over long periods of time. The apparatus allows considerably greater ease in variation of insulin dosage with less risk of hypoglycemic epidoses as compared with conventional subcutaneous injections. Several technical problems remain to be solved, but it is concluded that PIDRA represents a viable alternative as a means of achieving tight control, at least as a step toward the goal of an implanted glucose-contingent insulin infusion system.

Long-term continuous intraperitoneal insulin infusion with an implanted remote-controlled insulin infusion device.

This is a report of the implantation and first 100-day operation using a remote-controlled programmable insulin infusion device in an insulin-dependent diabetic. To prevent insulin aggregation, a special surface-active polymer developed by Hoechst AG, Frankfurt, was used as an additive. Implantation was completed on April 8, 1981, and good metabolic control was reached immediately and has continued to date (July 1981), with this unit providing the only source of insulin. There have been no hypoglycemic attacks. Patient acceptance is very good. The Siemens unit, PFA 01 (external) and DFA 01 (implanted) has proved reliable and precise.

Passive smoking and cardiovascular risk.

A possible relationship between passive smoking and coronary heart disease has been widely debated during the past decade. Convincing evidence links environmental (passive) tobacco smoke exposure to heart disease morbidity as well as mortality. In the United States, 37,000 coronary heart disease deaths per year are attributed to environmental tobacco smoke exposure, accounting for 70% of all deaths caused by environmental tobacco smoke. The analysis of 10 epidemiologic studies indicated a consistent dose-response effect related to exposure, but more proof is still needed. Evidence indicates that nonsmokers are more sensitive to smoke, including cardiovascular effects, and that sidestream smoke contains higher concentrations of gas constituents, including carbon monoxide. Pathophysiological and biochemical data after short- and long-term environmental tobacco smoke exposure show changes in endothelial and platelet function as well as exercise capacity similar to those in active smoking. Therefore, passive smoking is a relevant risk factor for heart disease morbidity and mortality.

Guar and its effects on metabolic control in type II diabetic subjects.

The effect of guar mini-tablets (5 g t.i.d.) on carbohydrate and lipid metabolism of outpatients with overt diabetes mellitus with glycosuria (is greater than 5 g/24 h) was determined in an open-controlled, randomized, multicenter, crossover study. A 4-wk pretreatment period was followed by a 6-wk treatment period. The treatment period consisted of a 2-wk guar period (treatment period II), which was followed by the wash-out period. The other half of the patients received treatment in the reverse order. Out of 93 patient records, 79 (41 sulfonylurea [SU] and 38 insulin-treated) were suitable for statistical analysis. No relevant weight-reducing effect of guar could be found in both 2-wk treatment periods. At the end of treatment period II, the lowering of the 1-h postprandial values of blood glucose (SU 12%, insulin 10%), cholesterol (SU and insulin 25%) was significant after 2-wk of guar treatment compared with the wash-out period. No clinically relevant changes in the safety laboratory parameters were observed during guar treatment. Side effects were observed in 40 of the 93 patients included in the trial. Treatment had to be discontinued in 11% of the patients due to gastrointestinal side effects. On the basis of our results,guar treatment in combination with sulfonylurea and insulin can be recommended for the improvement of carbohydrate and lipid metabolism.

Influence of radiation synovectomy on articular cartilage, synovial thickness and enhancement as evidenced by MRI in patients with chronic synovitis.

UNLABELLED: Radiation synovectomy is a safe and effective treatment for chronic synovitis that is refractory to the repetitive, intra-articular application of glucocorticosteroids in patients with rheumatoid or seronegative arthritis. Short-term and long-term effects of radiation synovectomy on articular cartilage, synovial enhancement and thickness were assessed in a prospective, clinical trial by MRI. METHODS: Thirteen patients (mean age 39+/-13 y) were treated with a median activity of 8.4 GBq 165Dy ferric hydroxide, a radionuclide with favorable physical properties and a well-documented clinical safety and efficacy profile. MRI was performed on a 1.5-T MR unit using a circular polarized knee coil. RESULTS: After a mean observation period of 13 mo, a marked reduction in synovial enhancement was observed in 10 patients. The mean reduction in baseline synovial thickness (mean 7.6+/-3.0 mm) was 24% (P = 0.03) at 1 wk and 42% (P = 0.01) about 1 y after treatment, respectively. Clinically, 9 of 13 patients (69%) exhibited persistent response to radiation synovectomy. The local clinical score, as defined by the reduction in pain, pannus, joint effusion and by the increase in the range of motion, improved significantly (P = 0.01), from a median of 7 (range 4-10) to a median of 2 (range 0-9). One year after treatment, changes in the local clinical score were related to the decrease in synovial enhancement in MRI (r = 0.7, P = 0.008, n = 12). There were no persistent adverse effects, nor was there evidence for any severe radiation-induced damage to the articular cartilage. On later follow-up images, the structure of the articular cartilage remained unaltered in all but 3 patients, who had new, superficial erosions most likely attributed to an active disease with persistence of inflammation. CONCLUSION: This study suggests that radiation synovectomy with 165Dy-ferric hydroxide is effective in terms of reducing chronic synovitis without causing detectable harm to the articular cartilage, as shown by MRI.

Controlled drug delivery in the treatment of diabetes mellitus.

Diabetes not only requires correction of an insulin deficiency but it also demands adequate insulin delivery. A short historical review is given over the first 60 years of insulin treatment, where emphasis was mainly on the correction of insulin deficiency. Despite concerted efforts, metabolic results were often poor, and there was a high incidence of late complications, which will be described briefly. A major aim of new treatment approaches, which emphasizes better routes of insulin delivery, is the prevention or reversal of these late complications. Closed-loop systems are infusion systems located outside the body which deliver insulin according to glucose values that are measured continuously. The state of the art for such systems will be described with examples of clinical applications and results. These systems aid and stimulate research, but offer no long-term application for treatment. Open-loop systems are portable, both external and implantable, and lack an accurate glucose sensor so that the loop can be closed. A number of insulin delivery systems have been developed in this category ranging from highly complex, fully implantable units, programable from outside, to simple basal-rate infusion pumps. Various pumps are designed to be used with varying delivery routes, and the evaluation of different routes will be a vital topic in this article. Pros and cons of the intravenous, intraperitoneal, and subcutaneous routes will be discussed, with supporting research referenced. Clinical experience will be cited for both the complex and the simple infusion systems. Other topics to be covered include feasibility of long-term treatment, complications of this new treatment approach, guidelines for patient instruction and supervision, requirements for treatment of large patient groups with pumps in a modern diabetes center, requirements for the physician, the influence of improved metabolic control on late complications (prevention or regression), the possibility for a portable closed-loop system, and future outlook. The primary author is the founder of an international study group on diabetes treatment with implantable insulin delivery devices. The common goals of this study group will also be presented. Special emphasis will be placed on a differentiated approach to treatment of Type I and Type II diabetes with a family of devices. Clinical work and results from a large patient group will be included throughout.

6-oxo-PGF(1 alpha)and 8-epi-PGF(2 alpha)in the arterial wall layers of various species: a comparison between intact and atherosclerotic areas.

PGI(2)and 8-epi-prostaglandin(PG)F(2 alpha)are antagonizing compounds. For both a key role in vascular pathology has been hypothesized. The isoprostane 8-epi-PGF(2 alpha)and the stable derivative of PGI(2), 6-oxo-PGF(1 alpha)were determined immunologically in the arterial wall of various species including humans. Human arterial tissue contained the highest amounts of 8-epi-PGF(2 alpha)and synthesized the lowest PGI(2). A significant negative correlation between 8-epi-PGF(2 alpha)and 6-oxo-PGF(1 alpha)was observed. Atherosclerotic segments showed significantly higher 8-epi-PGF(2 alpha)and lower 6-oxo-PGF(1 alpha). 8-epi-PGF(2 alpha)in the intima was higher than in the media, the highest amounts being found in foam-cell rich areas. Synthetic (activated) smooth muscle cells were associated with an enhanced 8-epi-PGF(2 alpha)as well as 6-oxo-PGF(1 alpha). Tissue samples derived from smokers contained more 8-epi-PGF(2 alpha)and produced less PGI(2). The by far highest 8-epi-PGF(2 alpha)/6-oxo-PGF(1 alpha)ratio was found in foam cell rich areas. Similar findings were obtained in rabbit and in minipig arteries. The total 8-epi-PGF(2 alpha)/6-oxo-PGF(1 alpha)ratio is low in normal tissue, increases significantly in an active atherosclerotic process and seems to be even further increased in an inactive atherosclerotic process. These findings are providing an information on the extent of oxidation injury at various sites of different types of atherosclerotic process.

Association of lipoprotein(a), prostaglandin I(2)--synthesis stimulating plasma factor, biological half-life of prostaglandin I(2)and high-density lipoproteins in HIV-1 infection of different stages.

Patients with human immunodeficiency virus show increased atheroembolism and premature arterial events (stroke, myocardial infarction), but no increased venous thromboembolism. This paper describes an association of elevated lipoprotein(a), a decreased prostaglandin I(2)(PGI(2)) synthesis stimulating plasma factor, diminished PGI(2)-stability in plasma and decreased high-density lipoprotein-cholesterol and apolipoprotein A. It is unclear to what extent these biochemical findings represent an acute phase reaction only or a disturbance in the prostaglandin system. Definitely, they are resulting in severe hemostatic imbalance decreasing local PGI(2)-availability with a dramatic reduction in the cytoprotective capacity favouring the onset of premature arterial events seen in some of the patients.

Chloroquine minimizes sampling artefacts for radioimmunological determination of thromboxane B2 in plasma.

Chloroquine is known to inhibit platelet activation by various mechanisms including arachidonic acid liberation from membrane phospholipids. We therefore examined the influence of chloroquine in addition to the conventional EDTA/acetylsalicylic acid cocktail on thromboxane B2-plasma values. In 11 healthy volunteers the influence of venous occlusion, needle diameter and EDTA (+ acetylsalicylic acid + chloroquine) was examined. In 27 healthy adults, 51 patients with clinically manifested coronary heart disease as well as in 31 patients with peripheral vascular disease parallel samples drawn in the presence of chloroquine showed lower thromboxane B2 in all these three groups of patients, especially in conditions associated with platelet activation and high thromboxane B2-values. These findings suggest that the routine addition of 10 mM chloroquine to the conventional stabilization cocktail can strongly be recommended.

Is a (n inborn) deficiency of prostacyclin synthesis stimulating plasma factor associated with increased lipoprotein(a)?

Patients with the antiphospholipid syndrome as well as those with a lack in the prostacyclin synthesis stimulating plasma factor (PF) are prone to develop thrombophilia and are at a higher clinical risk for vascular disease. As patients with the antiphospholipid syndrome have been reported to show elevated lipoprotein (Lp)(a) levels, we re-examined all our patients known to have an inborn or an acquired persistent deficiency of PF. Their non-affected relatives served as controls. In addition, 36 patients suffering from clinically manifested atherosclerosis as well as 16 healthy adults, all of them having elevated Lp(a) levels (> 30 mg/dl), were screened for a PF deficiency. In fact, all the patients with a deficient PF activity showed elevated Lp(a) values. While the prevalence of PF deficiency ranges about 1-2%, in 7 (19%) patients with clinically manifested atherosclerosis and 3 (19%) healthy adults with elevated Lp(a) this defect was found. The findings demonstrate an association between PF deficiency and Lp(a), indicating a biochemical interaction which needs to be further elucidated.

Isradipine lowers human arterial low density lipoprotein retention in vivo.

During the recent past it has been discussed that calcium antagonists may exert antiatherosclerotic actions at the vessel wall. Apolipoprotein B containing lipoproteins were isolated by immunoaffinity chromatography and radiolabeled with 123-iodine. The effect of 2 x 2.5 mg isradipine on the low density lipoproteins (LDL) entry into the carotid and femoral arteries of 12 hypertensive patients with primary hyperlipoproteinemia (total cholesterol >6.5 mmol/l [250 mg/dL) was examined. Cholesterol -1.7% (P< 0.05 664), high density lipoprotein (HDL) cholesterol +4.5% (P< 0.01 123), and LDL cholesterol -1% (P< 0.01 563) did not change, nor did any of the safety parameters. The types of entry kinetics reflecting vascular surface lining did not change while the LDL retention 20 h after tracer application was depressed by up to 23.5%. The data were comparable in the carotid and femoral artery segments, the significance level ranging up to 0.0009. These results indicate a decreased LDL retention in the arterial wall of hypertensive patients induced by isradipine. The clinical implications of the findings ought to be pursued in properly designed clinical trials.

Semotiadil, a new calcium antagonist, is a very potent inhibitor of LDL-oxidation.

The influence of semotiadil, a novel benzothiazine calcium antagonist on in-vitro copper-, 2,2àzo-bis-(2,4 dimethylvaleronitrile)[AMVN]-, and 2,2àzo-bis-(2-amidinopropane) [AAPH]-induced low-density lipoprotein (LDL) oxidation was assessed. The following parameters were measured: lag-time of oxidation, maximal rate of oxidation, dienes formed through continuous monitoring of developing conjugated dienes, thiobarbituric acid reactive substances, isoprostane(8-iso-PGF2alpha)-generation and relative electrophoretic mobility. The effect was compared with nifedipine, amlodipine and diltiazem. Besides the influence on isoprostane (8-iso-PGF2alpha)-generation where nifedipine was equipotent with semotiadil at 10(-3) M, semotiadil demonstrated a strong and significant effect in attenuating the indicated indices of LDL-oxidation, in particular, dose-dependently (10(-3) M to 10(-7) M). These results indicate that semotiadil may have the strongest antioxidant activity on LDL among the calcium antagonists examined.

6-Oxo-PGF1alpha and 8-epi-PGF2alpha in human atherosclerotic vascular tissue.

Isoprostanes are a new family of compounds generated by the free radical catalyzed action on arachidonic acid. Formed during oxidation they have been claimed to be a reliable indicator of in vivo oxidation injury. We assessed the amount of 8-epi-PGF2alpha in human surgical specimens as compared to PGI2 (via its stable metabolite 6-oxo-PGF1alpha), the major compound generated by vascular tissue. 8-epi-PGF2alpha is low in normal vascular tissue as is the 8-epi-PGF2alpha/6-oxo-PGF1alpha ratio. The vessels of smokers in general exhibited an increased 8-epi-PGF2alpha (r=0.82) and a decreased 6-oxo-PGF1alpha (r=0.71). The 8-epi-PGF2alpha/6-oxo-PGF1alpha ratio is, not significantly, increased in vessels derived from hyperlipidemics and hypertensives. These findings indicate that lipid peroxidation occurs within the human arterial wall as evidenced by 8-epi-PGF2alpha, probably further decreasing the synthesis of PGI2 and promoting atherogenic mechanisms.

Effect of isradipine on in-vivo platelet function.

In animal studies calcium channel blockers (CCB's) and especially isradipine, a second generation dihydropyridine, interrupt the sequence of events culminating in the formation of atherosclerotic lesions. The effect of 4 weeks isradipine treatment (5mg daily) on blood pressure and in-vivo platelet function (measured with 111Indium-oxine labeled autologous platelets) were investigated in a randomized, double-blind and placebo controlled trial in 40 patients with mild to moderate hypertension and scintigraphically diagnosed active atherosclerotic lesions of the carotid arteries. The average supine systolic/diastolic blood pressure was significantly reduced at the end of the treatment period in the isradipine group (group 1; p < 0.0001) but remained unchanged in the placebo group (group P). The heart rate was not significantly altered in either group. There were no serious side effects. The platelet uptake ratio (PUR) measured over the atherosclerotic region of the carotid artery on 4 consecutive days before and after treatment decreased significantly in group I from 1.20 to 1.15 (within groups: p < 0.0001) but remained unchanged in group P. Platelet survival increased significantly in group I (mean 5.70 hours, lower quartile 4.50, upper quartile 4.50 hours, within groups: p < 0.0001) and remained unchanged in group P. Isradipine has a beneficial effect on in-vivo platelet function as evidenced by a decreased platelet deposition on vascular lesion sites and an associated prolonged platelet survival in patients with hypertension and active atherosclerotic lesions.

Isradipine increases vascular prostaglandin I2-formation while the thromboxane B2-synthesis is diminished.

PGI2- and TXA2-synthesis from vascular tissue samples derived from cultured (endothelial and smooth muscle) cells, rabbit aorta and human bypass surgery were determined using specific radioimmunoassays for the stable derivatives (6-oxo-PGF1a and TXB2, respectively) of these compounds. Cultured cells were incubated in presence of isradipine, rabbits were pretreated for 4 weeks receiving 0.3 mg isradipine/kg*day, while patients were on isradipine (5-10 mg total dose/day, per os twice daily) since 6-19 weeks. In presence of isradipine, cultured cells produced significantly (p < 0.01) more 6-oxo-PGF1a and significantly less TXB2 (p < 0.05). 6-oxo-PGF1a-formation in rabbit aorta was significantly (p < 0.01) higher in isradipine treated normocholesterolemic animals while no significant changes were seen in isradipine treated hypercholesterolemic animals. TXB2 was significantly (p < 0.01) depressed in the abdominal and the thoracic aortic segment of isradipine treated hypercholesterolemic animals and was not significantly influenced in isradipine treated normocholesterolemic animals. Similarly, PGI2-synthesis in human arterial specimen was significantly (p < 0.01) enhanced as compared to the untreated controls. These findings indicate a beneficial behaviour of isradipine on vascular wall eicosanoid profile, which may contribute to a variety of antiatherosclerotic actions at the vascular wall level and to an improvement in hemostatic balance already described.

Passive smoking and platelet thromboxane.

While active smoking is known to enhance platelet thromboxane production, no data on passive smoking is available yet. The influence of single and repeated exposure to passive smoke for 60 minutes in a 18 m3 room was assessed in non-smokers as compared to sex and age matched smokers. All the evaluated measures (malondialdehyde, plasma thromboxane B2, 11-dehydro-thromboxane B2, serum thromboxane B2, conversion of exogenous arachidonic acid to thromboxane B2 and to hydroxy-5, 8,10-heptadecatrienoic acid) were higher in smokers than non-smokers at baseline, immediately and 6 hours after passive exposure to cigarette smoke. Repeated exposure of non-smokers rendered their platelets more activated becoming close to the behaviour of smokers. These results indicate that passive smoking may activate thromboxane A2 release from the platelets, contributing to the development of hemostatic imbalance.

The prostacyclin stimulating plasma factor activity improves thromboresistance only if vascular PGI2-production is intact.

PGI2 is important in regulating platelet vessel wall interaction (1). In perfusion chamber experiments the amount of PGI2 formed was inversely related to the amount of platelets deposited (2). In 1978 a plasma factor was described which stimulates vascular PGI2-production (3). In later years, this activity has been monitored in different patient groups (for review see 4). Interestingly, it has been found that diseases associated with an increased bleeding tendency such as uraemia (5) or hepatic failure (6) were associated with an increased PF-activity while others with an enhanced thrombophilia sometimes show an absence of PF-activity (7). Recently, the PGI2 stimulating plasma factor has been purified and cloned (8). It was the aim of these experiments to assess whether PF-activity plays a role in local hemostasis regulation under in-vivo flow conditions and whether this is dependent on the presence of an intact PGI2-formation.

[Imaging of early carotid artery atherosclerotic lesions with 111In-labeled polyelonalhuman IgG (HIG)]. / Darstellung früher atherosklerotischer Läisionen der A. carotis mit 111In-markiertem polyklonalem humanem IgG (HIG).

AIM: To assess the value of scintigraphy with 111In-HIG for diagnosis and evaluation of the stage and the clinical extent of carotid artery disease in humans a prospective clinical comparative trial of scintigraphy vs. sonography was performed. METHODS: 58 patients (38 male, 20 female; mean age 60 +/- 7 years) with hyperlipidemia and ultrasonographically detectable carotid artery lesions were studied. After i.v. injection of 18.5 MBq 111In-HIG, anterior scintigraphic images of the neck were acquired. Real time two-dimensional B-mode ultrasonography of the left and the right carotid arteries was performed. RESULTS: 111In-HIG-scintigraphy as compared to the morphological gold standard (ultrasonography) had a sensitivity of 70-73%, specificity of 33-41% and a positive predictive value of 77-82% for detecting carotid atherosclerotic lesions. There was, however, no significant correlation between scintigraphy and ultrasonography. CONCLUSION: However, the data provide evidence that the two imaging techniques are visualizing different aspects of atherogenesis. On the one hand a functional one reflecting the activity of the disease (111In-HIG) and on the other hand the morphological one resembling the extent of the disease (ultrasonography).

[Multi-drug management after myocardial infarct]. / Multi-Medikamentemanagement nach Myokardinfarkt.

Since the results of studies done with angiotensin-converting-enzyme(ACE)-inhibitors, systemic thrombolysis and primary percutaneous transluminal angioplasty (PTCA) have been published, post-myocardial infarction therapy has changed dramatically. In most european countries systemic thrombolysis as early as possible is the standard therapy. Cardiologists prefer more and more immediate revascularisation if the technical standard of the hospital is allowing an acute intervention. Pharmacological therapy is done initially with beta-blockers and platelet aggregation inhibitors, if necessary intravenously, since the results of the e.g. GUSTO- and the AIRE-study are known. If left ventricular dysfunction exists or develops, ACE-inhibitors are given after the third day post myocardial infarction.