[Personalised medicine. Paradigm shift within drug research and therapy]. / Personalisierte Medizin. Paradigmenwechsel in der Arzneimittelforschung und -therapie.

BACKGROUND: In the middle of the 1980s and 1990s, drug research underwent a significant change. With new knowledge gained from molecular medicine, it became possible to understand the development and course of many diseases in much more detail. As a consequence, truly new therapies were developed on the basis of natural sciences. PARADIGM SHIFT TO PERSONALISED MEDICINE: Progress in medicine is not only based on newly available therapeutic options but also implies the identification of the therapy which suits the patient best. And it is exactly here where medicine as well as drug development are currently undergoing a paradigm shift which can be characterised by the catchword "personalised medicine". TANDEMS OF THERAPEUTIC AND DIAGNOSTIC AGENTS: Personalised medicine encompasses defined tandems of therapeutic and diagnostic agents and leads to a therapy which is based on single patient groups rather than solely on disease diagnoses. In this therapy concept--in addition to the regular examination of the patient--a diagnostic test is performed to assess certain patient characteristics as a basis for the choice of therapy and/or therapy control. Primarily, it is the patient who benefits from personalised medicine by a higher probability of therapeutic success or by an increased tolerance. Thereby, personalised medicine may also increase cost efficiency in the health care sector. OUTLOOK: To introduce more personalised therapies and therefore achieve the best possible patient care as well as increased cost efficiency for the health care system in the future, all players in health care should work closely together to meet the challenges of personalised medicine.

Molecular orientation studies by pulsed electron-electron double resonance experiments.

Pulsed electron-electron double resonance (PELDOR) has proven to be a valuable tool to measure the distribution of long range distances in noncrystalline macromolecules. These experiments commonly use nitroxide spin labels as paramagnetic markers that are covalently attached to the macromolecule at specific positions. Unless these spin labels are flexible in such a manner that they exhibit an almost random orientation, the PELDOR signals will-apart from the interspin distance-also depend on the orientation of the spin labels. This effect needs to be considered in the analysis of PELDOR signals and can, moreover, be used to obtain additional information on the structure of the molecule under investigation. In this work, we demonstrate that the PELDOR signal can be represented as a convolution of a kernel function containing the distance distribution function and an orientation intensity function. The following strategy is proposed to obtain both functions from the experimental data. In a first step, the distance distribution function is estimated by the Tikhonov regularization, using the average over all PELDOR time traces with different frequency offsets and neglecting angular correlations of the spin labels. Second, the convolution relation is employed to determine the orientation intensity function, using again the Tikhonov regularization. Adopting small nitroxide biradical molecules as simple examples, it is shown that the approach works well and is internally consistent. Furthermore, independent molecular dynamics simulations are performed and used to calculate PELDOR signals, distance distributions, and orientational intensity functions. The calculated and experimental results are found to be in excellent overall agreement.

Spinal injuries after falls from hunting tree stands.

BACKGROUND CONTEXT: Spinal injuries are common sequelae of falls from hunting tree stands. Significant neurological injury is not uncommon and can result in significant morbidity as well as enormous expenditure of health care dollars. Recent literature on the subject is limited. PURPOSE: The purpose of this study was to identify precipitating causes, characterize the spectrum of spinal injury, and determine potential interventional safety and prevention recommendations. STUDY DESIGN: A retrospective study. METHODS: Medical record review of 22 patients admitted either directly or via referral to a level I spinal cord injury referral center over a 10-year period (1995-2005) after a fall from a hunting tree stand. RESULTS: All patients were men with a mean age of 46 years (range, 27-80 years). Initial acute care hospitalization averaged 10 days (range, 2-28 days). The average height of fall was 18 feet (range, 10-30 feet). Four of 19 falls (21%) occurred during the morning hours, 2 of 19 falls occurred during the afternoon, and 13 of 19 falls (68%) occurred during the evening hours. Time lapse from injury to presentation to an emergency department ranged from 30 minutes to 14 hours. Alcohol use was a factor in 2 of 20 falls (10%). Hypothermia complicated 3 of 21 cases (14%). Associated injuries were present in 12 of 21 patients (57%) and included fractures to the axial and appendicular skeleton, pneumothoraces, a retroperitoneal bleed, and a brachial plexopathy. Eight of 22 patients (37%) sustained injury to the cervical spine. Five of these 8 patients (63%) had neurological deficits (3 complete and 2 incomplete spinal cord injuries). Thirteen of 22 (59%) patients sustained injury to the thoracic or lumbar spine. Ten of these 13 (77%) had neurologic deficits (3 complete and 7 incomplete). Nine of 22 (41%) patients were treated nonoperatively; the remaining 13 (59%) underwent operative intervention. CONCLUSIONS: Falls from hunting tree stands remain a significant cause of spinal injury and subsequent disability. The best intervention for these injuries is prevention. There is a continued need for hunter safety education to reduce the incidence of these injuries with emphasis on safety harness usage, proper installation and annual inspection of tree stands, hunting in groups with periodic contact, the use of communication devices, and abstinence from alcohol consumption while hunting.

[Three-dimensional imaging in central serous chorioretinopathy]. / Dreidimensionale Bildgebung bei Chorioretinopathia centralis serosa.

BACKGROUND: Conventional optical coherence tomography (OCT) has brought new insights to retinal diagnostics, but it is restricted due to its low scanning speed and limited resolution. In this study, high-resolution raster scanning OCT (HR-OCT) was used to identify typical changes in central serous chorioretinopathy (CSC). METHODS: Fifteen consecutive patients with acute CSC were imaged using HR-OCT with an axial image resolution of 6 mum. The scanned area measured 6x6 mm2. Three-dimensional (3D) evaluation was performed using various analysing programmes. RESULTS: Topographic changes in CSC could be visualised with 3D reconstructions in all locations. Retinal thickness was measured with the automatic segmentation mode and quantified precisely. Results were presented in 2D and 3D maps. En-face imaging as a modality to present an integrative overview showed specific alterations in CSC. CONCLUSION: HR-OCT was able to provide essential additional information about CSC when combined with appropriate analysing programmes, allowing the identification of typical differences. Aside from precise volumetric measurements, exact localisation of pathological deviations could be achieved.

[New perspectives in diagnostic. High-resolution optical coherence tomography for age-related macular degeneration]. / Neue Perspektiven in der Diagnostik. Hochauflösende optische Kohärenztomographie bei altersbedingter Makuladegeneration.

BACKGROUND: Recent advances in optical coherence tomography (OCT) have made it possible to increase resolution and scan velocities so that even greater central areas of the retina can be scanned. The aim of this study is to describe the possibilities offered by this new technology for age-related macular degeneration. MATERIAL AND METHODS: The study included 20 patients with confirmed active choroidal neovascularization (CNV) as well as pigment epithelial detachment (PED). Three-dimensional imaging was performed with a high-definition raster scanning OCT system (HD-OCT) with an axial resolution of 6 microm and a scan velocity of up to 20,000 A-scans/s. The scanned area measured 6 x 6 mm with a depth of 2 mm. Two-dimensional imaging was carried out with a StratusOCT (Carl Zeiss Meditec). RESULTS: Comparison of the individual slices showed improved identification of intra- and subretinal structures with the HD-OCT. Demarcation of pathological changes in individual retinal layers is possible with the HD-OCT. Summation images permit accurate localization of a scan. Topographic and volumetric evaluations enable analysis of individual compartments in the entire scanned area and are suitable for monitoring treatment of CNV with anti-VEGF therapy. The raster method decreases the dependence on exploratory methods that have been necessary until now to generate retinal thickness maps. CONCLUSIONS: This report presents initial experience in using a raster scanning HD-OCT system in patients with neovascular age-related macular degeneration and describes new evaluation functions that aid in obtaining more precise assessment of treatment effect and its impact on the retinal ultrastructure. The results of this study clearly show that development of high-resolution OCT systems in conjunction with development of novel treatment options for exudative diseases offers promising perspectives.

Comparison of speech production in upright and supine position.

Speech is usually produced in an upright sitting or standing posture. Measurements and judgments of speech may be made in conditions requiring a supine position, however. These conditions include MRI recordings, and oral procedures, such as, adjustments to dental appliances, medical and surgical procedures. It is of interest, therefore, to see whether gravity has strong or systematic effects on tongue behavior. In the present study, 13 subjects repeated several words, which contained extreme consonant and vowel tongue positions, during upright and supine condition. Ultrasound imaging provided midsagittal tongue contours, in each condition, for comparison. A neck brace was used to stabilize transducer placement and the palate was used as a physiological reference to register the data sets. Results showed a significant subject effect. In supine position the tongue was more posterior than upright for seven subjects, more anterior for two subjects and varied by phoneme for four subjects. However, there was no significant phoneme effect. The direction of change and the amount of change were not directly related. Most subjects had small upright-supine differences. The largest differences, less than 3 mm on average, were in the posterior tongue.

Atrial natriuretic factor inhibits central angiotensin II pressor responses.

Intracerebroventricular (i.c.v.) administration of human atrial natriuretic factor (ANF), fragment 1-25, in the dose range 3 to 20 micrograms/kg did not alter resting arterial pressure or heart rate in rats anesthetized with chloralose/urethan (60:600 mg/kg i.p.), while angiotensin II (ANG II), 1 microgram/kg, produced a significant increase in arterial pressure after i.c.v. application. This pressor effect induced by ANG II was abolished by simultaneous administration of ANF (3 micrograms/kg i.c.v.). In isolated strips of rabbit aorta preconstricted with ANG II (10 nM), ANF caused a dose-dependent relaxation. In intact rats, the increase in blood pressure following intravenously administered ANG II (0.1 and 1 microgram/kg) was not altered by the highest dose of ANF (20 micrograms/kg) given intracerebroventricularly. These results suggest that atrial peptides may play an important role in the regulation of blood pressure by interacting with both the central and peripheral actions of ANG II. Inhibition of the central pressor action of angiotensin by ANF appears to be independent of any direct peripheral effect of the atrial peptides.

Effects of [D-Ala2]-methionine-enkephalin on blood pressure, heart rate, and baroreceptor reflex sensitivity in conscious cats.

Effects of intracerebroventricular (i.c.v) injection of [D-Ala2]-methionine-enkephalinamide (DAME) on blood pressure (BP), heart rate, and baroreceptor reflex sensitivity were studied in conscious cats. DAME was administered at doses between 5 and 100 nmoles. Blood pressure and heart rate increased dose dependently. The sensitivity of the baroreceptor reflex was attenuated for 15 to 60 minutes after DAME administration; this was independent of the BP changes. The effects of enkephalin on BP and baroreceptor reflex were abolished by i.c.v. naloxone. DAME caused pathological changes in the electroencephalogram (EEG) characterized by sharp waves in the hippocampus recordings and a loss of theta activity in the electrocorticogram. Behavioral changes were characterized by decreased physical mobility and anxiousness. These behavioral and EEG changes lasted for a longer period of time than the cardiovascular changes; they were also counteracted by naloxone. It is concluded that DAME produces a centrally mediated vasopressor response and a baroreceptor reflex attenuation and that, with respect to the time course, the effects on the baroreceptor reflex are separated from those on BP behavior and EEG, but not on heart rate. The fact that all effects of enkephalin on the parameters tested in the present experiment were completely antagonized by naloxone suggests that they are mediated by naloxone-sensitive enkephalin brain receptors.

Enkephalin effects on blood pressure, heart rate, and baroreceptor reflex.

The cardiovascular effects of opioid peptides have been studied. Leucine-enkephalin (Leu-ENK) produced blood pressure (BP) increases following administration into the lateral brain ventricles (i.v.t.), into the cisterna magna (i.c.i.), and following intravenous (i.v.) administration. Heart rate (HR) increases were observed following all routes of administration (threshold for BP and HR effects at 0.3 nmole, maximum at 360 nmoles). The cardiovascular effects were independent of generalized seizures, which may occur at higher doses of enkephalins (ENK). D-alanine-enkephalin (D-Ala-ENK) attenuated the vagal component of the baroreceptor reflex in cats. This was indicated by the findings that HR did not decrease following D-Ala-ENK-induced BP increases and that the compensatory decreases in HR following i.v. pressor doses of angiotensin II (ANG II) were markedly attenuated in cats treated with i.v.t. D-Ala-ENK. Naloxone inhibited the BP and HR effects following i.c.i. and i.v., but not following i.v.t., administration of Leu-ENK. The i.v.t. Leu-ENK effect were inhibited by beta-adrenergic receptor blockade. Bratteboro rats homozygous for hereditary diabetes insipidus with total absence of antidiuretic hormone (ADH) synthesis responded with BP decreases following i.v.t. Leu-ENK, while BP increases were observed in control Long-Evans rats. Blood pressure increases to i.v.t. Leu-ENK were markedly greater in spontaneously hypertensive rats of the stroke-prone strain (SHR-sp) than in normotensive control rats; SHR-sp exhibit a humoral pattern of increased ADH, ACTH, and catecholamines, presumably due to central peptidergic stimulation. The known effects of opioid peptides on these hormones and the observed cardiovascular responses suggest a possible participation of this peptide system in the maintenance of high BP in the SHR-sp.

Sexual dimorphism of blood pressure in spontaneously hypertensive rats: effects of anti-androgen treatment.

The mechanisms resulting in the greater predisposition of male subjects towards hypertension were investigated in different strains of rats with genetic hypertension [spontaneously hypertensive rats of the stroke-prone strain (SHRSP) and spontaneously hypertensive rats (SHR)] and their respective normotensive controls. Blood pressure was reduced in young (9 weeks of age) hypertensive rats by (1) surgical castration, (2) treatment with the testosterone receptor antagonist cyproterone acetate (CPA), which does not elevate testosterone, or (3) with the testosterone receptor antagonist flutamide, which leads to a feedback elevation of gonadotrophic hormones and plasma testosterone. These treatments had no effect on high blood pressure in old hypertensive rats aged 25 weeks. Both androgen receptor antagonists attenuated high blood pressure development when given for the first 10 days after birth. These data clearly relate the sexual dimorphism of hypertension to testosterone produced during male brain maturation in the early phase of hypertension development. Testosterone appears not to contribute directly to the maintenance of high blood pressure in established hypertension.

The AMPPA network as a successful model for public-private or private-private partnership.

In 1997, the Rockefeller Foundation and the Ernst Schering Research Foundation (a subsidiary of Schering AG, Germany, on a non-profit basis) mounted a multi-year global collaborative effort, involving a network of top-level research institutions to intensify research on the regulation of the male reproductive system with special emphasis on post-testicular activity, utilizing new approaches in molecular pharmacology (application of molecular pharmacology for post-testicular activity (AMPPA) network). The new venture proved a success as a public-private sector partnership, as a collaborative scientific program, and as an approach to identify new targets applicable and suitable for drug finding for male fertility regulation.

Sexual dimorphism of blood pressure: possible role of the renin-angiotensin system.

The prevalence of hypertension in men is higher than in women and the onset of this disease is earlier in male than in female subjects. In spontaneously hypertensive rats, males also have higher blood pressures than females. Evidence from epidemiological, physiological, molecular biological and morphological studies concerning this sexual dimorphism is reviewed. We demonstrate that the gonadal steroids testosterone and estrogen have important effects on the gene regulation of the renin-angiotensin system. This may in part contribute to the sexual dimorphism in blood pressure control. The direct effect of steroid hormones on genes related to hypertension provides a suitable paradigm to improve our understanding of molecular and cellular mechanisms of cardiovascular control.

Monoamine metabolites in the CSF of conscious unrestrained cats.

The dopamine metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) and the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) were measured repeatedly over a period of up to 5 months at different sites of the brain ventricular system in unrestrained, awake cats. Samples of 10 microliter CSF were analyzed by high pressure liquid chromatography and subsequent electrochemical detection. Concentrations were in the range of 30-130 ng/ml for DOPAC, 110-340 ng/ml for 5-HIAA and 180-750 ng/ml for HVA. The monoamine metabolites were constant even over a period of several months if measured in the same animal but there was a marked interindividual variation. A marked gradient for monoamine metabolites was found when CSF samples from frontal sites of the lateral ventricle were compared to CSF samples from the dorsal lateral ventricle. The concentrations of DOPAC and HVA were higher at frontal sites.

Renin-like immunocytochemical activity in the rat and mouse brain.

Renin-like immunoreactivity could be demonstrated in the nuclei paraventricularis, periventricularis and supraopticus of the hypothalamus and in the cerebellar cortex of rats and mice, with both the peroxidase-antiperoxidase (PAP) and fluorescence techniques. The findings are consistent with the assumption of an endogenous angiotensin-forming system in the brain.

Afferent connections of the nucleus centralis amygdalae. A horseradish peroxidase study and literature survey.

The central nucleus of the amygdala has been shown to be involved in cardiovascular regulation and the integration of arousal. In this study, the afferent input was investigated in cat by microinjecting horseradish peroxidase (HRP) into the central nucleus and examining retrogradely-labelled cells in the brain. Retrograde labelling was found in the cortex next to the sulcus ectosylvius anterior, fissura lateralis Sylvii, sulcus rhinicus anterior and posterior, sulcus suprasylvius, and pyriform and entorhinal cortices as well as in the insula and claustrum. Each of the sub-nuclei of the amygdaloid complex exhibited retrogradely-labelled perikarya. Labelled cells were also found in the diagonal band of Broca, nucl. lateralis septi, and nucl. proprius striae terminalis (bed nucl. of stria terminalis). In the hypothalamus the area preoptica medialis and lateralis, nucl. dorsomedialis, paraventricularis, periventricularis, arcuatus and mammilaris medialis were labelled. The nucl. subthalamicus, zona incerta, peripeduncular system, substantia nigra, and nucl. interpeduncularis contained HRP-marked cells. In the thalamus labelled cells were observed in the nucl. reuniens, nucl. centroposterior lateralis, nucl. latero-posterior, nucl. posterior, nucl. centro-anterior, antero-dorsalis, antero-medialis, antero-lateralis, centrum mdianum, nucl. reticularis, nucl. rhomboideus, nucl. parafascicularis and subfascicularis. The area tegmentalis Tsai and the corpora geniculata also contained labelled cells. In the brain stem, HRP-marked cells could be detected in the brachium colliculi inferioris, aqueductal grey matter, locus coeruleus, nucl. parabrachialis, in various nuclei of the formatio reticularis, in the nucl. retrofascialis, nucl. solitarius, nucl. commissuralis, nucl. ambiguus and nucl. dorsalis n. vagi. The results were compared to other neuroanatomical studies and to functional studies of the amygdala.

Influence of different progestogens on blood pressure of non-anaesthetized male spontaneously hypertensive rats.

The aim of the study was to find out if synthetic progestins with significant antimineralocorticoid activity would have a beneficial effect on blood pressure. Male spontaneously hypertensive rats were treated daily for four weeks with different progestogens by subcutaneous injection. Arterial pressure of the conscious animals was measured at three-day intervals. Progestogens were dosed on the basis of their progestogenic activity, whereby the dosages corresponded to the 10-fold effective dose for inhibition of ovulation in rats. For comparison, spironolactone as well as progesterone itself were included in the study. After four weeks' treatment, plasma volume, extracellular fluid volume (ECFV) and the sodium and potassium concentrations in the plasma were measured. In control animals, there was a slight decrease in blood pressure over the four-week experimental period. Progesterone and spironolactone similarly influenced blood pressure. A new progestin with significant antialdosterone activity, dihydrospirorenone (code No. ZK 30.595), slightly but significantly decreased the ECFV, plasma sodium concentration and slightly but insignificantly decreased blood pressure as compared to vehicle-treated controls. Synthetic progestins lacking this antimineralocorticoid activity did not decrease blood pressure, but rather induced a slight increase in this animal model. The results clearly support the hypothesis that synthetic progestins, like endogenous progesterone, all of them with inherent antialdosterone activity, decrease the ECFV and so might have an impact on extracellular fluid hemostasis as well as blood pressure regulation.

Potassium channel activation in vascular smooth muscle.

1. Numerous compounds and changes in physical state functions shift the membrane potential of vascular smooth muscle to more negative values. The consequence is a vasodilatation because Ca2+ channels are closed. K+ channel opening frequently causes the hyperpolarization. 2. Acidification of the blood substitute solution and a fall in O2 partial pressure dilate arterial vessels. Acidosis is associated with a rise in K+ permeability and a simultaneous fall in Na+ permeability. Prostacyclin has a 20-30% share, and EDHF a 70-80% share, in hypoxic vasodilatation. Experiments with iloprost (PGI2 analogue) confirmed the K+ channel opening properties of this drug. A voltage-dependent K+ channel and a Ca(2+)-activated K+ channel, via the influence of cA-PK or cG-PK, are responsible for the hyperpolarization with iloprost and with oxygen deficiency. 3. Cicletanine and ajoene cause a concentration-dependent membrane hyperpolarization and are potent vasodilators. A cicletanine concentration, which is attained by the dosage given to patients, is sufficient to produce these effects. Ajoene exerts a hyperpolarizing and vasodilating influence even in a concentration which may occur in the extracellular space by the administration of a single garlic clove. 4. The stationary activation curve 'developed force vs. membrane potential' satisfactorily explains the effects of K+ channel openers. The tight electromechanical coupling expressed by this curve comprises a 50% vasorelaxation for a 2.5 mV hyperpolarization. In the linear part of the curve, the coupling ratio is 5.1 mV/g. 5. In the vascular smooth muscle, vasorelaxation can be evoked by membrane hyperpolarization which is linked to a simultaneous increase in K+ outward current and 42K+ efflux. In the case of substances whose influence is solely or partially receptor-mediated, cyclic nucleotides may be involved in vasorelaxation. Since cyclic nucleotides also hyperpolarize through an increase in K+ conductance, the resulting dilatation often cannot be divided into its single components. Therefore, it is sensible not to give the term "K+ channel opener" too fine a definition. The term should be applied to all substances and changes in physical states which predominantly increase the open probability of K+ channels finally via a conformational change in the cell membrane. For example, giving an acidic blood substitute solution (acidosis) is an intervention opening K+ channels. Which K+ channel and which single channel conductance is concerned in a particular case, and which 'mediator' may participate, become secondary questions.

Collaboration between industry and academia--prospects for male fertility control.

Drug development within the pharmaceutical industry is probably the field with the highest level of regulations. Due to the complexity of the different components of drug development and drug surveillance the need for a sophisticated organization and infrastructure is obvious. In addition, there is a necessity for sufficient resources and long-term commitment as well as logistic and long-term knowledge management. In order to secure high professional standards at all levels of this highly complex value creating chain, the number of cooperative arrangements in the pharmaceutical industry are increasing. The identification of new targets in the drug finding process calls in particular for outside partners. At the same time the preparedness of non-industrial researchers to cooperate with industry has also increased significantly. The area of fertility control, especially male fertility control, provides an excellent example for this kind of cooperation between industrial and non-industrial partners. Here a cooperative network is described which probably meets practically all relevant criteria for both the non-industrial but also the industrial partner. Some principles for the management of such a cooperative network are discussed. We believe that this kind of network can serve as a model for similar networks in other fields.

Treatment of end-stage renal disease due to lupus nephritis: comparison of six patients treated with both peritoneal and hemodialysis.

End-stage renal disease (ESRD) is one of the most significant complications of systemic lupus erythematosus (SLE). Previous investigators have evaluated the morbidity and mortality of different renal replacement treatment modalities in these patients. Earlier reports have suggested that the systemic manifestations of SLE diminish, or "burn out," once ESRD occurs. These investigators also suggested that vascular access complications were a significant cause of morbidity and mortality in these patients treated with hemodialysis (HD). A retrospective review of the records of 6 patients with ESRD from lupus nephritis (LN), who received both HD and peritoneal dialysis (PD), was performed to determine if there was a difference in disease activity between treatment modalities, using patients as self-controls. The number of SLE flares was determined by clinical and/or serologic studies, and prednisone dosages compared for each treatment modality. Four of the 6 patients continued to have active SLE after renal replacement therapy was begun. There were no significant differences in the number of SLE flares or prednisone dosages while receiving either treatment modality. While PD eliminates problems associated with vascular access, both HD and PD were effective forms of renal replacement therapy. Most patients in this study continued to have active SLE after commencement of dialysis, with no differences in disease activity noted during HD or PD.

Lovastatin in the treatment of hypercholesterolemia in CAPD.

The authors studied the effect of lovastatin on five hypercholesterolemic CAPD patients with high risk of atherosclerotic cardiovascular disease. Patients took lovastatin 20 mg once daily for a mean period of 4.5 months. Pre- and post-treatment values of LDL and VLDL totals (325 mg/dl and 292 mg/dl, respectively) and of HDL (42 mg/dl and 43 mg/dl, respectively) had no significant statistical difference. Lack of significance may be due to low number of patients and short trial time. The study did demonstrate that lovastatin is well tolerated in CAPD patients.