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Biomedical subjects

Pauli Ylitalo

Publications and source records attributed to Pauli Ylitalo.

14 recordsLinked to original sources
PubMed2006

High-calcium vs high-phosphate intake and small artery tone in advanced experimental renal insufficiency.

BACKGROUND: Disturbed calcium-phosphorus balance significantly contributes to uraemic changes in large arteries. We examined the influences of high-calcium and high-phosphate intake on small artery tone in experimental renal insufficiency. METHODS: Sixty-five rats were assigned to 5/6 nephrectomy (NTX) or sham operation. After 15 week disease progression, NTX rats were given high-calcium (3%), high-phosphate (1.5%) or control diet (0.3% calcium, 0.5% phosphate) for 12 weeks. Then isolated segments of small mesenteric arteries were studied using wire and pressure myographs. RESULTS: Subtotal nephrectomy reduced creatinine clearance by 60% and increased parathyroid hormone (PTH) and phosphate 12-fold and 2.7-fold, respectively. High-phosphate intake further elevated PTH and phosphate (33-fold and 5.5-fold, respectively), while the calcium diet suppressed them (to 3.5 and 62% vs sham, respectively). Ventricular B-type natriuretic peptide synthesis was increased, and blood pressure was 27 and 18 mmHg higher in NTX rats on control and phosphate diet, respectively, than in calcium-fed rats. Vasorelaxation to acetylcholine was impaired by approximately 50% in uraemic rats, and was further deteriorated by high-phosphate intake, whereas the calcium diet improved endothelium-mediated relaxation via nitric oxide and potassium channels. Small arteries of all NTX groups featured eutrophic inward remodelling: wall-to-lumen ratio was increased 1.3-fold without change in cross-sectional area. CONCLUSION: High-phosphate intake had a detrimental influence on secondary hyperparathyroidism and vasodilatation, whereas high-calcium intake reduced blood pressure and PTH, alleviated volume overload and improved vasorelaxation in experimental renal insufficiency. Therefore, alterations in the calcium-phosphorus balance can significantly modulate small artery tone during impaired kidney function.

8,11,14-Eicosatrienoic Acid↗
PubMed2005

Effects of a mononitrate, a beta1-blocker and a dihydropyridine calcium channel blocker on cardiovascular responsiveness to passive orthostasis: a placebo-controlled double-blind study in normotensive volunteers.

OBJECTIVE: The aim of this study was to compare the influences of antianginal drugs such as mononitrate, beta-blocker and calcium channel blocker on cardiovascular responsiveness to orthostasis. METHODS: The responses to passive orthostasis (tilt provocation at 60 degrees for 3 min) were measured in normotensive healthy volunteers with whole-body impedance cardiography and finger blood-pressure monitoring after a single moderate oral dose of isosorbide-5-mononitrate (CAS 16051-77-7, 10 mg), the beta1-blocker bisoprolol fumarate (CAS 104344-23-2, 5 mg), the dihydropyridine calcium channel blocker nisoldipine (CAS 63675-72-9, 5 mg), and placebo in a randomised, double-blind fashion. RESULTS: In supine position, none of the drugs altered pre-tilt arterial pressure or heart rate (HR) when compared to placebo. Nisoldipine decreased systemic vascular resistance index (SVRI) when compared to either placebo or bisoprolol, and increased the cardiac index (CI) when compared to placebo. During the passive orthostasis, the mononitrate decreased SVRI when compared to placebo or bisoprolol. The mononitrate increased HR and pulse wave velocity (PWV) when compared to the other study groups, and decreased the stroke index when compared to placebo. In the bisoprolol group, the tilt responses of diastolic arterial pressure, HR, CI, left cardiac work index, and PWV decreased significantly compared to those in the placebo group. Nisoldipine did not alter the responses to orthostasis when compared to placebo. When compared to the mononitrate, both nisoldipine and bisoprolol decreased CI response to orthostasis. CONCLUSIONS: The mononitrate adversely affects the cardiovascular responsiveness to orthostasis. The beta-blocker reduces the responses and thus probably oxygen demand during orthostasis. The dihydropyridine calcium blocker seems to influence the responsiveness less than the mononitrate or beta-blocker.

Adrenergic beta-1 Receptor Antagonists↗
PubMed2005

Effects of adrenoceptor blocking drugs on cardiovascular responsiveness to passive orthostasis: a placebo-controlled double-blind study.

OBJECTIVE: To compare the acute effects of the beta-blocker propranolol (CAS 525-66-6), beta + alpha1-blocker carvedilol (CAS 72956-09-3) and alpha1-blocker tamsulosin (CAS 106463-17-6) on the cardiovascular responses to passive orthostasis. METHODS: The responses to passive orthostasis (tilt provocation at 60 degress for 8 min) were measured in normotensive healthy volunteers with finger-blood-pressure and whole-body impedance cardiography prior to drugs and three days after beginning the medications. The treatments were moderate oral doses of the beta-blocker propranolol HCl (40 mg twice daily, n = 7), (beta + alpha1-blocker carvedilol (12.5 mg once daily for two days and thereafter 25 mg daily, n = 7), alpha1-blocker tamsulosin HCl (0.4 mg once daily, n = 6), or placebo. The drugs were distributed in a randomised, double-blind fashion. RESULTS: When measured prior to the head-up tilt test, propranolol and carvedilol had decreased supine systolic arterial pressure (SAP) more than placebo, and heart rate (HR) more than placebo and tamsulosin. Propranolol had decreased also pulse wave velocity more than placebo. The cardiac index (CI), stroke index (SI) and systemic vascular resistance index (SVRI) were not changed with any drugs. During the head-up tilt, tamsulosin decreased SAP and SVRI and augmented CI but not SI. The SVRI response curve with tamsulosin differed from that with propranolol or carvedilol. Also, tamsulosin increased HR compared to the beta-blocking drugs. The propranolol and carvedilol groups did not differ from each other in terms of any parameter. CONCLUSIONS: Tamsulosin significantly decreases SAP in the passive head-up tilt, indicating that it is not purely uroselective alpha1-blocker. The responses with tamsulosin clearly differ from those with propranolol and carvedilol, the responses with the latter two being practically equal.

Adrenergic Antagonists↗
PubMed2005

Microcrystalline chitosan is ineffective to decrease plasma lipids in both apolipoprotein E epsilon 4 carriers and non-carriers: a long-term placebo-controlled trial in hypercholesterolaemic volunteers.

Chitosan is a deacetylated product of chitin. Microcrystalline form of chitosan has a large adsorption area claimed to decrease gastrointestinal absorption of cholesterol. However, the long-term effect of chitosan on plasma lipids is variable, the averaged influence being negligible or lacking in mildly-to-moderately hypercholesterolaemic (4.8-6.8 mmol/l) subjects. We evaluated whether this variation and inefficacy depend on apolipoprotein E genotype. 130 middle-aged, otherwise healthy men (n=55) and women (n=75) were randomized into two treatment groups for a 7 month trial. During a 1 month run-in period all participants received placebo. Subsequently, one half first took placebo twice daily for 3 months and then 1.2 g chitosan twice daily for 3 months, and the other half vice versa in a cross-over way. Altogether 84 participants completed the study. Plasma lipids and glucose were determined at the end of each phase of the study, and all subjects undergone to the cross-over phases were apolipoprotein E genotyped. Chitosan altered plasma total, low- and high density cholesterol, triglycerides, and blood glucose in neither apolipoprotein E epsilon 4 allele carriers (n=29) nor non-carriers (n=55), compared to placebo. In conclusions, chitosan is ineffective to decrease plasma lipids in apolipoprotein E epsilon 4 carrier and non-carrier phenotypes with mildly-to-moderately increased plasma cholesterol.

Adolescent↗
PubMed2004

The vasodilatory effect of alfuzosin and tamsulosin in passive orthostasis: a randomised, double-blind, placebo-controlled study.

OBJECTIVE: To compare in details the effects of urologically used alpha(1)-blockers alfuzosin and tamsulosin on the cardiovascular responses to passive orthostasis. METHODS: The responses to passive orthostasis (tilt provocation at 60 degrees for 8 min) were measured in normotensive healthy volunteers with finger blood pressure method and whole-body impedance cardiography prior to the administration of the drugs as well as three days after the beginning of the randomised, double-blind medications. The parallel treatments were standard clinically used doses of alpha(1)-blockers alfuzosin (5 mg twice daily, n=10), tamsulosin (0.4 mg once daily, n=10), or placebo (n=11). RESULTS: When measured prior to the head-up tilt test in supine position, neither alfuzosin nor tamsulosin significantly changed any of the cardiovascular variables. During the passive orthostasis, however, both tamsulosin and alfuzosin reduced systemic vascular resistance index compared to pre-drug responses (-540 and -462 dyns/cm(5)m(2), respectively, p<0.05). Both drugs also augmented orthostatic responses of heart rate (11 and 9 bpm, respectively, p<0.05) and cardiac index (0.50 and 0.40 l/min/m(2), respectively, p<0.05) but not those of stroke index when compared to the responses during placebo or before the administration of the drugs. The alfuzosin and tamsulosin groups did not significantly differ from each other in terms of any parameter. CONCLUSIONS: Both alfuzosin and tamsulosin have clear cardiovascular effects, which are most strikingly evident in the influences on systemic vascular resistance and cardiac output.

Adrenergic alpha-Antagonists↗
PubMed2003

The effect of long-term microcrystalline chitosan therapy on plasma lipids and glucose concentrations in subjects with increased plasma total cholesterol: a randomised placebo-controlled double-blind crossover trial in healthy men and women.

OBJECTIVE: To evaluate the long-term effect of microcrystalline chitosan (MCC) on plasma lipids, especially the concentration of low-density lipoprotein (LDL) cholesterol, in subjects with a moderately increased concentration of plasma total cholesterol. METHODS: A total of 130 middle-aged men and women without severe disease and with a total cholesterol of 4.8-6.8 mmol/l and triglycerides below 3.0 mmol/l were randomised into two treatment groups. At the beginning of the 10-month trial, all participants received placebo 1.2 g twice daily during a 1-month run-in period. Subsequently, group 1 first received 1.2 g placebo twice daily for 3 months and then 1.2 g MCC twice daily for 3 months. Correspondingly, group 2 received 1.2 g MCC twice daily during the first and 1.2 g placebo twice daily during the second 3-month period. During the final 3-month follow-up period, both groups received MCC. Altogether, 83 participants completed the study. RESULTS: No difference was detected in the change in the LDL-cholesterol concentration between the treatments during the crossover trial ( P=0.98 for interaction between time period and treatment group, repeated-measures analysis of variance for crossover design). In an otherwise similar analysis, no differences were detected between the treatments in the concentrations of total cholesterol, high-density lipoprotein cholesterol, triglycerides and glucose. CONCLUSIONS: Treatment with MCC had no effect on the concentrations of plasma lipids or glucose in healthy middle-aged men and women with moderately increased plasma cholesterol concentrations.

Adjuvants, Pharmaceutic↗
PubMed2003

AT1 receptor blockade improves vasorelaxation in experimental renal failure.

It is not known whether angiotensin II type 1 receptor antagonists can influence the function and morphology of small arteries in renal failure. We investigated the effect of 8-week losartan therapy (20 mg/kg per day) on isolated mesenteric resistance arteries by wire and pressure myographs in 5/6 nephrectomized rats. Plasma urea nitrogen was elevated 1.6-fold after nephrectomy, and ventricular synthesis of atrial and B-type natriuretic peptides was increased 2.2-fold and 1.7-fold, respectively, whereas blood pressure was not affected. Losartan did not influence these variables. The endothelium-mediated relaxation to acetylcholine was impaired in nephrectomized rats in the absence and presence of nitric oxide synthase and cyclooxygenase inhibition. Blockade of calcium-activated potassium channels by charybdotoxin and apamin reduced the remaining acetylcholine response, and this effect was less marked in nephrectomized than in sham-operated rats. Relaxation to levcromakalim, a vasodilator acting through adenosine triphosphate-sensitive potassium channels, was also impaired after nephrectomy. The arteries of nephrectomized rats showed eutrophic inward remodeling: Wall-to-lumen ratio was increased without change in wall cross-sectional area. All changes in arterial relaxation and morphology were normalized by losartan therapy. Aortic ACE content, measured by autoradiography, directly correlated to the plasma level of urea nitrogen, suggesting that renal failure has an enhancing influence on the vascular renin-angiotensin system. Losartan normalized relaxation and morphology of resistance arteries in experimental renal failure, independent of its influence on blood pressure, impaired kidney function, or volume overload. The mechanism of improved vasodilation by losartan may include enhanced relaxation through potassium channels.

Angiotensin Receptor Antagonists↗
PubMed2003

Pharmaceutical industry's barriers and preferences to conduct clinical drug trials in Finland: a qualitative study.

The objectives of our study were to explore the barriers, preferences and attitudes of the pharmaceutical industry towards conducting clinical trials in Finland. In-depth semi-structured interviews were conducted with 18 representatives of the pharmaceutical industry with different amounts of experience of clinical trials. The interviews were audiotaped, transcribed verbatim and analysed qualitatively. Overall, the respondents had a positive attitude towards conducting clinical trials in Finland. The major barriers seemed to occur at the beginning of the trial and mostly consisted of bureaucratic obstacles. The informants hoped for a more positive attitude of the public sector, more flexibility in hospitals and professionalism in practical implementation, e.g. having special research centres or site management services. The most dismotivating factors were the high costs and the constraints imposed by bureaucracy. The variety in practices of local ethics committees was considered problematic, and the need for common standard operating procedures was pointed out. The smallest barriers were encountered in subject recruitment by the investigators and their clinical work, documentation, investigational product logistics and communication with the regulatory authorities. The quality, know-how and reliability of the study personnel, the tightening of time lines in general, an investigator register/pool and collaboration with media in disseminating information about clinical trials to the general public were reported as the most appealing factors. Training in GCP, mainly incorporated in the medical education programme, and a certificate or equivalent were generally considered necessary, though a voluntary system was preferred. The barriers and preferences pointed out suggest various improvements and ways to produce high-quality, GCP-compliant clinical drug research and to ensure the availability of sufficient conditions to carry out clinical trials also in the future.

Attitude of Health Personnel↗
PubMed2003

Investigator barriers and preferences to conduct clinical drug trials in Finland: a qualitative study.

OBJECTIVE: To explore investigator barriers, preferences, and attitudes towards conducting clinical trials in Finland. METHOD: In-depth, semi-structured interviews with 20 clinicians working in the field of cardiovascular medicine were performed. The interviews were audiotaped, transcribed verbatim and analysed qualitatively. Twenty clinicians from all (five) university hospitals in Finland and from three subgroups: 1) with long experience, 2) with limited experience and 3) reluctant to carry out clinical trials, were sampled purposefully. MAIN OUTCOME MEASURES: Barriers and (de)motivating factors in carrying out clinical trials and need for training in Good Clinical Practice (GCP). RESULTS: Overall, the investigators had a positive attitude towards conducting clinical trials. The major barriers seemed to occur at the beginning of the trial: bureaucracy, lack of time and laboriousness. The informants hoped for more specific inhouse rules and flexibility in hospitals. The greatest investigator barriers were insufficient financial incentives, trial-related reasons and administrative affairs/bureaucracy. The smallest barriers were reported in subject recruitment, clinical work, documentation, investigational product logistics and communication with ethics committees. Financial incentives, a possibility to incorporate a personal sub-study or other benefits for personal research and scientific and clinical interest in the trial were reported as the most motivating factors. Carrying out studies in practice and an opportunity to participate in a trial during one's postgraduate specialist education were considered beneficial. Training in GCP, mainly in the course of postgraduate education, and a certificate or equivalent were generally considered necessary, although a voluntary system was preferred. CONCLUSION: The interviews of clinicians provide valuable information about the barriers and preferences related to the practical implementation of clinical trials. If the trial is scientifically/clinically interesting and involves a small administrative burden and sufficient financial compensation, investigators are motivated to participate. The barriers and preferences should be considered in decision-making, to meet the various needs of all parties involved and to produce high-quality GCP-compliant clinical drug research. This would ensure the availability of sufficient conditions to carry out clinical trials also in the future.

Attitude of Health Personnel↗
PubMed2002

The quality and characteristics of clinical drug study notifications reviewed by the regulatory agency in Finland.

The aim of our study was to investigate the validity of clinical drug study notifications reviewed by the regulatory agency in Finland during the 1990s. (In practice, the notification is equivalent to tacit authorization, which the agency has full powers to revoke before it takes effect.) All clinical drug studies reviewed by the agency during the years 1992, 1994, 1996, and 1998 were studied retrospectively. The main measurements used were the number of studies with no objection to start; the number and type of questions raised; the profile, phase, and type of study; and the study design. Additionally, the studies approved by two ethics committees of university hospitals during the same years were cross-checked to see whether the agency was notified of them in accordance with the national regulations. In total, 1174 study notifications were reviewed. Most studies were international (52%), phase III (46%), placebo-controlled with/without active control (35%) investigations of new chemical entities (38%) and were carried out in university hospitals (63%). The regulatory agency had no objections or questions regarding 55% of the notifications; 37% of the studies were permitted to begin after a clarification; 5% had to be clarified a second time; and 3% were rejected. Most questions dealt with subject information. Out of the 1140 permitted studies, 8% were later canceled or prematurely terminated as reported by the applicant. Altogether 71% of the studies that had been reviewed and approved by the ethics committees were reported to the authorities before commencement. Study completions were rarely reported. Most of the clinical drug studies planned in Finland are large international studies to investigate new chemical entities. More than half of the notifications are valid according to the regulatory authorities. Not all studies, nor the majority of study completions, are reported to the authority, though according to the regulations they should be so reported. The results show that better compliance with regulatory requirements is needed, and the contents of submitted documents should be improved to gain better Good Clinical Practice compliance. The regulatory agencies and committees that review clinical study documents should improve their current practices by a more specific division of responsibilities.

Clinical Trials as Topic↗
PubMed2002

Suppression of immunoreactive macrophages in atheromatous lesions of rabbits by clodronate.

Bisphosphonates inhibit the development of experimental atherosclerosis and decrease the intima-media thickness of human carotid artery. Since arterial macrophages have a key role in atherogenesis, we studied whether clodronate, an antiatherogenic bisphosphonate, will suppress the appearance of macrophages generated by atheromatous process in the rabbit aorta. The atherosclerosis was caused in rabbits by means of a high-cholesterol (1%) diet, and the animals were treated simultaneously with saline (n = 11) or 25 mg/kg of clodronate disodium (n= 12) intravenously twice a week for 6 to 12 weeks. The cholesterol diet for 6 weeks caused no visible atheromatous plaques in the aorta, but feeding for 6 more weeks produced progressively atheromatous lesions. Immunohistochemistry with specific antimacrophage antibody showed an intensive accumulation of macrophages in the subendothelial layer of the aorta in cholesterol-fed rabbits treated with saline or clodronate for 6 weeks. In the aorta of rabbits treated with cholesterol diet + saline for 12 weeks, the area of immunoreactive macrophages extended from the internal elastic lamina up to the luminal surface of the aorta. However, far less immunoreactive macrophages were present in the atheromatous regions of the aorta of rabbits medicated with clodronate for 12 weeks; in the clodronate-treated animals the macrophages were located closer to the luminal surface of the aorta than in controls on saline. No atheromatous lesions and macrophages appeared in the aorta of rabbits on standard diet (n = 7). The results suggest that clodronate suppresses the appearance of cholesterol-phagocyting macrophages in arterial walls during atherogenesis.

Animals↗
PubMed2002

Opposite effects of nicotinic acid and pyridoxine on systemic prostacyclin, thromboxane and leukotriene production in man.

The effects of nicotinic acid (2500 mg orally during 12 hr) and pyridoxine (300 mg orally twice daily for seven days) on the excretion of urinary 2,3-dinor-6-ketoprostaglandin F1alpha, 11-dehydrothromboxane B2 and leukotriene E4, the markers of systemic prostacyclin, thromboxane A2 and cysteinyl leukotriene production, respectively, were investigated in healthy male volunteers (n=6-8). Nicotinic acid increased 11-dehydrothromboxane B2 and leukotriene E4 excretions to 2.6- and 2.0 times the initial values (P<0.05), respectively. In the volunteers treated with pyridoxine, 11-dehydrothromboxane B2 and leukotriene E4 excretions were decreased to 70% (P<0.05) and 65% (P<0.01) of the initial values, respectively, but the excretion of 2,3-dinor-6-ketoprostaglandin F1alpha was increased 1.7 times (P<0.01). The results suggest that nicotinic acid increases thromboxane and leukotriene synthesis which may not be beneficial for patients with cardiovascular diseases or asthma. In contrast, the increase in prostacyclin production and the inhibition in thromboxane and leukotriene synthesis by pyridoxine might be beneficial in disorders where the production of prostacyclin is decreased and the formation of thromboxane and cysteinyl leukotrienes is enhanced.

6-Ketoprostaglandin F1 alpha↗
PubMed2002

Cholesterol-lowering properties and safety of chitosan.

Chitosan (CAS 9012-76-4) is derived by alkaline deacetylation from chitin, an abundant polymeric product of natural biosynthesis especially in crustaceans. It is available in a primary, unorganised structure, but also in a microcrystalline form. As a dietary supplement, chitosan has been claimed to control obesity and to lower serum cholesterol. A variety of chitosan products have been freely available worldwide in health stores and pharmacies. This review summarises the current knowledge about cholesterol-lowering and safety properties of chitosan and focuses its possible application for the treatment of hypercholesterolaemia. Chitosan behaves as a polycationic(+) cellulose-like fibrillar biopolymer that forms films with negatively charged surfaces. It is not specifically hydrolysed by digestive enzymes in man, but limited digestion of chitosan due to bacterial flora and to the unspecific enzymes might occur. Negatively charged molecules in stomach attach strongly to the positive charged tertiary amino group (-NH3+) of chitosan. Therefore, chitosan reduces fat absorption from gastrointestinal tract by binding with anionic carboxyl groups of fatty and bile acids, and it interferes with emulsification of neutral lipids (i.e., cholesterol, other sterols) by binding them with hydrophobic bonds. In short-term animal studies the safety of chitosan has been good. There are only few studies with chitosan in humans. In man, dietary chitosan has been reported to reduce serum total cholesterol levels by 5.8-42.6% and low-density lipoprotein levels by 15.1-35.1%. In short-term trials up to 12 weeks, no clinically significant symptoms have been observed with chitosan compared to placebo. Mild and transitory nausea and constipation have been reported in 2.6-5.4% of subjects. Although chitosan has been clinically well tolerated, it cannot be recommended to people allergic to crustaceans.

Animals↗