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Biomedical subjects

T Hedner

Publications and source records attributed to T Hedner.

At least 235 records · Page 13Linked to original sources
PubMed1991

A population study of the pharmacokinetics of felodipine.

1. The pharmacokinetics of felodipine was studied after continuous oral administration of 5 or 10 mg conventional tablets to a population of 140 male and female Caucasian subjects, of which 67 were hypertensive patients and 73 were healthy volunteers. In addition, 42 of these individuals received felodipine intravenously. 2. With increasing age the area under the felodipine plasma concentration vs time curve (AUC), the maximum plasma concentration (Cmax), and the terminal elimination half-life of felodipine increased, while the plasma clearance of felodipine decreased. The bioavailability and steady state volume of distribution and the time to Cmax were not consistently influenced by age. 3. The ratio of the AUC of the primary pyridine metabolite of felodipine and that of unchanged drug decreased with increasing age. 4. Neither Cmax, AUC nor the half-life of felodipine were related to body mass index. 5. The distribution of AUC for felodipine, as well as the ratio of the AUC of this first metabolite to that of unchanged felodipine, was unimodal. Thus, the presence of a sizable group of individuals, with a clinically significant different metabolism of 1,4-dihydropyridine due to genetic factors is unlikely. 6. The pharmacokinetics of felodipine did not seem to differ between hypertensive patients and healthy volunteers, when adjusted for age. Neither was there a difference between patients taking beta-adrenoceptor antagonists and those who did not. 7. As a group the elderly had higher total concentrations of unchanged felodipine in plasma compared with younger individuals. The variation in plasma concentrations of felodipine between individuals is, however, only partially explained by age. In clinical practice this emphasizes the need for dose titration of felodipine.

Adult↗
PubMed1991

Clinical pharmacokinetics of ketanserin.

Ketanserin is a serotonin S2-receptor antagonist introduced for the treatment of arterial hypertension and vasospastic disorders. Plasma concentrations of ketanserin (and some metabolites) can be measured with high performance liquid chromatography using ultraviolet or fluorescence detection, or by radioimmunoassay. The methods are sensitive, accurate and specific. Following oral administration ketanserin is almost completely (more than 98%) and rapidly absorbed and peak concentrations in plasma are reached within 0.5 to 2 hours. It is subject to considerable extraction and metabolism in the liver (first-pass effect) and the absolute bioavailability is around 50%. The compound is extensively distributed to tissues and the volume of distribution is in the order of 3 to 6 L/kg. In plasma ketanserin binds avidly to plasma proteins, mainly albumin, and the free fraction is around 5%. Ketanserin is extensively metabolised and less than 2% is excreted as the parent compound. The major metabolic pathway is by ketone reduction leading to formation of ketanserin-ol which is mainly excreted in the urine. Ketanserin-ol, which by itself does not contribute to the overall pharmacological effect, is partly reoxidised into ketanserin, and it is likely that the terminal half-life of the parent compound is related to the slow ketanserin regeneration from the metabolite. Following intravenous administration plasma ketanserin concentrations decay triexponentially with sequential half-lives of 0.13, 2 and 14.3 h. The terminal half-life is similar after oral administration. Following long term oral dosing (20 or 40 mg twice daily) the pharmacokinetics remain linear and steady-state concentrations, which can be predicted from single-dose kinetics, are reached within 4 days. During long term treatment with the common dosage of 40 mg twice daily, steady-state concentrations fluctuate between 40 micrograms/L (trough) and 100 to 140 micrograms/L (peak). The pharmacokinetic properties of ketanserin are predictable in a wide group of patients and there is no influence from the duration of treatment, age and sex of the patient or concomitant treatment with beta-blockers or diuretics. There is no direct relationship between plasma concentrations of ketanserin and the antihypertensive effect in a group of patients. Side effects, including prolongation of the Q-T interval, are dose-dependent and, at least in the individual patient, related to peak plasma concentrations. In separate studies the pharmacokinetics of ketanserin were investigated in special patient groups, namely the elderly and patients with hepatic and renal insufficiency.(ABSTRACT TRUNCATED AT 400 WORDS)

Aging↗
PubMed1991

Does antihypertensive therapy affect the natural protection against thrombosis?

Fibrinolytic activity was measured in a 14-day placebo-controlled study of propranolol and the calcium antagonist isradipine in 20 mildly hypertensive patients (diastolic blood pressure 95-115 mm Hg) compared with 24 healthy volunteers. The parameters under study included euglobulin clot-lysis time, and tissue-plasminogen activator activity and its inhibitor (PAI). The two drugs exerted equal antihypertensive effects in the patients who had raised blood pressure, but had markedly different actions on the fibrinolytic system. Propranolol substantially reduced the fibrinolytic activity in both the hypertensive and healthy control groups. Isradipine, on the other hand, had no effect on fibrinolytic activity in the controls, but augmented the activity in the hypertensive subjects. The possible mechanisms for the different actions of the two agents may be related to the vascular endothelium.

Adult↗
PubMed1991

Platelet function and fibrinolytic activity in hypertension: differential effects of calcium antagonists and beta-adrenergic receptor blockers.

Platelet function was investigated in healthy volunteers and patients with essential hypertension by measurement of thresholds for ADP and adrenaline-induced aggregation and plasma concentrations of platelet factor 4 (PF-4) and beta-thromboglobulin (beta-TG) after administration of antihypertensive drugs. Fibrinolytic activity was investigated by the euglobulin clot lysis time (ECLT) and tissue plasminogen activator (t-PA) activity. Compared to normotensive controls, patients with essential hypertension showed increased aggregation as evidenced by a decrease in ADP thresholds for ex vivo platelet aggregation. ECLT was significantly prolonged and t-PA significantly lowered, indicating impaired fibrinolytic activity in mild hypertension. In different studies, we have shown that various antihypertensive drug regimens differ in their effects on platelet function and fibrinolytic activity when given to healthy volunteers or patients with mild-to-moderate essential hypertension. In normal volunteers, treatment with the calcium antagonists verapamil, nifedipine, and felodipine lowered plasma concentrations of PF-4 and beta-TG, indicating a reduced platelet activity in vivo. Fibrinolytic activity was not influenced by calcium antagonist treatment in the normal volunteers. Interestingly, however, t-PA increased significantly in the hypertensive group. When compared to placebo or beta 1-selective blockers, propranolol, a non-selective beta-adrenergic blocker without partial agonist activity, reduced ADP and adrenaline threshold values for ex vivo platelet aggregation in hypertensive subjects and impaired fibrinolytic activity in the normal volunteers as well as in the hypertensive groups by increasing ECLT and reducing t-PA. Hypothetically, the effects of antihypertensive drugs on platelet function and fibrinolytic activity could be of importance for their proposed actions on cardiovascular morbidity and mortality.

Adrenergic beta-Antagonists↗
PubMed1991

Effects of antihypertensive therapy on glucose tolerance: focus on calcium antagonists.

The prohormone form of insulin is contained in the secretory granules of the pancreatic beta-cell and released as the mature peptide sequence by exocytosis. One of the factors believed to trigger the movement of the secretory granules to the cell surface and their fusion with the plasma membrane is an increase in the cytosolic Ca2+ concentration [Ca2+]i. Extracellular glucose depolarizes the cells and favours the opening of voltage-dependent Ca2+ channels, which results in a rise in [Ca2+]i and activation of protein kinases. The phosphorylation of proteins associated with the functions of the secretory granules will influence the movement of the granules towards the plasma membrane. Due to their effects on voltage-dependent Ca2+ channels, it is suspected that calcium antagonists influence glucose-stimulated insulin release. Current information on calcium antagonists suggests that they may have different effects on glucose tolerance in non-diabetic and diabetic subjects. In non-diabetic hypertensives, fasting blood glucose is generally not affected by verapamil, diltiazem or nifedipine taken in therapeutic doses, although some reports indicate that high-dose nifedipine or diltiazem may deteriorate glucose homeostasis. Studies of the effect of single doses of calcium antagonists on the response to a glucose challenge have yielded somewhat conflicting results. The general picture, however, is that under these circumstances glucose tolerance in non-diabetic individuals remains largely unaffected, although higher doses of verapamil and nifedipine have impaired glucose tolerance slightly in some studies. In patients with non-insulin-dependent diabetes mellitus (NIDDM), acute administration of calcium antagonists with or without glucose challenge does not generally cause any changes in the blood glucose or insulin profiles. During short-term calcium antagonist therapy, conflicting results have been obtained. Overall, the data suggest that these drugs do not significantly modify glucose homeostasis. However, some reports do suggest that diabetic patients may deteriorate on nifedipine treatment. There are as yet no clear indications of any consistent changes in glucose homeostasis during long-term administration of verapamil, diltiazem or nifedipine. However, isolated case reports have indicated unfavourable changes in glucose homeostasis in patients treated with calcium antagonists of the dihydropyridine type, such as nifedipine.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

Diltiazem compared with metoprolol as add-on-therapies to diuretics in hypertension. Swedish Diltiazem-Metoprolol Multicentre Study Group.

In a randomized, double-blind, parallel group study, diltiazem was compared with metoprolol as add-on therapy to diuretic treatment in 115 patients with hypertension. Following a placebo and diuretic period of four weeks, patients were randomized to either slow release diltiazem 90 mg twice daily or metoprolol 100 mg once daily using a double dummy technique. If after four weeks a target supine diastolic blood pressure (DBP) less than or equal to 90 mmHg pressure was not reached, the doses of diltiazem and metoprolol were doubled. Supine inclusion systolic/diastolic blood pressures (SBP/DBP) at randomization were 158 +/- 13 (mean +/- SD)/102 +/- 5 mmHg in the diltiazem group and 158 +/- 17/101 +/- 6 mmHg in the metoprolol group. Active therapy significantly lowered SBP and DBP in both groups by 7-10%. Heart rate was significantly lowered in both groups, although the effect of metoprolol was more pronounced. Response rates (supine DBP less than or equal to 90 mmHg and/or decreased by greater than or equal to 10%) were 43% on diltiazem 90 mg twice daily and 52% on metoprolol 100 mg once daily, increasing to 82% and 62%, respectively, after dose escalations. No serious side effects were seen, but three patients, two on diltiazem and one on metoprolol, were withdrawn from the study due to severe headache, nausea and bradycardia respectively. of mild to moderate adverse reactions, tiredness was most frequent, occurring in 14.5% and 15.8% on active diltiazem and metoprolol therapy, respectively. We conclude that both diltiazem and metoprolol lower BP when added to diuretics in hypertensive patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1990

Central, naloxone-reversible antinociception by diclofenac in the rat.

The antinociceptive effect of subcutaneously (s.c.), intracerebroventricularly (i.c.v.) or intrathecally (i.t.) administered diclofenac was studied in a series of experiments employing the tail-flick (0.01-10.0 mg/kg body weight i.p., 1-50 micrograms i.c.v., 1-10 micrograms i.t.) and hot-plate (0.01-50 mg/kg body weight i.p., 1-50 micrograms i.c.v., 1-10 micrograms i.t.) models representing somatosensory stimuli and the writhing test (0.001 mg-10 mg s.c., 0.1-200 micrograms i.c.v., 0.1-100 micrograms i.t.) and colorectal distension (1-200 micrograms i.c.v.) models representing noxious visceral stimuli. Diclofenac did not exert any antinociceptive effects in the tail-flick or hot-plate models. In the writhing test, diclofenac dose-dependently inhibited the number of writhings after s.c. administration (0.001-10.0 mg/kg body weight) with an ED50 of 1 mg/kg. A similar dose-dependent action of diclofenac was seen after i.c.v. (0.1-200 micrograms) and i.t. (0.1-100 micrograms) administration with an ED50 of 3 micrograms in both cases. The antinociceptive effect of diclofenac administered s.c., i.c.v. or i.t. was almost completely reversed by pretreatment with naloxone, (1 mg/kg body weight s.c.). In the colorectal distension model, the i.c.v. administration of diclofenac (1-200 micrograms), which attenuated the cardiovascular response to colorectal distension, was reversed by naloxone. The pressor and tachycardia response to a 20 s, 80 mmHg colorectal distension was inhibited by diclofenac 100 micrograms i.c.v. (16.1 +/- 1.7 mmHg or 58% and 39.4 +/- 0.4 bpm or 70% versus control, respectively). It is concluded that diclofenac exerts a central, naloxone-reversible antinociceptive action in experimental animals after noxious visceral stimuli but not after somatosensory stimuli.

Analgesics↗
PubMed1990

Comparative bioavailability of a cisapride suppository and tablet formulation in healthy volunteers.

The comparative bioavailability of cisapride as a 30 mg suppository and three 5 mg oral tablets was investigated in 12 non-smoking, healthy male volunteers. The two formulations were administered on two separate occasions following an overnight fast, according to a randomized cross-over design. The plasma concentration of cisapride was measured over 48 h after drug administration. The 30 mg suppository exhibited a mean time to the peak plasma concentration of 3.8 h, while the tablets showed a significantly earlier peak time of 1.5 h. The maximum plasma concentration of cisapride after the 30 mg suppository (50.3 ng.ml-1) was significantly lower than after the tablets (74.3 ng.ml-1). The AUCs following the two treatments did not differ significantly from each other. The comparative bioavailability of the 30 mg cisapride suppository in relation to the three 5 mg oral tablets was 85%, with a 95%-confidence interval of 67% to 102% (not adjusted for dose). Normalizing the mean AUC by dose, the relative bioavailability of the suppository was 43% of that of the tablet. The elimination half-life of cisapride was not significantly different following the administration of the two formulations (9.3 h for the suppository and 9.8 h for the tablet).

Adult↗
PubMed1990

A comparison of diltiazem and metoprolol in hypertension. Swedish Diltiazem-Metoprolol Multicentre Study Group.

A double-blind, parallel-group multicentre study has been done to compare the antihypertensive properties, effects on serum lipoproteins and adverse effect profiles of diltiazem and metoprolol given as monotherapy to primary hypertensive patients. 128 patients were included from 10 participating centers. Following a placebo wash-out period of 5 weeks, patients were randomized either to diltiazem or metoprolol treatment according to a forced titration regimen. Each dose was given for a 4-week period in a stepwise regimen. A total of 119 patients, 59 and 60 in the two groups, completed the study. Supine and standing BPs were reduced in a similar, dose-dependent fashion by diltiazem and metoprolol. In the former supine BP fell from 161/101 to 151/91 mmHg at the highest dose level. In the latter patients, supine BP at the highest dose level was reduced from 161/102 to 155/94 mmHg. Target pressures (DBP less than or equal to 90 mmHg and/or DBP reduction of greater than or equal to 10%) were reached in 63% and 48% of the patients, respectively. HDL-cholesterol was increased in diltiazem-treated patients and decreased in those on metoprolol. Otherwise, serum lipoproteins did not differ significantly between treatments. The incidence and severity of dose-dependent adverse effects did not differ significantly between treatments, although moderate to distressing side effects were reported more commonly by metoprolol-treated patients. Ankle oedema and breathlessness tended to be more common on diltiazem therapy, while tiredness, increased sweating and sleep disturbances appeared to be experienced more frequently by metoprolol-treated patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Pressure↗
PubMed1990

Dose-dependent effects of verapamil and nifedipine on in vivo platelet function in normal volunteers.

The effects of 1 week of treatment with low and moderate doses of verapamil or nifedipine upon platelet function has been studied in 12 healthy volunteers. The ex vivo platelet aggregation threshold for ADP or adrenaline was not altered by verapamil or nifedipine. The plasma concentrations of beta-thromboglobulin and platelet factor 4 were significantly reduced by low but not by moderate doses of verapamil and nifedipine. Low doses of verapamil and nifedipine inhibit in vivo platelet activity in healthy volunteers.

Adenosine Diphosphate↗
PubMed1990

Acute and long-term changes in plasma levels of atrial natriuretic factor in patients with renal replacement therapy.

In 14 patients on hemodialysis who received kidney grafts from living related donors, plasma levels of immunoreactive atrial natriuretic factor (Ir-ANF) were determined in a sequence covering the last hemodialysis treatment, the day of transplantation, and a follow-up period of 6-12 months. The geometric mean value before dialysis was 196 pg/ml, the range 32-634. Weight loss during dialysis was 1.5 +/- 1.1 kg (mean +/- SD), but only a nonsignificant reduction in Ir-ANF levels occurred. On the day of transplantation, plasma Ir-ANF levels increased from 143 pg/ml before to 391 post-transplantation (P = 0.02, n = 12), probably in response to deliberate volume expansion. Post-transplant Ir-ANF levels correlated significantly to diuresis during the first 24 h, which ranged from 3.7 to 17.81 (mean 6.6; r = 0.65, P = 0.02). On day 2, mean 24 h diuresis decreased to 3.3 +/- 1.41. Most patients had reached their true dry weight by day 5, but Ir-ANF levels remained high, the geometric mean being 180 pg/ml. During further follow-up and preserved graft function (GFR range 34-88 ml/min per 1.73 m2 body surface area), Ir-ANF levels declined to a geometric mean of 63 pg/ml by 2-6 months and to 36 at 12 months post-transplant. We conclude that plasma Ir-ANF levels are chronically elevated in patients with chronic renal failure but may be further stimulated by acute overhydration. Transplanted kidneys initially respond to the increased levels but adapt within a day. Even with good graft function, normalization of plasma Ir-ANF requires several weeks or months.

Adolescent↗
PubMed1990

Regional haemodynamic effects of endothelin-1 in rat and man: unexpected adverse reaction.

Endothelin-1 was infused into the non-dominant brachial artery in two male subjects. We then monitored intra-arterial mean blood pressure, right atrial pressure, the heart rate and forearm blood flow (by plethysmography). Endothelin-1 at a dose of 5 x 10(-14) to 5 x 10(-9) mol, infused over 5 min periods, elicited no major changes in mean arterial pressure, heart rate and right atrial pressure. We observed an initial increase in forearm blood flow, followed by dose-dependent decreases of 25, 34 and 42% at 5 x 10(-11) to 5 x 10(-9) mol. A higher dose of endothelin-1, 5 x 10(-8) mol, given to only one of the subjects, elicited sweating and vomiting. In this subject, mean arterial pressure, right atrial pressure and the heart rate did not change, while forearm blood flow increased transiently. A deep muscular pain developed in the forearm receiving the endothelin-1 infusion after 30 min (maximum 2 h, duration 10 h), and this pain was intensified by touch and muscle contractions. The force of muscle contractions in the forearm was markedly reduced and a visible oedema developed. In order to investigate the mechanisms of oedema formation, endothelin-1 (10(-10) to 5 x 10(-8) mol/l) was given intra-arterially in a rat hindquarter preparation which was perfused at a constant flow rate. In the rat, endothelin-1 increased both pre- and postcapillary resistance, leading to an increase in capillary hydrostatic pressure and a marked net transcapillary fluid transfer from the perfusate to tissue. There was no sign of increased vascular permeability.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Plasma concentration-effect relationships of intravenous and extended-release oral felodipine in hypertensive patients.

Felodipine, a dihydropyridine calcium antagonist, was given double-blind in a crossover design comparing once-daily doses of 20 mg felodipine extended-release (ER) tablets with placebo in 12 hypertensive patients. A 2-h intravenous infusion was given after a placebo washout. After oral felodipine, blood pressure (BP) was significantly lower than after placebo, both after the first dose and after 2 weeks of treatment. Supine BP 24 h after the first dose of placebo and felodipine was 159/97 and 153/92 mm Hg (p less than 0.01/0.05), respectively. Corresponding BPs at 2 weeks were 158/99 and 144/89 mm Hg (p less than 0.01/0.01). Approximately 75% of the maximal and 60% of the trough effect at steady state were obtained already after the first dose. The plasma concentration (CpF) vs. time curve after felodipine ER was relatively flat. After oral felodipine, a linear correlation was found between BP reduction and logarithmic CpF. After intravenous administration, CpF correlated well with a hyperbolic function. These data indicate that there is an almost linear relation between BP reduction and log CpF in the range from 2-20 nmol/L, and that little additional effect is to be expected above approximately 20 nmol/L. No hysteresis was found for the relationship between CpF and BP reduction. The absolute bioavailability of felodipine ER was 22%.

Adult↗
PubMed1990

Blunted renal response to atrial natriuretic peptide in congestive heart failure rats is reversed by the alpha 2-adrenergic agonist clonidine.

We wished to determine whether pharmacologic inhibition of the exaggerated sympathetic nerve activity in congestive heart failure (CHF) could restore the renal response to exogenous atrial natriuretic peptide (ANP) administration. Left ventricular (LV) myocardial infarction was induced in Sprague-Dawley rats (n = 16) by coronary artery ligature. Four to 6 weeks postoperatively, an isotonic saline (controls) or clonidine 5 micrograms/h infusion was given. Four hours later, all animals received incremental doses of rat ANP (99-126) (0.25, 0.5 and 1.0 microgram/kg/min). The continuous clonidine infusion transiently increased urinary volume (UV) as compared with the saline controls. Mean arterial pressure (MAP), heart rate (HR), and plasma norepinephrine (NE) were significantly decreased by clonidine. The graded ANP infusions significantly increased UV (saline 39.13 +/- 12.45 and clonidine 90.25 +/- 13.69 microliters/min, p less than 0.05) and UNaV (saline 4.26 +/- 1.10 and clonidine 8.81 +/- 1.59 mumol/min, p less than 0.05) in clonidine-pretreated rats as compared with saline-pretreated rats. We conclude that the diuretic and natriuretic responses to ANP are significantly increased in CHF after presynaptic inhibition of NE release by low-dose clonidine.

Animals↗