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The effects of repeated treatment cycles and different doses on intraindividual variation in oral bioavailability of chlorambucil and its first, active, and more toxic metabolite, phenylacetic acid mustard, were studied. Chlorambucil and phenylacetic acid mustard concentrations were measured with HPLC on Day 1 and on Day 4 in 15 timed blood samples from 11 chronic lymphocytic leukaemia patients receiving chlorambucil therapy cycles. Bioavailability was evaluated also after the first chlorambucil doses of six consecutive treatment cycles repeated every 4 weeks with increasing chlorambucil doses starting with 0.8 mg/kg/4 days, and increased by 0.1 mg/kg/4 days cycle. Area under the concentration-time-curve (AUC) from t=0 to infinite was in average 3.2 hr* microg/ml for the first cycle, and decreased by 17% in four days (P

Although theophylline has been used in the treatment of asthma for decades, it is not a first line choice any more. It is a well-known bronchodilator, but was recently discovered also to be an anti-inflammatory, immunomodulatory and bronchoprotective agent. Therefore we wanted to establish the role of theophylline on prostaglandin and leukotriene production, which plays a part in the pathogenesis of asthma. Theophylline was infused (bolus 5 mg/kg in 15 min and infusion 0.4 mg/kg/h for 1 h 45 min) into healthy volunteers. Thromboxane B2, prostaglandin E2 and leukotriene E4 were measured from the A23187-stimulated whole blood samples and stable metabolites of thromboxane A2; prostacyclin and leukotriene E4 were measured from urine. Theophylline increased prostaglandin E2 production and decreased leukotriene E4 production ex vivo in whole blood, thus increasing the prostanoid/leukotriene ratio. It did not change thromboxane B2 production stimulated by either spontaneous clotting or A23187 in the whole blood. Theophylline had hardly any effect on in vivo thromboxane, prostacyclin and leukotriene E4 production measured as urinary metabolites, 11-dehydro-thromboxane B2, 2,3-dinor-6-keto-prostaglandin F1alpha and leukotriene E4, respectively. Serum theophylline concentrations were at the lower level of normal therapeutic range during the infusion. The increase in PGE2 and the decrease in LTE4 synthesis ex vivo may offer a new explanation for the mode of antiasthmatic action of theophylline. It is notable that this phenomenon occurs at low serum theophylline concentrations. These results confirm the idea that theophylline has an anti-inflammatory and bronchoprotective action and support the use of theophylline as a therapeutic agent in asthmatic patients.

We infused noradrenaline (0.025 micrograms/kg/min for 60 min, n=7) and dopamine (3.0 micrograms/kg/min for 60 min, n=6) into healthy male volunteers to study the effects of these catecholamines on in vivo thromboxane A2, prostacyclin and leukotriene E4 production measured as urinary excretions of 11-dehydro-thromboxane (TX) B2, 2,3-dinor-6-keto-prostaglandin (PG) F1alpha and leukotriene (LT) E4, respectively. Plasma noradrenaline and dopamine concentrations were 2.9+/-0.3 and 233+/-17 nmol/l at the endo fo the noradrenaline and dopamine infusions, respectively. Noradrenaline decreased thromboxane production and increased leukotriene production almost two fold. It had hardly any effect on prostacyclin production. Dopamine had no significant effects on any of the variables, however, it had a tendency to increase prostacyclin and leukotriene production. The results indicate that noradrenaline is a more important modulator of arachidonic acid metabolism than dopamine in vivo.

We have previously demonstrated that adrenaline infusion increases the thromboxane/leukotriene (TX/LT) ratio in whole blood in healthy volunteers. The aim of the present study was to see whether other catecholamines--noradrenaline and dopamine--are also capable of modulating arachidonic acid (AA) metabolism in man. Low doses of noradrenaline (0.025 microgram/kg/min) and dopamine (3.0 micrograms/kg/min), which did not change hemodynamics, were infused for 60 min into healthy male volunteers. Both dopamine and noradrenaline decreased TX synthesis stimulated by spontaneous clotting, but no remarkable effect was seen when calcium ionophore A23187 was used as a stimulus. Dopamine but not noradrenaline increased prostaglandin E2 (PGE2) synthesis in A23187-stimulated whole blood. They both marginally decreased LTB4 formation in A23187-stimulated whole blood. The findings indicate that not only adrenaline but also noradrenaline and dopamine modulate AA metabolism in man.

Concentrations of leukotriene B4 (LTB4) and prostaglandin E2 (PGE2) in peritoneal fluid were measured in 19 women with suspected acute pelvic inflammatory d

BACKGROUND: Ischemia, such as that caused by a tourniquet, stimulates thromboxane (Tx) A(2) synthesis. TxA(2) might sensitize the operated limb to various complications, such as compartment syndrome and thromboembolic events. METHODS: We studied the effect of pretreatment with a single dose of acetylsalicylic acid (ASA) (25, 100, and 500 mg) given 3 hours before surgery on the formation of TxB(2), a stable metabolite of TxA(2), after tourniquet deflation in 32 knee or ankle surgery patients. RESULTS: Tourniquet time varied between 60 +/- 8 to 71 +/- 7 (SE) minutes. In control patients without ASA pretreatment, the platelet-produced femoral vein serum TxB(2) concentration over 30 minutes in vitro coagulation increased remarkably (from 40.0 +/- 20 ng/mL to 73.5 +/- 39 ng/mL) immediately after tourniquet deflation. Plasma concentrations increased similarly, approximately threefold. Pretreatment with 100 or 500 mg ASA prevented the increase in TxB(2) concentrations. Radial artery concentrations of TxB(2) were similar to venous concentrations in the different treatment groups. CONCLUSION: Pretreatment with a single 100-mg dose of ASA prevents the release of TxB(2) after tourniquet deflation.

Altogether 53 patients (31 women, 22 men) with definite rheumatoid arthritis were randomly divided into groups of 5-6 patients and treated for one day only with one of the following non-steroidal anti-inflammatory drugs (NSAIDs): acetylsalicylic acid, carprofen, diclofenac, indomethacin, naproxen, proquazone, timegadine, tolfenamic acid or paracetamol, and with prednisolone, in recommended doses. Synovial fluid samples were collected before and after the treatment. White cell count and its differentiation as well as the concentrations of protein, cyclic adenosine-3',5'-monophosphate (cAMP), prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) were measured from the synovial fluid. Synovial fluid leukocyte counts correlated with PGE2 concentrations, but showed no correlation with LTB4 levels before treatment. Significant changes were seen in the form of lowered PGE2 values following treatment with the clinically and experimentally most potent NSAIDs, and as depressed LTB4 levels following prednisolone treatment. The other markers of inflammation are obviously more resistant, changing only slowly during prolonged treatment, and may thus be, at least in part, secondary to the changes in prostanoids.

To evaluate further the complex role of prostanoids in rheumatoid arthritis we compared the immunoreactive prostanoid production of healthy and rheumatic synovial cells in a primary cell culture. During the first days in culture the adherent cells from rheumatic synovia produced higher amounts of prostanoids, especially the proinflammatory and immunosuppressive prostaglandin E2 (PGE2), than cells originating from non-inflamed synovia. This difference disappeared within one week culture and was partly explained by altered substrate availability.

A study has been made of the effects of intravenous atenolol, practolol and propranolol on the changes induced by exhaustive dynamic physical exercise in blood pressure, heart rate and blood levels of lactate, glucose, insulin, free fatty acids and potassium. The mean endurance of dynamic exercise was reduced by all three beta-blockers, most markedly by propranolol. After all the beta-blockers heart rate showed a similar decrease during the first 60 min of exercise; atenolol caused the smallest reduction at exhaustion. All three beta-blockers lowered the systolic blood pressure during exercise; propranolol was the most active agent both during exercise and during recovery. The diastolic pressure was higher during exercise after treatment with the beta-blockers, especially propranolol. The beta-blockers did not markedly affect the elevation of blood lactate induced by exercise. The increase in blood glucose was abolished by atenolol. Plasma insulin was reduced by exercise after beta-blockade, most markedly after propranolol and practolol. All the beta-blockers were equipotent in reducing up to 60 min the exercise-induced increase in plasma free fatty acids, although at exhaustion propranolol had a significantly greater effect than atenolol or practolol. Serum potassium was higher after propranolol and atenolol than after practolol during exercise and recovery.

Prostanoid formation may be stimulated by different events associated with anaesthesia and operation, such as positive pressure ventilation and tissue trauma. We investigated the effects of halothane and enflurane on plasma and serum prostanoid concentrations in 19 patients scheduled for minor operations. In 9 abdominal surgery patients, thromboxane B 2 concentrations were followed up to the fifth postoperative day. Prostanoid determinations were carried out with RIA. In general, the changes in prostanoid concentrations in patients anaesthetised with halothane or enflurane were similar. During spontaneous breathing there was a decrease in plasma PGE 2 and TxB 2 concentrations. During intermittent positive pressure ventilation and operation, PGE 2 and TxB 2 concentrations rose but 6-keto-PGF 1α did not. After operation, TxB 2 concentrations remained elevated but the other prostanoids returned to preoperative values. TxB 2 concentrations decreased to the preoperative level on the first postoperative day. The elevated TxB 2 concentrations during and after surgery can be regarded, in some patients, as a potential risk factor for cardiovascular and thromboembolic complications.

The effects of one-day treatment with nine nonsteroidal anti-inflammatory drugs and prednisolone on human synovial fluid concentrations of prostanoids were studied. The doses were calculated so as to be approximately equipotent according to clinical experience and the recommendations of the manufacturers. Most of the drugs used reduced clearly PGE2 and TxB2 levels in synovial fluid, but only a slight diminution in 6-keto-PGF1 alpha values was found. Carprofen, diclofenac, indomethacin, naproxen and tolfenamic acid reduced significantly the synovial fluid PGE2 concentrations. Diclofenac and indomethacin also reduced significantly the synovial TxB2 concentrations.

Fourteen patients with mild to moderate essential hypertension were randomized, after a baseline placebo period of 4 weeks, to receive the angiotensin converting enzyme (ACE) inhibitor quinapril or a placebo. During a 12 week, double-blind phase, the dosage of quinapril was increased from 10 to 40 mg twice daily being doubled every 4 weeks. At the end of the baseline period and of each month of the double-blind phase, 12 h overnight urine collections were made and morning blood samples were taken about 12 h after the last dose of medication. During the double-blind phase, blood pressure in the quinapril group (n = 7) decreased from 159 +/- 3/105 +/- 1 to 141 +/- 6/94 +/- 2 mm Hg (mean +/- SEM). Serum ACE activity and plasma angiotensin II concentration were reduced to 4 +/- 1% and 14 +/- 1% of the pretreatment values, respectively. Neither the plasma concentrations nor the urinary excretions of prostaglandin E2, 6-keto-prostaglandin F1 alpha (a prostacyclin metabolite), or thromboxane B2 (a metabolite of thromboxane A2) were affected by quinapril. In the placebo group, blood pressure tended to decline but the biochemical variables remained essentially unchanged. These results indicate that prostanoids are not involved in the antihypertensive action of quinapril, the principal effect of which seems to be inhibition of the renin-angiotensin system.

The effect of D-penicillamine (DPA) on immunoreactive prostanoid concentrations was studied in a primary culture of adherent synovial cells from patients suffering from rheumatoid arthritis (RA). DPA in clinically achievable concentrations increased the levels of prostaglandin E 2 (PGE 2 ) and thromboxane B2 (TXB 2 ) and reduced those of 6-keto-prostaglandin F 1α (6-keto-PGF 1α ) synthetized from endogenous substrate. The capacity for PGE 2 and 6-keto-PGF 1α production in the presence of exogenous arachidonic acid was decreased by DPA. These effects may be connected with the antirheumatic and immunosuppressive action of DPA.

For the measurement of the tetracyclic antidepressant maprotiline in human serum, a gas chromatographic method with flame-ionization detection has been developed. The assay specifications obtained are as follows: a precision (C.V.) of 3.5–6.4%, and a relative recovery of 97–109% using amitriptyline as internal standard. The sensitivity of the assay from serum was 40 nmol/l. The applicability of the method has been shown by measuring steady-state serum levels of five inpatients. The steady-state serum levels of maprotiline given at a daily dosage of 75 mg varied from 272 to 570 nmol/l.

The interaction of inhibition of prostaglandin (PG) synthesis by indomethacin (75 mg/day) with the antihypertensive effect of atenolol (50 mg b.i.d.) was studied in 11 untreated otherwise healthy men 35 to 45 years old with essential hypertension. Atenolol for 3 weeks decreased supine blood pressure (BP) from 157/109 mm Hg during placebo to 148/97 mm Hg. Indomethacin alone for 1 week slightly increased BP and antagonized the antihypertensive action of atenolol. Atenolol reduced plasma renin activity (PRA) to 40% but did not modify either the urinary excretion of vasodilatory PGs (PGE2 and prostacyclin measured as 6-keto-PGF1α) or plasma kininogen and urine kallikrein. Indomethacin suppressed PRA to 27% and PG excretion to approximately 70% but did not markedly change plasma kininogen and urine kallikrein excretion. The decreased excretion of 6-keto-PGF1α, the metabolite of the main vasodilatory prostanoid prostacyclin, correlated with the increased BP measured in standing subjects. The effects of indomethacin were practically the same when given with atenolol as when given alone. We conclude that the slight increase in BP by indomethacin in essential hypertension is associated with the reduced production of vasodilatory PGs but not with alterations in activities of the renin-angiotensin or kallikreinkinin systems. Clinical Pharmacology and Therapeutics (1985) 38, 443–449; doi:10.1038/clpt.1985.202

No significant differences were found in plasma concentrations and urinary excretion of prostaglandin E2 (PGE2), 6-keto-prostaglandin-F1 alpha (6-keto-PGF1 alpha) and thromboxane B2 (TxB2), between rheumatoid arthritis patients and controls. However, urinary excretion of PGEe and 6-keto-PGF1 alpha tended to be greater and plasma levels of TxB2 lower in rheumatoid arthritis. Plasma concentrations and urinary excretion showed no marked circadian variation, although night or morning values were slightly lower. Plasma and urine prostaglandins do not correlate with clinical symptomatology in rheumatoid arthritis.

The effects of D-penicillamine, sodium aurothiomalate, indomethacin, timegadine and tolfenamic acid on the lipoxygenase and cyclo-oxygenase pathways of arachidonic acid metabolism were studied in human polymorphonuclear leukocytes (PMNs) in vitro. In short-term incubations, D-penicillamine and aurothiomalate did not affect leukotriene B4 (LTB4), prostaglandin E2 (PGE2) or thromboxane B2 (TXB2) production. Each of the three non-steroidal anti-inflammatory drugs (NSAIDs) used were potent inhibitors of prostanoid synthesis. In higher concentrations they also reduced LTB4 production; timegadine and tolfenamic acid were effective in concentrations comparable to those measured in plasma during drug therapy, whereas indomethacin was needed in ten times higher concentrations. The different effects of NSAIDs on 5-lipoxygenase activity may be of importance in their therapeutic actions as well as in the appearance of some side-effects, e.g. gastric irritation and "aspirin-induced" asthma.

The effect of intravenous pindolol (0.0256 mg/kg) on changes in plasma arachidonic acid (AA), some of its metabolites, and catecholamines induced by submaximal exercise was studied in six healthy male volunteers. Exercise resulted in markedly increased plasma concentrations of thromboxane B2 (TxB2) from 0.13 +/- 0.01 to 0.27 +/- 0.02 pmol/ml (mean +/- SEM; p less than 0.05) and AA from 4.1 +/- 0.6 to 8.0 +/- 0.9 mumol/l (p less than 0.005). No significant changes were seen in plasma concentrations of 6-keto-PGF1 alpha or PGE2 during exercise. A marked increase in plasma noradrenaline was seen already at 15 min of exercise, while the adrenaline concentration increased significantly at 30 min of exercise and a very marked increase in the adrenaline concentration was seen at exhaustion. A positive correlation (r = 0.54; p less than 0.05) was seen between plasma TxB2 and plasma adrenaline during exercise. The peak increase in both of these parameters was seen simultaneously at exhaustion. Pindolol treatment resulted in almost total inhibition of the increase in plasma TxB2 and AA during exercise. Pindolol treatment also resulted in a significantly higher adrenaline level at exhaustion. These data seem to indicate that an increased sympathetic tone may result in an increased release of arachidonic acid in the formation of vasoconstrictive thromboxane A2.

The effects of direct adrenergic stimulation, achieved by 60-min adrenaline infusion (0.1-0.2 microgram kg-1 min-1), on thromboxane B2 (TxB2) production by platelets in whole blood ex vivo and on ADP-induced platelet aggregation were studied in seven healthy male volunteers. The effects of two beta-adrenergic blocking agents, pindolol and practolol, on the adrenaline-induced changes were furthermore analyzed. Adrenaline administration resulted in an about ten-fold elevation in plasma adrenaline, and an about three-fold increase in TxB2 production by platelets at 30 min of infusion. The increased TxB2 production persisted throughout the entire adrenaline infusion, and up to 30 min of postinfusion period (recovery). Pindolol blunted markedly the effects of adrenaline on platelet TxB2 production, whereas practolol seemed to have only a weak effect. The sensitivity of platelets to ADP-induced aggregation did not change during the 60 min of adrenaline infusion. However, at 60 min of recovery the platelets showed a significantly increased sensitivity to ADP. Correspondingly, pindolol treatment did not affect platelet sensitivity during the infusion period, but at 60 min of recovery it had caused a significantly decreased sensitivity of platelets to ADP-stimulation. Plasma-free fatty acids increased markedly during the adrenaline infusion. This increase was totally blocked by pindolol, but only partly by practolol. The present results demonstrate that adrenaline, at plasma levels seen for example, in complicated myocardial infarction, stimulates platelet TxB2 production and increases the sensitivity of platelets to ADP after the infusion. Pindolol, but not practolol, inhibits these adrenaline-induced changes in platelet behaviour.

Concentrations of thromboxane (Tx) B2 in plasma and its production by platelets were measured in 20 spinal and 10 epidural anesthesia patients scheduled for small operations in the lower extremities. The main metabolite of prostacyclin, 6-keto-PGF1 alpha and prostaglandin (PG) E2 in plasma were also determined. Plasma TxB2 and TxB2 production by platelets increased during both spinal and epidural anesthesia. Plasma TxB2 levels also remained elevated 1 h after anesthesia. The plasma concentrations of 6-keto-PGF1 alpha and PGE2 did not change during spinal or epidural anesthesia. In in vitro studies, only low concentrations of lidocaine (0.5-1.0 micrograms/ml) and bupivacaine (0.5-3.0 micrograms/ml) increased platelet TxB2 production. In platelet rich plasma, neither lidocaine nor bupivacaine in concentrations of 0.5-3.0 micrograms/ml caused constant changes in ADP-induced platelet aggregation, but they inhibited it in toxic concentrations (12 micrograms/ml). The results suggest that the increased TxB2 plasma levels and platelet TxB2 production during regional anesthesia are not caused by local anesthetics itself but by other factors, e.g. tissue trauma. In clinically found concentrations, local anesthetics do not cause any constant changes in platelet aggregation.

Iloprost (ZK 36 374), a stable analog of carbaprostacyclin, was infused for 72 h to nine patients with advanced obliterative arterial disease. Iloprost caused a marked vasodilation and a compensatory increase in cardiac output. The glomerular filtration rate increased by 45% and tubular reabsorption of sodium and water were reduced by 80% and 107%, respectively. The urine excretion rate increased by 122%. Tubular handling of potassium and calcium were not influenced by iloprost but magnesium reabsorption was stimulated. The renin-angiotensin system was not activated while serum angiotensin converting enzyme activity was decreased. Kallikrein excretion in urine was increased 4.4-fold but plasma kininogen, a substrate for kallikrein in producing vasoactive kinins, was unaffected by the drug. Plasma levels of 6-keto-PGF 1 α and TxB 2 were decreased and their excretion in urine increased. Plasma catecholamines were not changed by iloprost. Several of the changes persisted for at least the first postinfusion day. The results indicate that iloprost increases urine excretion rate by increasing glomerular blood flow and by inhibiting sodium and water reabsorptions. The kinin-forming system, but not the renin-angiotensin system or plasma catecholamines, may be activated. The decrease in plasma level of prostanoids can be, at least partly, due to their increased excretions in urine.

The possible role of vasodilatory prostanoids in the antihypertensive action of captopril was investigated in spontaneously hypertensive rats (SHR). Captopril (100 mg/kg/day for 5 days) decreased systolic blood pressure and increased water consumption, urine excretion and plasma renin activity (PRA). It also enhanced the urinary excretion of the prostacyclin metabolite 6-keto-PGF1 alpha, but did not change the excretion of PGE2. Indomethacin (3 mg/kg/day), given both alone and in combination with captopril, reduced markedly the urinary excretions of 6-keto-PGF1 alpha and PGE2 but did not alter PRA, compared with corresponding groups without indomethacin. The suppression of prostanoid synthesis caused by indomethacin did not affect the antihypertensive effect of captopril or the basal blood pressure in SHR. Neither did indomethacin influence drinking or urine excretion in SHR not receiving captopril, but it reduced the dipsogenic and diuretic effects of captopril. The results suggest that captopril augments the production of vasodilatory prostacyclin. Yet prostanoids have no significant role in the antihypertensive mechanism of captopril in SHR.

Production of various arachidonic acid metabolites from both endogenous and exogenous substrate was measured using cultures of synovial fibroblasts from healthy and rheumatic synovia. At first, the rheumatic cells showed retarded growth and an altered histological picture. Rheumatic cells produced more 6-keto-PGF1 alpha, the main metabolite of prostacyclin, and prostaglandin E2 than did normal cells, which synthesized more thromboxane B2. Later on these differences diminished or disappeared, except regarding 6-keto-PGF1 alpha. When fairly high concentrations of exogenous arachidonic acid were used, for 2-hour incubation of the cells, the production of identified metabolites, 6-keto-PGF1 alpha, PGF2 alpha, PGE2, PGD2, PGA + PGB and thromboxane B2, was slightly less in rheumatic cells. In general, the main metabolite formed was 6-keto-PGF1 alpha. Some kind of feedback mechanism between prostaglandins and cyclic nucleotides is suggested.

We examined the effects of beta-blockade with the nonselective antagonist propranolol, the cardioselective antagonist atenolol, and the cardioselective antagonist with partial agonist activity, practolol, on the levels of free arachidonic acid (AA), thromboxane B2 (TxB2), prostaglandin (PG) E2, and 6-keto-PGF1 alpha in plasma, and TxB2 production by platelets during clotting in six normal subjects during submaximal dynamic exercise. The drugs were given intravenously in equipotent increasing doses before the exercise test. Exercise induced a clear increase in AA, TxB2, and 6-keto-PGF1 alpha in plasma. During the first 60 min of exercise all three beta-blockers decreased the plasma levels of AA and TxB2. Propranolol (0.19 mg/kg) was slightly more effective than atenolol (0.19 mg/kg) or practolol (0.64 mg/kg); however, at exhaustion, propranolol was markedly more effective than the other two blockers. Plasma 6-keto-PGF1 alpha and PGE2 levels were less affected by beta-blockade during exercise, and no significant effect was seen on TxB2 formation by platelets. The plasma 6-keto-PGF1 alpha/TxB2 ratio was markedly higher after propranolol treatment than after treatment with the other two blockers during the exercise period. These results suggest that the capability of a nonselective blocker to inhibit both beta 1- and beta 2-adrenergic receptors may be of advantage because of the more effective inhibition of thromboxane formation than with a cardioselective blocker, especially when the sympathetic tone is markedly increased.