Alpha-receptor function changes after the first dose of prazosin.

The effect of oral prazosin on blood pressure and antagonism of phenylephrine-induce blood pressure increase was investigated in six healthy subjects during a dosing interval after the first dose and 3 days after the first dose of the drug. Prazosin lowered standing blood pressure more after the first dose than after the same dose 3 days later, despite similar plasma levels. Blood pressure decrease correlated with plasma prazosin levels during the elimination phase at the first dose, but not after 3 days of therapy. The phenylephrine log dose-response curves shifted to the right after prazosin, which indicates alpha-receptor antagonism of the drug. On day 4, the phenylephrine curve before prazosin dose shifted to the right of the pretreatment curve on day 1, despite very low prazosin plasma levels. On day 4 after after prazosin dosing the phenylephrine dose-response curves were shifted to the left of that on day 1. Our data indicated tolerance to prazosin effect on blood pressure and to phenylephrine agonism after 3 days dosing. Our data suggest that this might be due to desensitization of alpha-adrenoceptors with differential effects of agonists and antagonists.

Prazosin kinetics in hypertension.

Prazosin kinetics were studied after single doses (intravenous and oral, 0.5 mg) and after increasing multiple doses (0.5 to 5 mg three times daily) in eight patients with hypertension. After intravenous administration the kinetics could be described by a linear two-compartment open model. Terminal half-life (t1/2 beta) was about 3 hr and apparent volume of distribution (Vd beta) about 0.6 l/kg. After oral doses bioavailability ranged between 55% and 82%. Since total plasma clearance was low (0.14 l/kg x hr) incomplete bioavailability was the result of incomplete absorption rather than of first-pass liver metabolism. The estimated extraction ratio was about 14%. Renal clearance was negligible; only 1% to 2% of the dose was recovered unchanged in urine. Binding to plasma proteins to both albumin and alpha 1-acid glycoprotein was substantial (97%), with albumin being most important. Increasing multiple doses showed that prazosin followed first-order kinetics with a linear correlation between dose and steady-state plasma concentration (P less than 0.001). There were substantial variations in plasma concentrations between patients and there were also day-to-day variations in concentration within the same patient.

Prazosin dynamics in hypertension: relationship to plasma concentration.

The antihypertensive effects of prazosin in relation to its kinetics were studied after single doses (intravenous and oral, 0.5 mg) and during increasing multiple doses (0.5 to 5 mg three times a day). There was a fall in systolic and diastolic blood pressures of 10% to 14%, which was greater in the standing than in the sitting position. Prazosin plasma concentrations correlated with dose (P less than 0.001). After intravenous prazosin the fall in systolic and diastolic blood pressure and prazosin plasma concentration correlated (P less than 0.01) during the beta-elimination phase in all patients. In only five of eight patients, however, did mean plasma concentration and antihypertensive effect during continuous treatment with different doses correlate. The maximal fall in systolic blood pressure correlated (P less than 0.01) with that after the first oral steady-state dose (0.5 mg three times daily), which indicates limited possibility of early identification of prazosin responders. There were no signs of overshoot of blood pressure when prazosin was withdrawn for a week. On rechallenge with a single oral dose of 2.5 mg prazosin there were no signs of enhanced hypotensive effect.

Influence of pentobarbital on metoprolol plasma levels.

Induction of microsomal enzymes with barbiturates in rats has little effect on the metabolism of metoprolol, compared with propranolol and alprenolol, which undergo extensive hepatic extraction in animals and man. Our study was designed to examine whether the metabolism of metoprolol is inducable by barbiturate in man. In 8 healthy subjects the area under the plasma concentration/time curve after 0.1 gm metoprolol was reduced by a mean of 32% after treatment with 0.1 gm pentobarbital at bedtime for 10 days. There was considerable interindividual variability in the reduction after pentobarbital treatment (2% to 46%).

Influence of pentobarbital on effect and plasma levels of alprenolol and 4-hydroxy-alprenolol.

Six healthy subjects were given placebo and a single oral 0.2-gm dose of alprenolol (Aptin) before and after 0.1 gm pentobarbital at bedtime for 10 days. The plasma concentrations of alprenolol and its metabolite 4-hydroxy-alprenolol and the inhibition of exercise tachycardia were studied for 7 hr after the alprenolol. Alprenolol and 4-hydroxy-alprenolol plasma levels were decreased by about 40% by pentobarbital but plasma half-lives were unchanged. The inhibition of exercise tachycardia during a 7-hr period was reduced from 14.0% to 10.7% by pentobarbital. The reduction was proportional to the decreased drug plasma levels. There was a significant contribution of the metabolite to alprenolol effect. The estimation of relative potency of metabolite against parent compound was 0.9 before pentobarbital and 1.9 after pentobarbital.

Absorption of ocular timolol.

The absorption of timolol after topical administration to the eye was studied in 11 healthy volunteers and in 5 patients with bilateral open angle glaucoma. The volunteers received 2 drops of 0.5% timolol ophthalmic solution in each eye, equivalent to 0.8 mg of timolol maleate. Overflow was absorbed by paper tissue. The patients received the same dose twice daily for 2 weeks and were then investigated. In the paper tissue, 12 to 88% of the dose administered was recovered. Plasma concentrations were never above 5 ng/ml and not always detectable (detection limit 1 to 2 ng/ml). However, timolol was absorbed as the drug was found in the urine samples from all volunteers and glaucomatous patients.

Lack of effect of paracetamol on the pharmacokinetics of indomethacin and paracetamol in humans.

Paracetamol is an analgetic drug with additive effect if combined with indomethacin. In rat experiments, paracetamol has been shown to be gastro-protective, and in animal experiments, indomethacin blood levels decreased during combined treatment with paracetamol. The kinetic effect of paracetamol on indomethacin has been investigated in ten healthy volunteers. The mean area under the indomethacin plasma concentration curve AUC 0-alpha was 10.4 +/- 4.21 micrograms/mL x hr and did not change during combined paracetamol treatment (11.0 +/- 3.24 micrograms/mL x hr NS). Paracetamol levels were unchanged. In this study, no evidence was found that paracetamol can alter the pharmacokinetics of indomethacin in humans.

Adverse drug interactions with nonsteroidal anti-inflammatory drugs (NSAIDs). Recognition, management and avoidance.

The prevalence and incidence of adverse drug interactions involving nonsteroidal anti-inflammatory drugs (NSAIDs) remains unknown. To identify those proposed drug interactions of greatest clinical significance, it is appropriate to focus on interactions between commonly used and/or commonly coprescribed drugs, interactions for which there are numerous well documented case reports in reputable journals, interactions validated by well designed in vivo human studies and those affecting high-risk drugs and/or high-risk patients. While most interactions between NSAIDs and other drugs are pharmacokinetic, NSAID-related pharmacodynamic interactions may be considerably more important in the clinical context, and prescriber ignorance is likely to be a major determinant of many adverse drug interactions. Prescribing NSAIDs is relatively contraindicated for patients on oral anticoagulants due to the risk of haemorrhage, and for patients taking high-dose methotrexate due to the dangers of bone marrow toxicity, renal failure and hepatic dysfunction. Combination NSAID therapy cannot be justified as toxicity may be increased without any improvement in efficacy. Where lithium or anti-hypertensives are coprescribed with NSAIDs, close monitoring is mandatory for lithium toxicity and hypertension, respectively, and aspirin (acetylsalicylic acid) or sulindac are preferred. Phenytoin or oral hypoglycaemic agents may be administered with NSAIDs other than pyrazoles and salicylates provided that patients are monitored carefully at the initiation and cessation of NSAID treatment. Digoxin, aminoglycosides and probenecid may be coprescribed with NSAIDs, but close monitoring is required, particularly for high-risk patients such as the elderly. Indomethacin and triamterene should be avoided due to the risk of renal failure. High dose aspirin should be replaced by naproxen in patients on valproic acid (sodium valproate) and care is required when corticosteroids are administered to patients taking salicylates long term in high dosage. Interactions between NSAIDs and antacids or cholestyramine are generally avoidable. Adverse drug interactions involving NSAIDs may be limited by rational prescribing and by careful monitoring, particularly for high-risk patients, drugs and therapy periods.

Pharmacokinetics of ibuprofen enantiomers in plasma and suction blister fluid in healthy volunteers.

After a single oral dose of (R,S)-ibuprofen (1200 mg) to five healthy volunteers, paired plasma and blister fluid concentrations of drug were determined by a stereospecific HPLC assay. A pharmacokinetic model that incorporated blister fluid as a separate peripheral compartment adequately characterized the data. The plasma concentrations were consistently higher for (S)-ibuprofen than (R)-ibuprofen in both plasma and blister fluid. No significant difference in the elimination half-life of the enantiomers was observed. Similar to synovial fluid, there were relatively small fluctuations in blister fluid concentrations of both enantiomers. Blister fluid, similar to synovial fluid, therefore behaves pharmacokinetically as a peripheral compartment for drug distribution. This use of skin blisters, which can be sampled repetitively, may therefore prove to be a valuable experimental technique in pharmacokinetic and pharmacodynamic studies of drugs, especially in patients in whom synovial fluid is not available for sampling.

Better effect of methotrexate on C-reactive protein during daily compared to weekly treatment in rheumatoid arthritis.

Treatment with methotrexate (MTX) is well established in rheumatoid arthritis (RA), but dosing remains arbitrary as studies on the effect of different dosing schedules are lacking. In a randomised crossover design of 20 patients with RA, the effect of low (2.5mg) oral daily doses of MTX (15 mg weekly) was compared to intermittent weekly dosing (15 mg). C-reactive protein (CRP) values were lower and more stable on daily dosing compared to the significant (p < 0.05) changes in CRP observed during treatment with the same weekly dose. It may be postulated that nonresponders or patients with dose-dependent side effects may have clinical advantage from daily MTX dosing if hepatotoxicity and other side effects are not increased.

Reduced sulphoxidation capacity in D-penicillamine induced myasthenia gravis.

Myasthenia gravis may be observed due to treatment with penicillamine (D-PA). The sulphoxidation capacity was measured in nine Swedish patients with rheumatoid arthritis (RA) who had developed myasthenia gravis toward D-PA. The results show that in eight of nine patients tested, this parameter was markedly reduced. A patient with poor sulphoxidation capacity has a twelve-fold greater risk of developing this rare side effect. The significance of this is discussed.

Effect of felodipine in refractory hypertension.

Felodipine (Plendil), a new drug, has been used in the treatment of five patients with refractory essential hypertension (WHO II-III). Their mean blood pressure at the last outpatient visit before the study was opened was 195 +/- 25/129 +/- 21 mmHg (mean +/- s.d.) (range 175-235/110-165 mmHg), despite treatment with combinations of diuretics, beta-blockers and vasodilators, including minoxidil and captopril. Felodipin is a dihydropyridine derivative, a calcium antagonist that exerts a relaxant effect on resistance vessels. The first period of the study consisted of a 5-day stay in hospital followed by 3 months during which observations were carried out at the Outpatients' Department. After the first days in hospital felodipine therapy was introduced at a dose of 25 mg three times daily, given together with diuretics, beta-blockers and, in one case, captopril. At 8.00 immediately before the first dose was given, the blood pressure was 178 +/- 19/118 +/- 19 mmHg (mean +/- s.d.); 2 h later it was 144 +/- 18/85 +/- 4 mmHg, at which level it remained throughout the rest of the study. At the 3-month follow-up the mean pressure (recorded at the Outpatients' Department) was 138 +/- 20/89 +/- 14 mmHg. Side-effects included headache, flushing, palpitations and ankle oedema (in two patients during the second part of the study); they were of a mild to moderate degree and did not interfere with the treatment. There was no evidence of general fluid retention, and the body weight remained constant.(ABSTRACT TRUNCATED AT 250 WORDS)

NSAIDs, musculoskeletal disorders and gastrointestinal adverse effects.

Paracetamol should be considered as first line treatment for the common painful musculoskeletal disorders, especially osteoarthrosis. NSAIDs, which are beneficial should this fail and inflammation be present, should be prescribed in the lowest dose for the shortest possible time.

Additive effect of combined naproxen and paracetamol in rheumatoid arthritis.

The clinical effect and plasma naproxen levels were studied in 20 patients with RA receiving three doses of naproxen and two naproxen doses combined with paracetamol (acetaminophen) in a randomized, double-blind, comparison in five 2-wk treatment periods. A significant dose-concentration effect relationship was found for the three naproxen doses (500, 1000 and 1500 mg daily). The following variables were measured: global clinical effect, joint index, morning stiffness, activity of daily living (ADL), pain during movement and at rest. The naproxen dose-concentration effect relationship curve was moved to the left by the addition of 4 g paracetamol daily. No major side effects were observed, but complaints concerning the gastrointestinal tract were fewer on lower naproxen doses and these were not increased by concomitant paracetamol treatment. The results show that the clinical effect of naproxen in RA may be significantly increased by concomitant paracetamol administration.

Paracetamol in rheumatoid arthritis.

The need for supplementary analgesic treatment in RA has partially been neglected. Increasing evidence now support that paracetamol supplementation can increase the effect of NSAIDs. A hypothesis may be postulated that prostaglandin (PG) mediated anti-inflammatory effects of NSAIDs are only marginally increased by higher NSAID doses and that non PG mediated analgesic effects obtained at higher NSAID doses may instead be obtained by supplementing NSAIDs with paracetamol. Combined paracetamol treatment may increase the effect and decrease dose-dependent side-effects of NSAIDs.

Methotrexate--the relationship between dose and clinical effect.

Methotrexate (MTX) is an effective anti-rheumatic drug. Despite its frequent use, the relationship between different MTX doses and clinical effects remain unclear. In a randomized double-blind study in patients with RA, the effects of four MTX doses (5 to 20 mg) was studied. MTX (5 mg) induced a significant effect on the Ritchie joint index, morning stiffness, pain, ESR and C-reactive protein. The effect of MTX on those variables was related to the dose in the range from 5 to 20 mg MTX weekly. Interindividual differences in dose-response curves were observed. The study shows that MTX doses should be adjusted individually for each patient in order to improve efficacy and decrease dose-dependent side effects.

Pharmacokinetic interactions of penicillamine in rheumatoid arthritis.

The pharmacokinetic effect of the combined treatment of penicillamine with indomethacin and chloroquine was investigated in patients with rheumatoid arthritis. The mean plasma penicillamine concentration increased by 26% during indomethacin and 34% during chloroquine treatment. This new pharmacokinetic interaction may have important clinical implications.

Equianalgesic effects of paracetamol and indomethacin in rheumatoid arthritis.

The therapeutic and adverse effects of 2 weeks of treatment with high-dose indomethacin (150 mg/day) were compared with those of low-dose indomethacin (50 mg/day) combined with paracetamol (4 g/day) in a double-blind, double-dummy, cross-over study in 17 patients with active rheumatoid arthritis. Grip strength, Ritchie's index, joint circumference, joint pain, and patient's and physician's global assessments were estimated, and conventional laboratory parameters were followed. In addition, the time-concentration profiles of indomethacin and paracetamol were assessed during steady state. All patients had measurable plasma drug levels, indicating adequate compliance, and responders and nonresponders (five on each treatment) had equal drug levels, indicating that the variation in therapeutic efficacy was not secondary to pharmacokinetic differences. While there were fewer and milder side-effects during treatment with the drug combination, there was no difference in therapeutic efficacy. Hence, it appears that the main therapeutic profit of indomethacin in daily doses greater than 50 mg is enhanced analgesia. As such dosage involves pronounced side-effects, it seems more appropriate to employ the combination of 50 mg indomethacin and 4 g paracetamol, whereby similar analgesia can be obtained without an increase in side-effects.

Naproxen and paracetamol compared with naproxen only in coxarthrosis. Increased effect of the combination in 18 patients.

In a double-blind study of 18 patients with coxarthrosis the effect of 3 naproxen doses (0.5, 1.0, and 1.5 g daily) and 2 naproxen doses combined with paracetamol (0.5 g + 4 g daily and 1.0 g + 4 g daily) was investigated. Plasma levels of naproxen and paracetamol were measured (HPLC), and clinical assessment of pain, joint movement, activity of daily life and side-effects were performed at the end of the 5 treatment periods. A relationship was found between the 3 naproxen doses, naproxen plasma levels, pain at rest, and pain during movement. The combined treatment was more effective than treatment with the same naproxen dose alone. The effect of naproxen (0.5 g daily) combined with paracetamol (4 g daily) did not differ from that obtained during treatment with higher naproxen doses only. Furthermore, the effect of the highest naproxen dose was not better than the effect of the lower naproxen dose (1.0 g daily) combined with paracetamol. The main finding was that treatment with naproxen and paracetamol is more effective than treatment with higher naproxen doses alone.

Cerebral blood flow and indomethacin drug levels in subjects with and without central nervous side effects.

1. Central nervous system (CNS) side effects are observed during treatment with all nonsteroidal anti-inflammatory drugs (NSAIDs) but their effects are more common during treatment with indomethacin. 2. The aim of the study was to elucidate the mechanism of the CNS related side effects of indomethacin. Two groups were obtained, one with (n = 11), and one without (n = 7), CNS symptoms. Cerebral blood flow was measured in these groups with Doppler equipment, indomethacin levels with h.p.l.c. and CNS symptoms graded on a VAS scale. 3. Blood flow was reduced by 18-30% and was most marked 60 min after dose and did not differ between the two groups. The maximum CNS effect coincided with indomethacin peak levels 60-70 min after dose. These results could implicate that CNS symptoms may be related to indomethacin levels in sensitive patients.