Steady state pharmacokinetics and dose equivalents of oral clodronate in renal failure.

OBJECTIVE: Clodronate is used in the treatment of osteoporosis, and malignancy-associated bone disease. The steady state pharmacokinetics and the dose equivalents of oral clodronate were assessed in subjects with various degrees of renal failure. MATERIALS AND METHODS: 1,600 mg of clodronate was given orally mornings for 11 days to 14 healthy volunteers (creatinine clearance, CLCr, > 80 ml/min), and 18, 12 and 16 subjects with mild (50 - 80 ml/min), moderate (30 - 50 ml/min) and severe (< 30 ml/min) renal failure, respectively. Trough drug levels at 4, 7 and 11 days, and concentration-time curves for 72 h after the last dose were followed. RESULTS: In all study groups, the trough drug levels achieved the kinetic steady state within 11 days. The area under the 24-h concentration-time curve (AUC0-24) enlarged and the elimination half-life (t1/2elim) prolonged progressively when the renal function was impaired. The maximum drug level and the time to maximum were not changed significantly in the renal failure. In the steady state phase, the diurnal drug excretion (E0-24) was not changed by the kidney function, but the renal drug clearance (CLD) decreased in close correlation with CLCr. The normal-to-failed AUC0-24 ratios in mild, moderate, and severe renal failure were 0.53, 0.43 and 0.31, respectively, when the ideally-matched counterpart was assumed as the normal reference to each renal failure group. CONCLUSIONS: In mild, moderate and severe renal failure, 53%, 43% and 31% oral clodronate doses, respectively, resulted in drug AUCs similar to those in controls with normal (> 80 ml/min) CLCR.

The effect of CYP2C19 substrate on the metabolism of melatonin in the elderly: A randomized, double-blind, placebo-controlled study.

The metabolism of melatonin to 6-sulphatoxymelatonin (aMT6S) and N-acetylserotonin (NAS) is catalyzed by cytochrome-P450 (CYP) isozymes CYP1A2 and CYP2C19 respectively. We studied the in vivo effect of CYP2C19 substrate (citalopram, omepratzole, or lansopratzole) on the metabolism of endogenous and exogenous melatonin by measuring the excretion of urinary aMT6S, the main metabolite of melatonin, and a reliable estimate of plasma melatonin in 15 insomniac psychogeriatric inpatients. The effect of melatonin treatment on sleep parameters was also assessed. The patients with or without CYP2C19 substrate were treated for 21 days randomly in a double-blind manner with placebo or 2 mg exogenous melatonin orally. aMT6S excretions were measured radioimmunologically from night urine at baseline (day 0), on day 21, and one day after the treatment was discontinued (day 22). Sleep parameters were assessed using the Sleep Assessment Scale and the Sleep Quality Scale. In the control patients receiving only melatonin, aMT6S excretion increased 72-fold and returned to baseline on day 22. In the patients receiving melatonin + CYP2C19 substrate, aMT6S excretion increased 156-fold and was, on day 22, still 6.4-fold higher than at baseline (p = 0.04). The 22/0 day aMT6S excretion ratio was 10-fold higher in the patients treated with melatonin + CYP2C19 substrate when compared with that in the subjects treated with placebo + CYP2C19 substrate (p = 0.02). CYP2C19 substrate did not affect the metabolism of endogenous melatonin. The sleep parameters in the patients on melatonin treatment did not differ from those in the patients treated with placebo. In conclusion, it may be inferred that CYP2C19 substrate slows the metabolism of exogenous melatonin and increases its bioavailability, as shown by the augmented excretion of aMT6S, probably by inhibiting the conversion of melatonin to NAS via CYP2C19 isozyme. Melatonin therapy may not affect the sleep parameters in our psychogeriatric inpatients.

Effects of bisphosphonates on prostaglandin E2 and thromboxane B2 production in human whole blood and monocytes stimulated by lipopolysaccharide and A23187.

Bisphosphonates are antiatherosclerotic, suppress monocyte-macrophages, and modulate proinflammatory mediators. Prostaglandin (PG) E(2), thromboxane (TX) A(2), and cyclooxygenase-2 (COX-2) enzyme are involved in inflammation and atherosclerosis. We studied the effects of four bisphosphonates (etidronate, clodronate, tiludronate, and alendronate) on PGE(2) and TXB(2) production in human whole blood and monocytes. PGE(2) and TXB(2) were determined by direct radioimmunoassay and COX-2 expression by Western blot. In whole blood, the bisphosphonates did not modulate the increase in PGE(2) and TXB(2) concentrations induced by calcium ionophore A23187 or lipopolysaccharide (LPS). None of the bisphosphonates did change PGE(2) and TXB(2) concentration after spontaneous clotting. A23187- and spontaneous clotting-induced PGE(2) and TXB(2) productions were inhibited over 90% by acetylsalicylic acid (ASA), and LPS-induced PGE(2) and TXB(2) formations were inhibited over 90% by nimesulide. None of the bisphosphonates altered these inhibitions. In monocytes, etidronate and clodronate augmented A23187-stimulated PGE(2) production 2.5- to 3.2-fold (p < 0.05). LPS- or A2318-induced elevations in TXB(2) were not influenced by the bisphosphonates. The tested bisphosphonates neither induced COX-2 expression nor modulated LPS-induced COX-2 expression in monocytes. The results suggest that the antiatherosclerotic effects of bisphosphonates are not mediated via PGE(2), TXA(2), or COX-2, and the bisphosphonates do not interfere with the suppression of platelet COX-1 activity by ASA and COX-2 activity by nimesulide.

Hemodynamic effects of iloprost, a prostacyclin analog.

Iloprost is a chemically stable derivative of carbaprostacyclin. We studied its hemodynamic effects in 10 patients in an intensive care unit. Iloprost was infused intravenously for 3 days for the treatment of advanced obliterative arterial disease of the lower extremities. Clinically significant hemodynamic responses were obtained with an infusion rate of 0.5 ng/kg/min. All subjects tolerated the dose of 4 ng/kg/min, which increased heart rate an average of 11% and cardiac index an average of 26%. This infusion rate decreased mean arterial pressure by 15%, total peripheral resistance by 31%, and pulmonary vascular resistance by 34%. Mean pulmonary arterial pressure, pulmonary capillary wedge pressure, left and right ventricular stroke work indices, and rate pressure product did not change. At higher doses of up to 8 ng/kg/min, responses were augmented only slightly, but side effects such as headache, nausea, and abdominal colics became more prominent. The data show iloprost to be a potent vasodilator that reduces both pre- and afterload and presumably induces a compensatory increase in cardiac output and heart rate, but does not increase the work load or oxygen demand of the heart.

Inhibition of prostaglandin synthesis by indomethacin interacts with the antihypertensive effect of atenolol.

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-PGF1 alpha) 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-PGF1 alpha, 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 kallikrein-kinin systems.

Theophylline infusion modulates prostaglandin and leukotriene production in man.

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.

Effects of smoking cessation and nicotine substitution on systemic eicosanoid production in man.

This study investigated the effects of smoking cessation with and without nicotine substitution on the excretion of major urinary metabolites of thromboxane A2 and prostacyclin, 11-dehydrothromboxane B2 and 2,3-dinor-6-ketoprostaglandin F1alpha, respectively, as well as on the excretion of leukotriene E4 in man. Urine samples were obtained from 20 healthy non-smoking controls and from 60 healthy smoking volunteers before, and 3, 7 and 14 days after smoking cessation. Fifteen smokers quit smoking without nicotine substitution, 15 used nicotine chewing gum and 30 used nicotine patches as a substitution therapy. Urinary thiocyanate as well as cotinine and trans-3'-hydroxycotinine excretions were used as compliance and nicotine substitution indicators. 11-Dehydrothromboxane B2, 2,3-dinor-6-ketoprostaglandin F1alpha and leukotriene E4 excretion was about two, three and five times higher in smokers than in controls, respectively. Three days after smoking cessation without nicotine substitution, 11-dehydrothromboxane B2 and 2,3-dinor-6-ketoprostaglandin F1alpha levels were lowered to 75% (P<0.01) and 80% (P<0.05) of the initial values, and after 14 days to 50% (P<0.01) and 60% (P<0.05), respectively. In 3 days leukotriene E4 excretion was dropped to 70% of the initial value (P<0.05), but no further decrease was observed during the study. In individuals using nicotine chewing gum or nicotine patches no significant changes were observed in the analytes during the 2-week follow-up. The increased systemic eicosanoid synthesis observed in smokers may be involved in the harmful cardiovascular effects of smoking. The fact that eicosanoid production remains at pre-cessation level in volunteers who quit smoking but use nicotine substitution may be involved in the risk of cardiovascular complications reported during nicotine replacement therapy.

Control of mesenteric arterial tone in vitro in humans and rats.

The majority of the findings concerning arterial physiology and pathophysiology originate from studies with experimental animals, while only limited information exists about the functional characteristics of human arteries. Therefore, the aim of the present work was to compare the control of vascular tone in vitro in mesenteric arterial rings of corresponding size (outer diameter 0.75-1 mm) from humans and Wistar-Kyoto rats. The relaxations to acetylcholine (ACh) were clearly less marked in the mesenteric arteries of humans when compared with rats. However, when calcium ionophore A23187 was used as the vasodilator, the endothelium-mediated relaxations did not significantly differ between these species. The NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) attenuated the relaxations to ACh and A23187 in both groups. The endothelium-independent relaxations to the beta-adrenoceptor agonist isoprenaline and the nitric oxide (NO)-donor nitroprusside were somewhat lower in human arteries, while vasodilation induced by the K+ channel opener cromakalim was similar between humans and rats. Arterial contractile sensitivity to noradrenaline and serotonin was slightly lower in human vessels, whereas contractile sensitivity to KCl was similar between these species. The contractions induced by cumulative addition of Ca2+ with noradrenaline as the agonist were effectively inhibited in both groups by the calcium channel blocker nifedipine, the effect of which was clearly more pronounced in human arteries. In conclusion, the control of vascular tone of isolated arteries of corresponding size from humans and rats appeared to be rather similar. The most marked differences between these species were the impaired endothelium-mediated dilation to ACh and the more pronounced effect of nifedipine on the Ca2(+)-induced contractions in human arteries.

Skeletal deposition of clodronate is related to parathyroid function and bone turnover in dialysis patients.

AIMS: Bisphosphonates inhibit osteoclastic bone resorption, and in the future, they may also have a role in the therapy of renal osteodystrophy. Our aim was to study whether the severity of hyperparathyroidism has an effect on the clearance of clodronate via routes other than dialysis or kidneys (nonrenal, non-dialysis clearance, CL(NRD)), which most likely represents the deposition of the drug in the skeleton. METHODS: We studied 31 dialysis patients (9 female/22 male, aged 28 - 79, median 58 years), 18 on hemodialyis (HD) and 13 on peritoneal dialysis (PD). HD patients were studied on a non-dialysis day. An intravenous infusion of 300 mg clodronate was given during 60 min at 8:00 a.m. Blood, urine and PD fluid samples were collected for 1 + 24 h, and pharmacokinetic parameters were calculated. RESULTS: In PD patients, 7% of the infused drug was excreted into PD fluid within 24 h, and in those HD or PD patients with residual diuresis 11% was excreted via the kidneys. The highest CL(NRD) was seen in patients with the most severe hyperparathyroidism. There was a positive correlation between CL(NRD) and plasma intact PTH (r = 0.79, p < 0.001). CL(NRD) was also related to the serum levels of bone markers PINP (procollagen type I N-terminal propeptide, r = 0.81, p < 0.001), osteocalcin (r = 0.65, p < 0.001) and ICTP (type I collagen cross-linked telopeptide, r = 0.68, p < 0.001). However, even in the patients with normal PTH, more than one-third of the infused drug was taken up by bone. CONCLUSION: In dialysis patients, the skeletal deposition of clodronate is related to bone turnover being highest in severe hyperparathyroidism. However, even in the case of low turnover, the uptake of the drug in bone takes place in amounts that might be clinically significant.

Clinical pharmacology of eicosanoids, nicotine induced changes in man.

Smoking is an important risk factor for respiratory and cardiovascular diseases. The role of numerous chemical, partly uncharacterised compounds existing in tobacco smoke is not known. (-)-Nicotine, its stereoisomer (+)-nicotine and main metabolite cotinine are biologically active compounds influencing e.g. catecholamine and eicosanoid systems. The precise mechanisms are not well known. The purpose of the present study consisting of a PhD thesis (11) and five original papers was to investigate the in vitro effects of nicotine isomers and cotinine on eicosanoid production in polymorphonuclear leukocytes, platelets and whole blood in vitro, and to clarify the effects of smoking without and with nicotine substitution on eicosanoid production in vivo and ex vivo. It was found that all the tested compounds modulated blood cell eicosanoid synthesis. Nicotine isomers and cotinine increased PGE2 but decreased TXB2, LTB4 and LTE4 synthesis in vitro. Eicosanoid synthesis in vivo and ex vivo was higher in smokers (n = 60) than in non-smoking controls (n = 20). This may contribute to the harmful cardiovascular effects of smoking. Cessation of smoking without, but not with, nicotine substitution reduced eicosanoid synthesis measured ex vivo as whole blood production or in vivo as urinary excretion of eicosanoid metabolites after 3, 7 and 14 days. Thus long-term nicotine substitution diminishes the beneficial effects of smoking cessation.

Effects of short-term lamotrigine treatment on pharmacokinetics of carbamazepine.

AIM AND METHOD: The effects of short-term treatment with lamotrigine (LTG) (100 mg twice daily for one week) on single dose pharmacokinetics of carbamazepine (CBZ, 200 mg) were investigated in a randomized, double-blinded, placebo-controlled cross-over study with 10 healthy volunteers. RESULTS: Pharmacokinetic parameters for CBZ or for CBZ-10,11-epoxide, the main metabolite of CBZ, were not significantly affected by LTG pretreatment. The mean (+/- SEM) elimination half-life of CBZ was 33.0+/-1.8 h after pretreatment with placebo and 30.1+/-2.0 h after a one-week-pretreatment with LTG (NS). The area under the serum concentration curve to infinity (AUC) of CBZ was 638+/-45 micromol/l after placebo and 624+/-53 micromol/l after LTG (NS). Changes in the peak serum concentration, from 9.0+/-0.3 micromol/l to 9.2+/-0.4 micromol/l (LTG), and in the time to peak serum concentration, from 9.3+/-1.1 h to 9.1+/-1.2 h (LTG), were also not significant. CONCLUSION: These data support the earlier findings that LTG does not significantly affect the rate or extent of absorption, or elimination of CBZ.

Influence of captopril, propranolol, and verapamil on arterial pulse wave velocity and other cardiovascular parameters in healthy volunteers.

OBJECTIVE: The effects of antihypertensive agents on cardiovascular parameters, especially on arterial pulse wave velocity, remain largely unknown in normotensive subjects. Therefore, the present investigation was designed to evaluate acute effects of ACE inhibitor captopril,beta-adrenoceptor blocker propranolol and calcium entry blocker verapamil on cardiovascular and ventilatory function in healthy volunteers. MATERIAL: The influence of single doses of captopril (25 mg), propranolol (40 mg), and verapamil (80 mg) on cardiovascular function and exercise capacity were compared in healthy volunteers in a randomized, double-blind, placebo-controlled fashion. METHODS: Cardiac output and beat-by-beat blood pressure were estimated non-invasively before and after the drug administrations by whole-body impedance cardiography and Finapres finger blood pressure monitoring, respectively. Arterial pulse wave velocity was obtained from the time delay between flow pulses measured from the root of the aorta and the popliteal artery, and systemic vascular resistance was calculated from cardiac output and mean arterial pressure. In addition, a progressive maximal exercise test was performed after the treatments. RESULTS: Propranolol reduced heart rate, cardiac output and arterial pulse wave velocity, and increased systemic vascular resistance clearly more effectively than placebo. In addition, captopril effectively decreased arterial resistance and pulse wave velocity. However, the influence of verapamil on cardiovascular parameters did not significantly differ from those observed in placebo-treated subjects. Exercise peak heart rate, peak blood pressure, and minute ventilation were reduced in subjects treated with propranolol, but not in those treated with captopril and verapamil, when compared to placebo. CONCLUSIONS: Acute administration of captopril and propranolol but not verapamil clearly modulated cardiovascular parameters in rest, suggesting differential effects of these compounds on cardiovascular function in healthy volunteers. These drugs seem to have disparate effects on arterial pulse wave propagation as an indicator of arterial compliance after short-term administration in healthy subjects. Captopril and verapamil had no effect on cardiovascular and ventilatory function during maximal exercise, while propranolol markedly altered also these variables in the present study.

Comparison of pharmacokinetics of clodronate after single and repeated doses.

OBJECTIVE: Pharmacokinetics of orally given clodronate disodium, a drug for the treatment of hypercalcemia and bone resorption, were studied after a single dose of 400, 800 and 1600 mg given randomly to 11 healthy volunteers in a crossover manner, in 7-14 hospitalized cancer patients given 400, 800 and 1600 mg twice daily, each dosage for one week, and during the customary therapy in 15 additional cancer patients treated in hospital with 400 mg thrice daily for > or = 2 weeks. METHODS: Clodronate concentrations in serum and urine were measured by capillary gaschromatography with mass-selective detection. Pharmacokinetic parameters were calculated with a three-compartmental model. RESULTS: After a single oral dose to healthy volunteers the absolute clodronate concentrations increased almost dose-dependently. The mean cumulative excretion in urine was 1.72-2.77% of the dose, an interindividual range being from 0.92% to 5.52%. With 800 and 1600 mg twice daily for one week to cancer patients the serum drug concentrations increased almost progressively with increasing the dose. In cancer patients serum drug concentrations were clearly higher and renal drug clearances (mean 25-62 ml/min) lower than in healthy volunteers (mean 123-149 ml/min). The mean urinary excretions were 2.24-3.14% of the dose and interindividual ranges from 0.18% to 19.0%. During the routine cancer therapy with 400 mg thrice daily, the clodronate excretions in urine on two successive days were on an average 3.26% (range 0.0-10.5%). CONCLUSIONS: Absolute concentrations in serum and excretions in urine of orally given clodronate increase dose-dependently, but during the maintenance therapy in hospitalized cancer patients the renal drug clearances seem to be lower than in healthy volunteers. This and the large interindividual variation in kinetics propose therapeutic monitoring of clodronate for optimizing the oral dose of the drug.

Analysis of (dichloromethylene) bisphosphonate in urine by capillary gas chromatography-mass spectrometry.

An anion exchange extraction method of bisphosphonates from urine is described. More than 90% of the (dichloromethylene) bisphosphonate (Cl2MBP, clodronate) was recovered from urine. The extracted bisphosphonates were trimethylsilylated and analysed with capillary gas chromatography-mass spectrometry (GC/MS). The mass spectrometric techniques used were electron ionization (EI), ammonia chemical ionization (CI), ammonia CI tandem mass spectrometry and methane negative chemical ionization (NCI). The limit of detection of Cl2MBP was 25 pg/injection in the NCI/selective ion recording (SIR)-mode. At 100 ng ml-1 of Cl2MBP the precision of the whole assay method was 17.9% (N = 6). The NCI/SIR technique offers a sensitive and highly selective method for the quantitation of Cl2MBP in urine.

Pharmacokinetics of clodronate in peritoneal dialysis patients.

OBJECTIVE: To study the pharmacokinetics of clodronate in patients on continuous ambulatory peritoneal dialysis (CAPD). DESIGN: A single intravenous dose pharmacokinetic study. SETTING: University hospital. PATIENTS: Ten CAPD patients (3 female, 7 male, age 39-79 year, median 55). METHODS: Clodronate disodium in serum, urine, and dialysate was collected for 24 hours and analyzed by capillary gas chromatography with mass-selective detection. RESULTS: Only 7% of the infused dose of clodronate was eliminated through peritoneal dialysis during 24 hours. Clearance via CAPD (CL[CAPD]) was 2.4 +/- 0.6 mL/min, which was less than 10% of the total serum clearance (CL(tot), 26.0 +/- 19.3 mL/min). Even the kidneys were a more important route of elimination than CAPD in those patients with residual diuresis of more than 500 mL/24 hr. However, in all patients most of the clodronate serum clearance (77% +/- 13%) took place via routes other than peritoneal dialysis or kidneys, that is, via nonrenal-non-CAPD clearance (CL[NRD]). CL(NRD) most likely represents the part of the drug deposited in the skeleton. There was a positive correlation between CL(NRD) and the plasma intact parathyroid hormone concentration. CONCLUSIONS: CAPD removed clodronate poorly from the circulation. Most clearance took place via routes other than CAPD or kidneys. This CL(NRD) most likely represents the skeletal deposition of the drug, and this is related to the severity of hyperparathyroidism. When treating CAPD patients with hyperparathyroid bone disease, the administration of clodronate should be adjusted as in those subjects with severe renal failure.

Acetylator phenotyping with sulphadimidine in patients receiving isoniazid.

The possible competition of isoniazid for the acetylation of sulphadimidine was studied by comparing the degree of acetylation of urine sulphadimidine (1 g orally) in isoniazid-treated and in isoniazid-untreated patients. The former group (isoniazid 300 mg once daily) consisted of 5 slow and 5 rapid acetylators and the latter group of 5 and 6 respective acetylator phenotypes. In all of the 4-8, 8-12 and 12-24 h urine fractions, the acetylation percentage of sulphadimidine and its distribution pattern were practically unaffected by the isoniazid. This suggests that isoniazid therapy does not interfere significantly with the routine acetylator phenotyping by means of sulphadimidine.

Serum levels and urinary excretion of mequitazine after a single oral dose.

Pharmacokinetics of mequitazine, a recently introduced peripheral H1-histamine receptor antagonist of phenothiazine type, was followed up to 72 h after the single oral dose of 5 mg of the drug to eight fasted healthy volunteers. Each subject was treated thrice with a dosing interval of 15 days or more. Thus all the results were triplicated. Serum mequitazine was measured by mass fragmentography using a gas-liquid chromatograph/mass spectrometer set in the electron impact mode. Urine phenothiazines were determined fluorometrically before and after cleaving phenothiazines from their glucuronide conjugates. Peak concentration of mequitazine in serum was 3.19 +/- 1.70 (s.d.) ng.ml-1, time to peak concentration 5.67 +/- 1.68 h, elimination half-life 45 +/- 26 h, and elimination rate constant 0.018 +/- 0.007 h-1. Only 10.9 +/- 3.3% of the dose appeared in urine in unconjugated plus the glucuronidated form during the first 72 h. About 46% of the urinary phenothiazines were glucuronide conjugates. The results suggested that after the oral administration only low mequitazine concentrations appeared in serum, most of the drug seemed to be deactivated by the extrarenal route, and the kinetic properties of the drug resembled those of several phenothiazines used for psychiatric therapy.

Comparison of the acute physical and mental effects of ephedrine, fenfluramine, phentermine and prolintane.

Physical and mental effects of a single oral dose of ephedrine (ephedrine HCl 30 or 40 mg), fenfluramine (fenfluramine HCl 15 or 20 mg), phentermine (7.5 or 11.25 mg) and prolintane (prolintane HCl 10 or 20 mg) were compared in a double-blind placebo-controlled study. Each group consisted of 16-43 healthy volunteer medical students. The subjects fasted for at least 3 hr before drug administration and further until the end of the experiment. All the parameters were measured just prior to giving the drug, and 1.5 hr and 2.5 hr afterwards. Ephedrine significantly increased systolic blood pressure (p less than 0.05) and heart rate (p less than 0.01), whereas the other sympathomimetics affected these parameters only slightly or negligibly. None of the drugs markedly changed the tapping rate of the dominant hand. Mental activity was evaluated with a self-rating check list consisting of various mental modalities. None of the sympathomimetics significantly modified the mental activity. Memory, learning and concentration ability were evaluated with sign recording and digit span tests. In the digit span test no changes were obtained. In the sign recording test (for 3 min), phentermine increased significantly the recording score at both 1.5 hr (p less than 0.05) and 2.5 hr (p less than 0.005), and prolintane at 2.5 hr (p less than 0.05) after drug administration. The results suggest that in the doses given, which are commonly used in medical practice, ephedrine has the most pronounced cardiovascular effects, while phentermine and prolintane seem to be most active in the performance of some mental tasks.

Decrease in serum LDL cholesterol with microcrystalline chitosan.

Peroral microcrystalline chitosan (MCCh; 3 capsules, each 400 mg b.i.d.) or placebo was given for 8 weeks in a double-blind manner to 51 healthy obese women just before routine hospital and home meals. Weight records, serum lipids (total, LDL and HDL cholesterol, triglycerides) and safety laboratory parameters were monitored before the trial and at 4, 6 and 8 weeks of treatment. In a subgroup of subjects with a body mass index > or = 30 who had not changed their eating habits, serum LDL cholesterol decreased 0.57 +/- 0.72 mmol/l (n = ll) at 4 weeks in the MCCh group and 0.10 +/- 0.60 mmol/l (n = 14) in the placebo group (p < 0.05). At 8 weeks, LDL cholesterol reduction was 0.48 +/- 0.91 mmol/l in the MCCh group and 0.26 +/- 0.57 mmol/l in the placebo group (p > 0.1). In all subjects, the reduction in LDL cholesterol at 4 weeks was 0.48 +/- 0.72 mmol/l (n = 24) in MCCh subjects and 0.18 +/- 0.58 mmol/l (n = 27) in placebo subjects (p = 0.057), and 0.52 +/- 0.69 mmol/l and 0.31 +/- 0.63 mmol/l, respectively, at 8 weeks (p > 0.1). MCCh did not significantly alter serum total and HDL cholesterol (p > 0.1), but slightly increased serum triglycerides compared to placebo (p = 0.015-0.06). No reductions in weight were observed in any treatment group. Chitosan was well tolerated and no serious adverse events or changes in safety laboratory parameters were noted including serum fat-soluble vitamins A and E, and serum Fe++ and transferrin.

Neurobehavioral toxicity with low doses of sarin and soman.

The acute effects of single subtoxic doses (1/48-1/9 of LD50) of two potent organophosphates (OPs), sarin (12.5 and 50 micrograms/kg i.p.) and soman (4 and 20 micrograms/kg i.p.), were studied on behavior, motor performance and nociception in male Wistar rats. On the elevated plus-maze with two open + two closed arms, higher doses of soman and sarin decreased the proportion of entries made onto open arms (p less than 0.05), while the total number of entries onto open + closed arms was unchanged. On the narrow elevated horizontal bridge, the latencies to reach the safe platform were prolonged with the higher dose of sarin (p less than 0.05) but not with that of soman. On the broad and rod bridges, the latencies of OP-treated rats did not differ significantly from those of controls. OPs did not significantly impair either learning frequency in one-trial passive avoidance test, rotarod performance or nociception in hot plate test. The results suggest that in acutely nontoxic doses sarin and soman affect the behavior of rats, and that the action profiles of the OPs differ from each other. Both soman and sarin change the behavior of rats in the plus-maze test but only sarin seems likely to impair motor coordination/balance.