Fast camera studies at an electron cyclotron resonance table plasma generator.

A simple table-size ECR plasma generator operates in the ATOMKI without axial magnetic trap and without any particle extraction tool. Radial plasma confinement is ensured by a NdFeB hexapole. The table-top ECR is a simplified version of the 14 GHz ATOMKI-ECRIS. Plasma diagnostics experiments are planned to be performed at this device before installing the measurement setting at the "big" ECRIS. Recently, the plasma generator has been operated in pulsed RF mode in order to investigate the time evolution of the ECR plasma in two different ways. (1) The visible light radiation emitted by the plasma was investigated by the frames of a fast camera images with 1 ms temporal resolution. Since the visible light photographs are in strong correlation with the two-dimensional spatial distribution of the cold electron components of the plasma it can be important to understand better the transient processes just after the breakdown and just after the glow. (2) The time-resolved ion current on a specially shaped electrode was measured simultaneously in order to compare it with the visible light photographs. The response of the plasma was detected by changing some external setting parameters (gas pressure and microwave power) and was described in this paper.

Terminal nerve gonadotrophin-releasing hormone (GnRH) neurones express multiple GnRH receptors in a teleost, the dwarf gourami (Colisa lalia).

Gonadotophin-releasing hormone (GnRH) peptide released from the terminal nerve (TN)-GnRH neurones of the dwarf gourami primarily modifies the electrical properties of various neurones, including the TN-GnRH neurones themselves. However, our knowledge on the expression of GnRH receptors (GnRHRs) in the TN-GnRH neurones is still limited. Here, we used the single-cell reverse transcriptase-polymerase chain reaction after whole-cell patch-clamp recording to study the distribution of various GnRHR types expressed in the individual TN-GnRH neurones. We found that TN-GnRH neurones express two of the three types of GnRHRs cloned in the dwarf gourami: GnRHR1-2 and -R2, but not -R1-1. Furthermore, in agreement with our previous findings, all TN-GnRH neurones contained mRNAs of salmon GnRH but not chicken GnRH-II.

Positive inotropic effect of the inhibition of cyclic GMP-stimulated 3',5'-cyclic nucleotide phosphodiesterase (PDE2) on guinea pig left atria in eu- and hyperthyroidism.

The significance of PDE2 on the atrial inotropy was studied in eu- and hyperthyroidism. The contractile force was measured and negative inotropic capacity of N6-cyclopentyladenosine (CPA) was determined on left atria isolated from 8-day thyroxine- or solvent-treated guinea pigs, in the presence or absence of EHNA (adenosine deaminase and PDE2 inhibitor) or NBTI (nucleoside transporter inhibitor). EHNA was administered to inhibit PDE2, while NBTI was used to model the accumulation of endogenous adenosine. The reduction of the contractile force caused by EHNA was smaller in the thyroxine-treated atria than in the solvent-treated samples. Contrary, NBTI induced a decrease in the contractile force without significant difference between the two groups. In addition, EHNA enhanced the efficiency of CPA in thyroxine-treated atria and did not affect it in solvent-treated samples, while the response to CPA was decreased by NBTI in all atria, especially in hyperthyroidism. On the basis of greater retention of the contractile force and sustained/enhanced responsiveness to CPA in the presence of EHNA we conclude that PDE2's inhibition has a significant positive inotropic effect in guinea pig atria and this effect is proven to be augmented in hyperthyroidism.

Effects of toxins Pi2 and Pi3 on human T lymphocyte Kv1.3 channels: the role of Glu7 and Lys24.

Pandinus imperator scorpion toxins Pi2 and Pi3 differ only by a single amino acid residue (neutral Pro7 in Pi2 vs. acidic Glu7 in Pi3). The binding kinetics of these toxins to human Kv1.3 showed that the decreased ON rate (k(ON) = 2.18 x 10(8) m(-1)sec(-1) for Pi2 and 1.28 x 10(7) m(-1)sec(-1) for Pi3) was almost entirely responsible for the increased dissociation constant (K(d)) of Pi3 (K(d) = 795 pm) as compared to Pi2 (K(d) = 44 pm). The ionic strength dependence of the association rates was exactly the same for the two toxins indicating that through-space electrostatic interactions can not account for the different ON rates. Results were further analyzed on the basis of the three-dimensional structural models of the toxins. A 3D structure of Pi3 was generated from the NMR spectroscopy coordinates of Pi2 by computer modeling. The Pi3 model resulted in a salt bridge between Glu7 and Lys24 in Pi3. Based on this finding our interpretation of the reduced ON rate of Pi3 is that the intramolecular salt bridge reduces the local positive electrostatic potential around Lys24 resulting in decreased short-range electrostatic interactions during the binding step. To support our finding, we constructed a 3D model of the Ser-10-Asp Charybdotoxin mutant displaying distinctly reduced affinity for Shaker channels. The mutant Charybdotoxin structure also displayed a salt bridge between residues Asp10 and Lys27 equivalent to the one between Glu7 and Lys24 in Pi3.

Blockage of human T lymphocyte Kv1.3 channels by Pi1, a novel class of scorpion toxin.

Using the patch-clamp technique we determined that Pandinus imperator toxin Pi1, a recently described peptide toxin having four disulfide bridges instead of the usual three in scorpion toxins, blocked Kv1.3 channels of human T lymphocytes from the extracellular side with a 1:1 stoichiometry. Kv1.3 block was instantaneous and removable with toxin-free extracellular solution. The toxin did not influence activation or inactivation of the channels. We found that Pi1 blocked Kv1.3 with less affinity (K(d) = 11.4 nM) than the structurally related three disulfide bridge containing toxins Pi2 (50 pM) and Pi3 (0.5 nM). The fourth disulfide bridge in Pi1 had no influence on the channel binding ability of the toxin; the less effective block was due to differences in amino acid side chain properties at positions 11 and 35.

Avoidable mortality. Is it an indicator of quality of medical care in eastern European countries?

Age-standardized time trends (1979-1988) for avoidable mortality in two Eastern European countries (Hungary and Czechoslovakia) and selected developed countries (England and Wales, France, Italy, Japan, Portugal and USA) have been analysed. Mortality from both all avoidable causes and all other causes declined in the selected developed countries during the period of observation, the decline in rates for avoidable causes was faster than that for all other causes. In Hungary and Czechoslovakia the death rates from both groups of causes increased in the first part of the period studied and a decline in mortality from both types of causes could be observed from 1985. As a consequence, the difference in avoidable mortality between the Eastern European countries and the developed countries increased by the end of the observation. Studies on mortality from individual amenable causes showed that the death rates are usually much higher in Hungary and Czechoslovakia than in the developed countries and the differences did not diminish during the period of study. In Hungary and Czechoslovakia the bad pattern of mortality from conditions amenable to medical interventions is believed to reflect, at least in part, the crisis in the health services which these countries have experienced for the past decades.

Penbutolol: pharmacokinetics, effect on exercise tachycardia, and in vitro inhibition of radioligand binding.

The pharmacokinetics of penbutolol 40 mg, its reduction in exercise-induced tachycardia, and the in vitro inhibition of radioligand binding to beta-adrenoceptors by plasma have been investigated in 7 healthy volunteers. The peak penbutolol concentration of 285 ng/ml was observed 1.2 h after administration, and the maximum of 4'-OH-penbutolol of 4.76 ng/ml was found after 1.64 h. Penbutolol was detected for up to 48 h, and 4'-OH-penbutolol dropped below the limit of detection after about 10 h. The terminal plasma concentration of penbutolol declined with an average half-life of 19 h. The maximum reduction in exercise-induced tachycardia was 33 beats/min 2.6 h after taking penbutolol. There was still a significant reduction of about 7 beats/min after 48 h. This effect could be adequately explained by the concentration-time course of penbutolol in combination with Clark's model of the concentration-effect relationship. Antagonist activity in plasma caused 91% inhibition of radioligand binding in vitro to beta 2-adrenoceptors on rat reticulocyte membranes 1.6 h after intake of penbutolol. By 48 h after intake, radioligand binding was still significantly inhibited (23%). The in vitro inhibition of radioligand binding by plasma showed a linear correlation with the reduction in exercise-induced tachycardia for all phases of the workload. The time course of the reduction in heart rate was completely explained by the in vitro inhibition of radioligand binding. However, it was not possible to explain the in vitro inhibition of radioligand binding by the concentration-time course of penbutolol using a simple competition model, although both variables were based on the same sampling site. When the in vitro inhibition of radioligand binding was plotted against the penbutolol concentration at the same sampling times (with both variables transformed to multiples of the apparent inhibition constant) the discrepancy became even more apparent as time-related counterclockwise hysteresis. None of the known metabolites of penbutolol can explain the discrepancy between the penbutolol concentration and the inhibition of radioligand binding in vitro. It appears that an other active metabolite is formed, which contributes to the effect in vitro and in vivo and so can explain the observed discrepancy.

Direct assay of conjugates of penbutolol and its metabolites in urine.

The metabolites of 1-tert.-butylamino-3-(2-cyclopentylphenoxy)propan-2-ol (penbutolol, Betapressin), penbutolol 2-glucuronide, 4'-OH-penbutolol 2-glucuronide, 4'-OH-penbutolol 4-sulfate and 1"-dehydropenbutolol 2-glucuronide were determined in urine by high-performance liquid chromatography (HPLC). The compounds were determined after direct injection, that is to say without prior cleavage of the conjugates to the corresponding aglycones. In the case of the glucuronides, the urine was injected into the HPLC system without further sample preparation. The sulfate was determined after ion-pair extraction. Fluorimetric detection was employed. Depending on the compound, the detection limits lay between 0.07 and 0.3 micrograms/ml. This method was used to determine the cumulative urinary excretion of a subject.

Isolation, identification and in vitro synthesis of conjugates of penbutolol and its metabolites.

The metabolites of 1-tert.-butylamino-3-(2-cyclopentylphenoxy)propan-2-ol (penbutolol Betapressin) penbutolol 2-glucuronide, 4'-OH-penbutolol 2-glucuronide, 4'-OH-penbutolol 4'-sulfate and 1''-dehydropenbutolol 2-glucuronide were isolated from the urine of patients, purified by high-performance liquid chromatography and characterised by 1H-NMR and mass spectroscopy. Penbutolol 2-glucuronide and 4'-OH-penbutolol 4'-glucuronide were synthesised in vitro from penbutolol and 4'-OH-penbutolol, respectively, using glucuronyltransferase.

Single and multiple dose pharmacokinetics of intravenous cefpirome (HR 810), a novel cephalosporin derivative.

After intravenous injection of single doses of 1.0 g of cefpirome (HR 810) and multiple doses of 1.0 g b.i.d. for five days to the same ten healthy male volunteers in an open design, concentrations of unchanged drug were estimated at various times in serum and urine, over 24 h and 48 h, respectively. Cefpirome concentrations were determined using both high pressure liquid chromatography (HPLC) and a microbiological assay. The measurements obtained were compared by linear distribution independent regression, and were found to be equivalent, indicating no major antimicrobially active metabolites of cefpirome. Biological half-life (t1/2,beta) was determined by fitting a two-compartment open model to the data: t1/2,beta was 2 h (HPLC, median values). During the multiple dose phase of cefpirome (1.0 g b.i.d.) no accumulation of the serum levels could be detected with this dosage regimen. Urinary concentrations of unchanged cefpirome remained clearly above the minimal inhibitory concentration for Escherichia coli (0.03 mg/l) for about 36 h (microbiological assay). The general tolerance was good.

Dose linearity testing of intravenous cefpirome (HR 810), a novel cephalosporin derivate.

After intravenous injection of single doses of 0.25, 0.5, 1.0, 1.5 and 2.0 g of cefpirome (HR 810) to 46 healthy male volunteers in an open manner, concentrations of unchanged drug were estimated at various times in serum and urine, over 24 h and 48 h, respectively. Cefpirome concentrations were determined using both high pressure liquid chromatography (HPLC) and a microbiological assay. The measurements obtained were compared by linear distribution independent regression, and were found to be equivalent. A linear relationship between dose and AUC00 (r = 0.96) for both HPLC and microbiological assay was demonstrated for the doses tested (0.25 g to 2.0 g). The biological half-life (t1/2,beta) was determined by fitting a two-compartment open model to the data: t1/2,beta was about 2 h (HPLC, median values) and was not relevantly dose dependent. A general twice daily dosing will be recommended for the treatment of infections. Clinically relevant high concentrations of unchanged cefpirome were detected in urine already after the lowest dose (0.25 g) for about 12 h, and after the highest dose (2.0 g) for at least 24 h. General tolerance was good, only slight temporary taste disturbances immediately after injection were claimed by one volunteer after both 0.5 g and 1.0 g doses and by four volunteers receiving 2.0 g of cefpirome; however, no counter-measures were needed.

Pharmacokinetics of ramipril in the elderly.

Ramipril (HOE 498) is a pro-drug of which the main metabolite (HOE 498 diacid or ramiprilat) is a potent angiotensin converting enzyme inhibitor. Thirteen healthy white volunteers (5 females and 8 males, ages 65 to 76 years) participated in a study to investigate the pharmacokinetics of HOE 498 in the elderly. After administration of 10 mg of HOE 498, sequential urine and serum specimens were obtained for assay of HOE 498 and metabolites (HOE 498-glucuronide, diacid, diacid-glucuronide, diketopiperazine and diketopiperazine acid). Side effects, clinical chemistry and hematology were monitored. HOE 498 reached peak concentrations of 62.4 +/- 23.3 ng/ml in serum after 0.7 +/- 0.3 hours. Serum levels decreased with an apparent half-life of 0.9 +/- 0.4 hours. The diacid was rapidly formed in serum, reaching peak concentrations of 40.6 +/- 14.0 ng/ml after 2.0 +/- 0.6 hours and declining with a half-life of 2.2 +/- 0.5 hours. A prolonged terminal phase of serum concentration versus time curve was observed at concentrations less than 1 ng/ml. The mean recovery of HOE 498 and metabolites in urine, up to 26 hours after administration, was 35 +/- 14% of the dose. The apparent half-lives, calculated from urine parameters, for HOE 498 and the diacid were 2.6 +/- 0.9 and 4.0 +/- 1.1 hours, respectively. The mean peak concentration and half-life of HOE 498 in serum are slightly higher in the elderly than in younger volunteers. Complete urinary collection was not possible, but urinary recovery did not seem different from younger volunteers.

Influence of renal function on the pharmacokinetics of ramipril (HOE 498).

The pharmacokinetics of ramipril (HOE 498) were studied after oral administration of a single 10 mg dose to 24 hypertensive patients with different degrees of renal function. The creatinine clearance ranged between 4.1 and 126 ml/min/1.73 m2 and was below 35 ml/min/1.73 m2 in 16 patients. Angiotensin converting enzyme activity and the concentrations of ramipril and its active diacid metabolite ramiprilat were measured in plasma up to 10 days after drug intake. Urine levels of ramipril, ramiprilat, their glucuronides and 2 major metabolites (a diketopiperazine and a diketopiperazine acid) were measured up to 4 days after medication. The plasma concentration-time curve of ramiprilat was polyphasic with an initial steep decline after the peak level and a subsequent very long terminal phase at low concentrations. Impaired renal function resulted in higher peak levels of ramiprilat, longer times to peak and a markedly slower decline of plasma ramiprilat levels. Hence, the duration of angiotensin converting enzyme inhibition was considerably prolonged in renal failure and depended on the severity of renal impairment. The urinary excretion of ramipril and its metabolites decreased with decreasing renal function and was linearly related to the creatinine clearance, suggesting an alternative pathway of elimination. The pattern of excretion rates of ramipril and its various metabolites was not affected by renal failure. In contrast to the marked changes in the renal elimination, no relevant differences were observed in the absorption of ramipril from the gastrointestinal tract. Systolic and diastolic blood pressure decreased in all groups. The single 10 mg dose of ramipril was well tolerated.

Interference by the new antibiotic cefpirome and other cephalosporins in clinical laboratory tests, with special regard to the "Jaffé" reaction.

The new cephalosporin, cefpirome, was investigated for its possible interference in clinical laboratory tests, especially the determination of creatinine. Tests for bilirubin, cholesterol, protein, urea, and uric acid were also studied. A selection of commercially available compounds such as cefoperazone, cefazolin, cefamandole, cefoxitin, latamoxef, ceftriaxon, cefotiam, cephaloridine, cephalotin, cefotaxime, cefazedone and cefuroxime, and cefodizime (a compound under development) were also included in these investigations. Interference was found only with the "Jaffé method" for the determination of creatinine. Pronounced interactions with alkaline picrate were observed with cefpirome, cefoxitin, cephalotin and cephaloridine, whereas the other compounds showed only weak reaction or no reaction at all. The cephalosporins did not interfere in any of the other tests mentioned above. Care must therefore be taken in the determination of creatinine in samples from patients under treatment with these drugs. The assay methods of choice at present are enzymatic or specific HPLC assays.

Dose linearity and other pharmacokinetics of cefodizime after single-dose intravenous administration.

Pharmacokinetics of cefodizime, a broad-spectrum cephalosporin antibiotic, were determined after intravenous (IV) administration of single doses of 1.0, 1.5, and 2.0 gm to 12 healthy male volunteers in an open study. In a separate pilot study, data were obtained after IV administration of 0.5 gm of cefodizime to six healthy male volunteers. Determinations of cefodizime in serum and urine using a microbiological assay agreed with determinations using high-pressure liquid chromatography (HPLC), which specifically measures the unchanged drug. Active metabolites of cefodizime were not detected. After IV administration of 1.0, 1.5, and 2.0 gm of cefodizime, initial mean serum concentrations were 215, 322, and 394 mg/L, respectively (HPLC determinations). A linear response to dosage was shown (coefficient of correlation r = .89), as was the case for area under the serum concentration-time curve to infinity, AUC infinity (r = .82), and 48-hour urinary recovery of cefodizime (r = .94). In all cases, the corresponding values obtained after the 0.5-gm dose showed that the linearity extended to this dose. The kinetics of single-dose administration of cefodizime corresponded to a two-compartment open model with an apparent steady-state volume of distribution of about 40 L. Volume of distribution, terminal elimination half-life, serum and renal clearance, and percent urinary recovery were not dose dependent. Cefodizime combined a long terminal elimination half-life (mean, 2.5 hours) with a high urinary recovery (80%). After IV administration of cefodizime, urinary concentrations of the unchanged drug remained above 5 micrograms/ml for at least 24 hours after drug administration and were dose dependent. Mean values for the 1.0-gm and 2.0-gm doses were, respectively, approximately 12 mg/L and 30 mg/L, several times the minimal inhibitory concentrations (MIC90) for most clinically relevant bacteria. These results suggest that once- or twice-daily IV dosing with cefodizime (depending on the dose regimen) would be suitable for clinical use. The drug was safe and well tolerated.

Pharmacokinetics and dynamics of penbutolol in humans: evidence for pathway-specific stereoselective clearance.

The pharmacokinetics and dynamics of the D- and L-isomers of the beta-adrenergic blocking agent penbutolol were investigated in healthy human volunteers. In Study One, subjects received a single 40-mg oral dose of L-penbutolol (the pharmacologically active stereoisomer), and matching placebo on two occasions. A mean peak serum penbutolol concentration of 268 ng/ml was reached at 0.9 h after dosing. Elimination half-life averaged 1.6 h, and total clearance 16.6 ml/min per kg body weight. Changes in blood pressure, ventricular rate, and rate of circumferential fiber shortening (Vcf) did not differ between L-penbutolol and placebo. In Study Two, subjects received 40 mg D-penbutolol, L-penbutolol, and placebo on three occasions. Total clearance of D-penbutolol was higher than for the L-isomer (43.7 vs 15.9 ml/min/kg; P less than 0.01); this was reflected in correspondingly increased area under the serum concentration curve for conjugates of the oxidized metabolite 4-hydroxy penbutolol (2.25 vs 0.66 micrograms/ml X h; P less than 0.005). In contrast, direct conjugates of L-penbutolol achieved higher serum concentrations than conjugates of D-penbutolol. Alterations in blood pressure, ventricular rate, and Vcf for D-penbutolol, L-penbutolol, and placebo were quantitatively small. Thus the clearance of penbutolol after oral administration in humans is stereoselective, but the oxidative pathway is more stereosensitive than the parallel conjugative pathway. Penbutolol causes minimal alterations in parameters of cardiac function after single 40-mg doses in healthy humans.

Multiple-dose pharmacokinetics of ofloxacin, a new broad-spectrum antimicrobial agent.

Twelve healthy male volunteers received 14 oral doses of ofloxacin (300 mg each), and the concentrations of the unchanged drug were measured at various times in serum and urine over a period of 15 days. Serum and urine ofloxacin concentrations were determined in specific assays using high-pressure liquid chromatography (HPLC); urine levels were also determined by means of a microbiological assay. A washout period of 72 hours followed the first and 14th doses, allowing comparison of serum pharmacokinetics at the beginning and end of the multiple-dose regimen. Doses 2 to 14 were administered at 12-hour intervals. Maximum serum concentration (Cmax), concentration at 12 hours after dosing (C12), and area under the serum concentration-time curve (0 to 72 hours) were all 1.3 to 1.7 times greater after the 14th dose than after the initial dose. A 1.6-fold increase in C12 was already evident after the third dose; C12 remained more or less constant thereafter. Thus it is concluded that ofloxacin rapidly attained steady-state serum levels under a multiple-dose regimen, at levels only slightly above those following a single dose. High serum Cmax levels (4.6 and 5.9 micrograms/ml after the first and 14th doses, respectively) and long serum half-lives (6.0 and 7.3 hours after the first and last doses, respectively) indicated long-lasting, clinically relevant serum ofloxacin concentrations after oral administration. Serum ofloxacin levels 24 hours after the last dose were in the range of 0.3 to 0.7 microgram/ml, above the minimal inhibitory concentration (MIC90) for most bacterial strains. Cumulative urinary recovery remained high throughout the study. After 14 doses of ofloxacin (total, 4.2 gm), 88% of the unchanged drug was recovered in the urine; urinary concentrations remained above 1 microgram/ml, far above the MIC90 for most bacterial strains, for at least 108 hours after the final dose. High renal clearance values relative to total clearance (98%) confirmed the importance of the renal elimination route. Determinations of ofloxacin in urine using a microbiological assay were in close agreement with the HPLC determinations for all samples obtained throughout the study. Thus no detectable appearance of active metabolites occurred under the multiple-dose regimen. Ofloxacin was well tolerated; mild, probably drug-induced side effects were reported by three subjects, but they did not require any countermeasures.

Penbutolol Pharmacokinetics: the influence of concomitant administration of cimetidine.

A possible interaction of penbutolol and cimetidine was investigated in healthy volunteers treated orally for 7 days. The plasma levels of unmetabolized penbutolol showed a slight but non-significant increase. The biphasic elimination kinetics of penbutolol (half-lives 0.8 and 17 h) was not affected by coadministration of cimetidine. Plasma levels of penbutolol were not significantly altered by chronic treatment with cimetidine, whereas the levels of 4-hydroxypenbutolol and 4-hydroxypenbutolol glucuronide were significantly reduced.

The effect of the converting enzyme inhibitor HOE 498 on the renin angiotensin system of normal volunteers.

The converting enzyme inhibitor HOE 498 was evaluated in 12 normotensive male volunteers aged 21 to 26. The efficacy of single 5, 10 or 20 mg oral doses in blocking the pressor response to exogenous angiotensin I was tested in 3 of the subjects. All 3 doses of HOE 498 reduced the pressor response to exogenous angiotensin I to below 50% of control within 1,5 h following administration of the drug. Plasma renin and converting enzyme activity, blood angiotensin I, as well as plasma angiotensin II and aldosterone were measured serially before and up to 72 h following oral administration of a single dose of 2.5, 5, 10 or 20 mg of HOE 498 to groups of 5 volunteers each. As expected, blood angiotensin I levels and plasma renin activity rose while plasma converting enzyme activity, plasma angiotensin II and aldosterone concentration fell after administration of the drug. While the dose of 2.5 mg did not reduce plasma converting enzyme activity below 20% of control, the higher doses all resulted in plasma converting enzyme inhibition exceeding 90%. No side-effects were observed. It is concluded that in normal volunteers HOE 498 is an effective potent and long-acting converting enzyme inhibitor. Based on these preliminary findings it is expected that 5 mg HOE 948 will turn out to be adequate for therapeutic use.

Pharmacokinetics of pheniramine (Avil) and metabolites in healthy subjects after oral and intravenous administration.

The pharmacokinetics of pheniramine and its two metabolites (N-desmethyl pheniramine and N-didesmethyl pheniramine) were determined in six healthy male subjects after intravenous (n = 3) or oral (n = 3) administration (30.5 mg of pheniramine - free base). Serum and urine levels were measured by HPLC. After i.v. administration, serum concentrations of pheniramine between 231 and 894 ng/ml were reached and after oral administration peak serum concentrations between 173 and 274 ng/ml were reached after 1-2.5 h. AUC values up to 72 h were 3035-4662 (i.v.) and 3507-5768 (ng/ml X h) (oral). The terminal half-lives were estimated to range between 8 and 17 h (i.v.) and 16 and 19 h (oral). Serum levels of the N-desmethyl derivative remained very low (up to 21 ng/ml), but were still detectable after 72 h. Serum levels of the N-didesmethyl derivative were below the detection limit. The amount of pheniramine excreted in the urine for up to 120 h varied between 5.7 and 11.6 mg and 10.2 and 13.2 mg after i.v. and oral administration respectively. Unlike the serum, considerable fractions of the drug occurred as metabolites in urine. Values were 8.1-16.4 mg (i.v.) and 7.4-13.3 mg (oral) for N-desmethyl pheniramine, 0.4-2.9 mg (i.v.) and 0.2-0.8 mg (oral) for N-didesmethyl pheniramine.